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Chapter34 General Approach to the Treatment of Diabetes Mellitus

Ramachandiran Coopp an Sinceth elasteditionoft histextbook,major scien tificadvan ceshaveincreasedouru nder stan din gofth e pat hophysiologyun derlyingbothty pe1andtyp e2diabe tesan dhavefue led newap proachest oth erapy. Newinsightsintoth eme chan ismofinsu linaction andinsu linr esist an ce,gre ater unde rstandingofthe mechanismsofcon trollinginsulinsecre tion, an dadvancesingen eticsan din immu nologyh ave contribut edtothisexplosionofknowle dge.Fur ther more,anu mber ofrandomizedpr ospe ctiv estudies demon stratingth ebene fit softightg lyce miccon trolandth eavailabilit yofn ewor alther apiesan din sulin formu lation sp rov ideacompellin grationaleforimprovingth eoverallle velofdiabe tescar e. The r esultsoftheDiabete sControlandC omplicationsTrial(1),the Kumamot oTrial(2), andt heUn it ed KingdomProspectiveDiabete sSt udy(3)hav eprovid edcon clusiveeviden cethattight g lyce miccon trol willpreve ntth eonset, aswellasdelayt heprogre ssion,ofth elong-t ermmicrovascu larcomplications of type 1an dtype 2diabet es.Amore recen tfollow-u pofth eKumamotost udy(4)not edth atth eoptimal degr eeofglyce miccon trolt opre vent orde laycomplication sisaglycosylate dhemog lobin (HbA 1 c )lev el oflesst han 6.5%,afastin gglucos ele veloflessth an110mg/dL, and a2-h ou rpostpran dialb lood glucoseleveloflessth an 180mg/d L.
DIABETES AS A WORLDWIDE HEALTHCARE PROBLEM

Diabetesmellitu shasbe comean in tern ationalhe althcarecrisisthatrequ ire snewapproache sto pre vent ionan dtre atment .Du ringth elast20years,th eprev alence ofdiabet eshasin creased dramatic allyinman ypart softh ewor ld. Alth ou ghgen eticfactorsplayaroleinth eet iology,e speciallyof type 2diabe tes,th egrowin gproble mofobe sit ythatparallelsimproved e con omicst atu sin some deve lopingcount rie sisamajoren vir on men talfact orint hisepid emicofd iabetes. Onth eot herh an d,in manyp artsofthe developin gworld,lowb irt hweightandmate rnalmalnu tritiondu ringpre gnan cymaybe amajorfactorun derlyingth einsulinresistancesyn drome andt husinanincreasedriskofdiabetesin late rlife. Atleast 120millionpeople throug houtth ewor ldsu fferfromty pe2diabe tes,anditisproject edth atth e nu mbe rwillin crease to220million bythe year2010.Thisdise aseisnowaworldwidepu bliche althissue th atn otonlycostsmanyn ation smillion sofdollarsfor h ealth care butalsorobsmanydev eloping economiesofthe irmostpreciou sresource ,th eir worke rs.Dataalmostade cade oldgave ane stimat ed pre valence oftyp e2diabe tesinth eUnite dSt ate sof14millionpersonst hat cause dane stimat ed 300, 000deathsandre sultedinhe althcareex penditu resof$100billion (5). Someofthe world'smosthighlyindebt edan dpoorest nat ionsdonothavesufficientr esou rcestopay bac ktheirde btan dtoalsoprovidecar eforpatient swith diabete s,adding t oth eproblem. Inth ese ar eas, alackofadequ ate in sulin supplie sisamajorproblemforyoung c hildre nwithtyp e1diabe tes, an dmanydonotsur viv emoret han 1yearaft eronsetofdisease .Solutionstothisproblemmust b e forthcomin g,becausetr eat men tfor patien tswith type1diabet esexistsan dshouldbewidelydist rib uted (6).
CHANGING DIAGNOSTIC CRITERIA FOR DIABETES

In1997, t heAmerican Diabet esAssociat ion(ADA) ch an gedth ediagnosticcriteriafordiabet esme llitus an drecommen dedth at th euseofRomannu me ralsfor t hetwomajorformsofdiabe tesmellitusbe discontinu edandth atArabic nu me rals1and2be usedinst ead. Th eearlier chan geinth eclassificat ionfromins ulin -depen dent diabet esme llitus(IDDM)an dnon-insulin-depe nden tdiabet esme llitus(NIDDM)tot ype1orty pe2was an att empt tomoveawayfromat reat men t-basedclassificationt oonebasedonun derlying pat hophysiology.Thisne wsystemremov edthe con fusion t hat eme rgedwh enpatientsclassifiedas havingNIDDMu nde rthe oldnome nclatu rewere treatedwithinsu linbe cause ofdisease progression . Wouldthe sepatien tsnowbeclassifie dashavingIDDMorwe rethe yme relypat ien tswithNIDDMwh o nowrequ ir edin sulinthe rapy ?The path oph ysiolog icapproachallowsforth espectr umofchange sin t he un derlyingdiseas eprocessthatdeve lopwithtime and prov ide sarat ionale fortr eatmen tchangesbased onth isprogre ssion. Inmaking t hese chan ges,t heADAalsorev ised thediag nost iccr ite riafor d iabetesandintr odu cedan ew cat egory,impair edfast in gglu cose ( IFG).The oldcriteriare quiredafastingplasmaglucoseleve lof140 mg/dLor higherorag lu coseleve lof200mg/dLor higher 2hoursaftera75-gglu cose challenge to establish adiagn osisofdiabe tes.Th eseolde rcriteriaalsowere inlinewitht here comme ndat ionsofthe World He althOrg anization. Th ene wcrit eriawere developedtoallowearlierdiag nosisofdiabete sthat would,in tur n,leadtoe arlytre atment and, it ishoped, toaredu ction ind iabetes-r elatedcomplicat ions P. 588
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(7). StudiesinEg yptan dthe UnitedSt atesde monstr ate dacorrelationbet we ent hedev elopment of ret in opathy andafastingglucoselevelofmoreth an108to116mg/d L(8,9).Notallgr ou psare en thu siasticaboutth esech ange sin thediagnosticcr ite ria.Some areconce rnedt hat undoemphasison th efastinggluc oseconce ntration swillr educe t heu seoft heoralglucosetole ran cetestt hat maybe ne cessar ytoiden tifyin dividu alswith impairedg lu coset olerance(IGT),whichisassociate dwith greater rateofp rogr ession t oclinicaldiabetesandisariskfact orforcardiovasculardisease(10,11). Furth ermor e,th ereisconcern thatthe newcrite riamayin creasethe prevale nceofdiabete sin many par tsoft heworld andst rainalre adylimitedh ealthcarere sou rces(12,13), although ,ofcour se,th ene w criteriad onotincre aset heactualpre valen ceofdiabe tesbu ton lyt hat ofdiagn ose ddiabetes. Advancesinmolecu larbiologyandge neticshaveh elp edtoelu cid atet hemechanismofin sulin actionan d toide ntifyspecificg enemut ation s[e.g. ,glucokin ase g eneinmat urity-onset diabetesofthe you ng-2 (MODY2)]t hat canleadtod iabetes. Inadd ition,outcomedat aclearlysup port thebe nefitsofstrict glycemiccontr olin retardingbotht hede velopment andp rogr essionofthe long-t ermmicrovascu lar complication sin bot htype 1an dtype2diabete sme llit us.Th esestu die son g lu cosecont rolhavebee n complement edbystu die son macr ovasculardiseaseth atde monstr atet hemajor bene fitsde riv edfrom agg ressivetre atmen tofh yperch oleste rolemiaan delevat edbloodpressu reinpatie ntswithdiab etes. The incr ease in t hen umberoforalmedicat ionsfortreatingtyp e2diabe teshasnowmadeitpossiblefor providersn otonlytochoose ther apiesbase don theu nde rly in gpath oph ysiology ofdiabet esbut alsoto use drugst hat worksyn ergisticallybyaddr essin gdiffe ren tpath oph ysiolog icabnormalities.Th eben efit s oft hisapproach ,whichoften allowsthe useofsubmaximaldosesofdiffe ren tage nts,areimpr ove d glycemiccontr olan dared uction ofth eadv ersee ffe ctsoft hemedicationsuse d.Thech alle ngeinty pe2 diabet esist ostarttr eat men tearly andtouse combinat ionth erapie st hat addre ssbot hthe in sulin resistanceandinsu linsecr etorydefe ctsofth edisease .Theint rodu ction ofrapid- actingh umaninsu lin, aswe llasth ene wlong-actin gin sulin an alogu es,h asmadeitpossibletoapp rox imate normalinsu lin secre tion through the u seofbasalan dpremeal(bolus)in sulinregimens. The cure fordiabe tesstillelud esus.Howeve r,th eprogressmadeint hedev elopment ofne w app roachest ogrowingan dtransplan tin g-cellsandinimmun osu ppressiveth erapyle ndshopet oth e possibilit ythattransplant ed-cells,even thosen otr ender edimmunone utr al,willsurviveforth elong ter mandren derpatients with type1diabete sins ulin -in depen dent ( 14). The approach toachronicdisease su chasdiabetes r equirest reat me ntgoalsthatincludebotht he mainten an ceoft hewell-beingoft heaffectedindividualandth eprev entionoft helon g-ter m complication sassociatedwitht hedisease.The relationshipofg lu cosecont roltothe microv ascular complication shasb eenv alidated;th echallen geistomake pract icalu seofth is informationbyimpr oving th edeliv eryofappropriate care .Thisrequ ire sclosecollaborationamongallmembe rsoft hehe althcare teaminv olvedinth ecar eofpatientswith d iabetes. Desp ite thedr amaticresu lt softh eDiabe tesCont rol an dComplicationsTrial(DCC T),for mostpat ien ts,t here hasbe enn omajor shiftin the careoftype1 diabet esthatwillprovid ethe bene fitsn ote din the int ensivet herapytrials.It isgratifyin gthatthose pat ie ntswhowere in theint ensivetr eatmen tarmofDCC Tandarenowpar tofth eEpidemiolog yof DiabetesIn terv entionsan dComplication s(EDIC)trialhavecontinu edtobene fit fr ompart icipat ioninth e inten siv etre atment armforaslongas4yearsaft erth etrial'se nd.U nfortun ate ly, thisgrouphas expe rienced s omedete rioration inover allglycemiccon troloutsideth een vir on men tofarigorously controlle dclinicaltrial(15).The cost-e ffe ctivene ssofinte nsivetre atment alsoh asbee nexamine dand foundt obeworth while compare dwith the costoftreatingth ecomplication swhen they occur .Toachieve agg ressivegoalsofglycemiccont rol,se lf-mon it oringofbloodglucose(SMBG)mu stbeastan dardforall pat ie nts. Moreover, patien tsshouldhaveacce sstot heappropriatemon it oring e quipme nt, in depen dent oft hety peofdiabetes, andwith thefre quen cyoft estingdet ermin edbyth emedicalp rofe ssionalsand th epat ien t. Many variat ionsofpract icegu id eline sfordiab etesarenowavailable;h owe ver, adhe rence tot hese guidelinesh asnotbee noptimalinmany in stan ces(16).The rear emanyre asonsforthis,andth esemust beassessedcarefu llyifpr ogr essist obemade in thisare a.C urre nttr eatmen tguidelinesarebase don outcome sdataderivedfromc ont rolledclin icalt rialsandex tensiveph ysicianexp erience. Amech an ismis nownee dedtotranslate these guidelin esintoaformatthatwillbebothpr acticalan drealisticin clinical practice.The careofpat ien tswithach ronicdise asesu chasdiab etes, wh ilebe nefitingfromt hemode rn rev olutionininfor mationt echn olog y,stillhasasitsbasisth ecaring ,compassionat e,andun derst anding relat ionsh ipsbe tween the p atient and membersofthe health care team.U nfortun ate ly, curr ent reimburse men tsyste msdonotsupportt heest ablish me ntormainten an ceofth eser elation shipsand t hus workagain steffortstoprovid eopt imalcare topatient swith diabete s. The majorclin icalissueinpatient swith type2diabete s,in addition tothatofachievingsymptomatic controlofhy perglycemia,isthe e normousr iskofcard iovascu lardisease andt heproblemsarisin gfrom microvascularcomplications.Anappreciat ionofthe in terre lations hipsofth evar iousriskfact orst hat leadt ocoron ary heartdisease andt hebe nefitsoft reat in gthe sevigorouslyisgrowin grapidly.Multiple stu die son ch olest erollowe rin g[Scan din avian SimvastatinSurv ivalStu dy(4S)andC holest eroland Rec urre ntEv entst rial(C ARE)](17, 18);bloodpr essure con trol[U nitedKingdomProspectiveDiabet es Stud y(UKPDS)an dHypert ensionOptimalTre atmen t(HOT) st udy](19, 20);andth euse ofaspirin(21),
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inhibitorsofangiote nsin-conve rtingen zyme [Hear tOutcome sPre vent ionEv aluat iontr ial(HOPE)](22), an d-blocke rsreve alsign ifican tben efit sin p atient swith diabete s.Whilethe seran domizedcontr olle d clin icaltr ialsh aveb eencondu ctedpr imarilyin subjects withoutdiabe tes, t hesu bgroupswithdiabe tesalsohad sign ifican tredu ctionsinmajorcard iovascu lar eve ntsanddeath. There centdatafr omthe At herosclerosisR iskinC ommu nities(ARIC)Stu dyshowed th atth eriskfor diabetes inpatient swith hype rten sionisin creasedbytwoan dahalf. Th estu dyalso noted t hat ther iskofdeve lopme ntofdiabete swasnotincre asedby t hiazidediure ticsb utwasincr ease d by-bloc kers.Howeve r,th ebene fits ofth euseof-blocke rsfollowingmyocardialin farctionhavebe en validat edin the literatur e,sothe risk ofdeve lopingdiabet esshouldbeconsidere dofsecond ary importanceinth isgr ou pofpatients(23). The t reatme ntplan forpatientswith d iabetesalsowillbeaffe ctedbyth epre valence ofth edisease in t he population.The prevale nceoftype2diabete sish igh erincer tainet hnicgroups, suchasNative Ame ricans(e speciallyt hePimaIn dians)(24),Hispan icAmerican s,AfricanAmerican s,an dAsian Ame ricans(25, 26, 27).Forman yoft hesegr ou ps,acce sstogoodme dicalcareisaffecte dbyfactorssu ch associoeconomicstatus, in surancecover age, culturalbackgroun d,langu age barrier s,in div idu aland grouph ealth b eliefs, education allev el, and p eerbe havior.The sefactorspre sent specialprob lemsth at willhavetobeadd ressedifthe sepat ien tsar etoachieve opt imalou tcomes. Diabetesinth eolde rpop ulation alsoisaspe cialissueb ecau seoft heincre aseinth eprev alence of diabet eswit haging ,the mu ltipleother con ditionsbeingt reat edinthe elderlypopulation ,an dthe ris ks associate dwith polyph armacy. Th ere isanurge ntn eedtoapp roachth etre atment ofdiabet esinthe se pat ie ntswithe nthu siasmandtosetappropriate goalsforthe rapy .Treatme ntmustbe in dividu alize d,an d th erelationshipofrisk stobe nefitsmustalwaysbecar efully e valuated, butage,per se,isnotare ason toaltert hetarget goalsforglycemiccontr ol.Although mostelderlypat ie ntswithdiabe tesh avety pe2 disease ,manyofthe mh avet ype1(insu lin-d epen dentdiabetes)diseasen ot onlybe cause type1 diabet escan presen tforthe firstt imeinth eelderlybut alsobecause man ypat ie ntswithty pe1diabe tes ar elivinglon genoug htobeincludedinth eelderlygroup .Theelder lydonotalway spresen twithth e classicalsymp tomsan dsign sofh yperglycemia,sothe physicianmustconsider t hisdiagnosis, especially inth osewith n eur opathy ,nonhe alin gulcers, andr ecurr entinfe ctions(28). Although t hischap terwillfocu son the gene ralapproach tothet reat men tofthepatientwith diabetesin th eou tpat ie ntset tin g,th eprinciplesalsoapplytoinp atient s.Themat erialpresen tedh ereisinten dedas age ner alove rvie wofth etre atment ofdiabet es;other chapt ersinth iste xtar edevotedt ospecific issues. P. 589
AN INITIAL APPROACH
Once thediagnosisofdiabete shasbe enes tablish ed, t hequ estion ofinitiatingt herapymustbe add ressed. Thos epatien tswhoprese ntwithdiabe tick etoacidosisorwhoaremar kedlyhype rglycemic an dsymptomat icsh ou ldbe admitt edtothe h osp italforur gent treatme nt. Th ene edfor hos pitalizationat diagn osisappliesprimarilytopat ie ntswithty pe1diabe tes, e specially childre n. Atth isinitialstage ,th ephysicianorhe althcareprofession alwhoisse ein gthe patien tshouldobt aina det ailed h is tor yandp erformacomple teex amin ation with appr opriat elaboratoryt esting.Th efutu re progressionoft hepatient'scare willb eaffect edbyan umberoffactors,includingt heph ysician 's tre atment philosophy,t hepatient'shealthcarebeliefsand c ompeten ceat self- care, and t heavailability ofateamconsistingofadietitian, diabete seducator,exe rcise physiologist ,an d,whe nne eded, social workersandpsych ologist s.Un fortu nately,notallcomponen tsoft histeammaybeavailablein the gen eraloffice p ractice;h owev er,most commu nitiesdoh ave these resource s,an dpatien tsshouldbe refe rredt oth em, asapprop riate, toachieveoptimalglucosecont rol. The approach mu stcon side rthe whole personwithdiabe tes,n ot ju stthe le velsofglycemiccontr olto beachievedorth eth erapy tobe usedt oaccomplisht his(i.e .,insu linororalan tidiab eticther apies).To th isen d,as trong,inte grat edteamapproachisth eon emostlikelytosu cceed. Alth ou gh, asnoted above, the comple tete ammay notexistinmostcases,th ephy sician andt hepatientcanmake considerable p rogr esstogeth er,withoth ercompone ntsofthet eam,espe ciallyth ediabet eseducatoran d dietitian, comin gfromth ecommunity.
The Patient History

Adetailedh ist ory isth efou ndationofgooddiabe tescare.Kn owledge aboutth eage ofth epat ie ntan d th eclinicalpre sentation ofte nhe lpth eph ysician deter mine wh eth erth epat ien thastype1or type2 diabet es.Thisisnotalaborat ory -validateddiagnosisbu taclin icalassessment toassist in ch oosingth e initialt reatme nt.Th eclinician b asesth eclassification onaspectsofthe patien t'sh istorysu chasage, bodyweight, familyhistory,du rat ionofsympt oms,an dthe resu ltsofthe blood glu coseandth e HbA 1 c dete rmination s.Considerable het erogene ity exists,espe ciallyintype 2diabe tes,inth eclin ical pre sentation aswellasin the u nde rly in gpath oph ysiology .Somepatie ntsactuallymayhaveaslowly progressiveformofautoimmu ne d iabetes. Theset endtobeyoun geradultsan dgen erallyrequ ire in sulin th erap yrelativelysoon .These patien tscan bediagnosedby measuringce rtainautoimmun emarkersin
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th eblood,such asantibod iest oinsu linandglutamicaciddecarboxylase(GAD).Th ein creasin g pre valence oftyp e2diabe tesinadolescen tsmakesitne cessary todiffere ntiate type1fromtype 2 diabet esinthisgroupofpatien ts.An oth erproblemisth edifficultyinassign in gade fin ite date forth e onsetofdiabet es,particularlyfortype2diabete s,whichcanbeasympt omaticformanyye ars,a det ermin ation thathasimplicationsconce rningth eriskfordiabete scomplicat ions. At theJoslin Clin ic, bothpatientswith n ew-onset d iabetesandth ose seekingconsu lt ation fore xist in gdise asearemaile da det ailed met abolicque stionn aireabou tsymptoms,cu rren tthe rapy ,familyhistory, e xercisepatter ns,and other medicalproblemsandt herapie s.Particular atte ntion mu stbepaidtohistoriesofcoronaryart ery disease ,periph eralvasculardisease,hy perte nsion ,an drenald iseaseinth epat ien tan dthe family. Patient salsoareask edtokeeparecordon adietaryasse ssme ntsh eetorinafoodd iaryfor 2or3days, includingth etime softh eirmealsandth etyp esan dquan titie soffoodse ate n.Thisinformation h elpsthe dietitiande sign an appropriate mealplanbase don thepatient 'sfoodpre feren cesan dlifesty le. Wit hne w information -techn ologysystems,patientscanaccessthe seque stionn airese lect ron ic allyanden tert he information fr omhome .Thiswillavoidmailde lays,he lpge tthe in format ioninat imelymann er,and en han ceth epat ien t'sv isitwithth ephys ician .
Physical Examination
The p hysicalexaminat ionisafu ndamen talpart ofth einitiale valuation. Specialatte ntion shouldbepaid tothe heightandweigh t,bodymassin dex(BMI),bloodpre ssure (lyingdownandstandingu p),an d vascularstatus. Ac arefu le xamin ation ofpe rip heralpu lse sand auscu lt ation ofcarot idandfemor al vesse lsforbru itsisext remelyimpor tan tin obt ainingab aselin eforthe fu tur e.The neu rologic examination mus tin clu deacarefu lsearchforeviden ceofn eur opathy .Notonlyar emu scle stren gthand reflexe steste d,vibrat ion, p osition sense, an dappre ciation ofapplication ofa10-gmon ofilamentt oth efeet mu stalsobe assesse d.Whilethe seclin icalmeth ods lackth eprecision ofadetailedlaborat oryn eur olog icev aluat ion,t heyst illp ermitt heclin ician toobtain a bas eline pict ureandtoob tainfur the rin vestigat ionsinappropriatepatients. Inastudy of189patients with diabetes and88contr olsubjects, Thivolete tal.(29)use dagraduated tu ningforktomeasure these nsitivit yofth efeet tovibratorysens ation sand not edth at51%ofpatients withclin icalsy mptomsofne uropat hyinth eextr emities,70%oft hosewit habse ntte ndonre flexe s,an d 75%ofth osewith abnormalner ve-conduct ionve locitie shadlimitedvibration sensation. Onth eot her hand, t hest udybyDycketal. (30)revealedthe prob lemspres entinassessingth eepidemiologicdat aon diabet icn europathy. Par tofth eproblemisth evar iet yofclin ic alt ypesofneu rop ath yand t he charact erizationofneu rologicdysfu nction.With multipleclinicalen titie sandv ariablepre sent ation ,th e best thecliniciancan doistolook foranddocument thepr esen ceofn europathy. I nare cent st udy, Pe rkinset al. (31)reported ont heu sefulnessoffou rsimplete sts:10-gSemmes-We in stein mon ofilame ntex amination ,supe rficialpain sensation, vib rationtest in gbythe on -offmethod,and vibrat ionte stingbyth etime dmet hod.They foun dexce llent sensitivityan dspecificityforeachoft he test sfromthe reporte doper atingch aracteristics.The timed-v ibration met hodtooklon gertoper form th ant heothe rs,but each ofth eother teststookle ssthan10secondsan dshouldth ereforebe p artof th ean nuale xamin ationfor neu ropathy .Ifthe histor yand p hysicalexaminationareatypicalfordiabe tes, an addition alwork upshouldbeu nder take nan dare ferraltoan eurologistconsidere d. The p hysicianalsoshouldpayspe cialatten tion toth epatie nt'sfeet, carefu llypalpatingth edor salis pedisan dpos terior tibial,poplit eal,andfemor alp ulses.Skelet aldefor mitiessuch ashallux v algus, bun ions, callouse s,an dhammertoesmustbe carefu llydocument ed.The combin at ionofvascu lardise ase an dneu ropath yist hemajor cause offootinfe ctionandn on trau maticamputationinpatient swith diabet es. Fin ally, acar efulfun duscopice xamin ationisdone ,alth ou ghth issh ou ldn otsu bstitute foranev aluat ion byanop hth almologistwit hexpe rienceindiab eticeyedisease.Somen ewme thodologiesusing nonmydriat icdigitalretinalimagingser veasanexce llen tscree ningtech nique t opr ioritiz ethe need for formalopht halmologicevalu ation. P. 590
Laboratory Studies
The ch oiceoflabor atoryte stsperformedisin partde terminedbyt heclin icalp resen tationofthepatient . Ifthe patien tisinastat eofdiabe ticketoacidosisorissy mptomaticfrommarke dhype rgly cemia, the degr eeofhyper glyce mia, theacid -basestatu s,electrolytes, andth epre sence oface ton ear eurg ently asse ssed.Forthe n on acu tesituation ,att hepatie nt'sfir stvisit, theminimumtest srequ ire dare a complete urinalysisan ddete rmination sofbloodglucosean dHbA 1 c . Itisn owu sualtoaddt oth esea che mistrypanelth atinclude smeasure men tsoflipid s,liver andk idn eyfun ction ,an dele ctroly tesan da complete blood c oun t.Ifpossible ,the lipidmeasure men tsshouldbedone on thepatientint hefastin g statetoobt ainan accu rate deter minationofthe trigly ceridelevel.Itmaybe nece ssaryforth epatien tto makeasepar ate v isittothe officeorlabor atoryforthe setest s.Inmost c ases, lipids als oar eevalu ate d onth efirst visit. Totalch oleste rol,tr iglycer ide s,high-de nsitycholester ol,an dlow-den sit ychole sterol ar edete rmine d.Lipidst udiesar ean impor tan taspec tofdiabe tesasse ssme ntbec ause ofth ehighriskof
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macrovascu lardisease ,especiallyin the patien twit htype 2diabet es(32). Atest formicr oalbu minu riaalsoisrecommen ded, since the p resen ceofmicropr ote in uriah eraldsth e fut urede velopmen tofre naldisease (33,34)an disanindepe nden triskfactorforcardiovascu lardisease . Many differ entmeth ods areavailablefor d eterminingth eprese nceanddeg reeofalbumin excre tion, includinganalbumin-to-creatinineratioinaspotu rin e,t imedur in ecollection ,an d24-houru rin e collection.The latter testalsoallowsth edete rmination ofcreatinineclearan ce.The testforalbumin-tocreatinineratioisnowwide lyavailablean dcan e asily b eperformedinthe office,witht hecaveat that moder ate tointe nseph ysicalactivitymayresu lt in afalseincre aseinalbu minex cretion.Itisusu allyn ot ne cessar yin clinicalpractice tomeasureisletcellant ibodies,insulinau toant ibodies,oran ti-GAD an tibodiesinpatientsatthe clinicalonsetofthe dise ase. Th epre senceofan ti-GADant ibodiesmay ident ifyasubgroupofpat ien tswithad ult-on setdiabe teswhoact uallyhaveaslowlyev olvingfor mof au toimmu net ypediabet es[laten tau toimmu nediabe tesofadults(LADA)].Thes etests, tog ethe rwit hth e intraven ou sglu cose t olerancet est,areu sedin researchse ttingstodet ermin ewhichpat ie ntsareat high riskfor developin gdiabete s(35,36).The r ou tin emeasu rement ofinsulinlevelsor C-pept ide isnot recommen dedasaroutine testinclin icalpr actice. In selected inst anc es,th esemeasu rement smay indicate themoreappr opr iateselectionoft herapy.In the olderpatientorinpatie ntswithh igh blood pre ssureorafamilyhistoryofcardiacdisease ,abaselin eelectrocar diogramsh ou ldbe p erforme d.If add itionalcar diovas cularriskfact orsarepre sent orifthe patien tisplan ningtobeginanexe rcise program,consider ation shouldbegiven t ope rformingacardiacstr esstest .Theph ysiciancan orde ra che stx-rayfilmandothe rstudiesasnee ded.Patien tswit htype 1diabet esshouldalsoh ave a th yrotropin lev elmeasure don t hefirstvisitbecauseofthefr eque ntcoexisten ceofimmun e-mediated th yroiddisease.
EDUCATION
Fort hepatie ntwithachronicdisease ,edu cation isalifelon gprocessan danopportu nitytoimproveselfcar etech niquesandtorecognize t heonse tofcomplications.Accesst oprint ededu cation almaterialsand tothe servicesofskilleddiabet esnur seedu catorswillhelpfacilit atet hisproce ss.Accesstodiabet es edu cationalmater ialsonth eInt erne tisincr easing, andp rovidingadvice aboutt hemostr eliable site sfor information canbe animp ort ant p artofthe education alproce ss.Caremustbe take nnottoov erwhe lm th epat ien twit hasu rfeitofinformation.The on setofdiabetes ,either type1ort ype2,isadifficulttime emot ionallyforthe p atient ,an dthe physicianmustbe asourceofencour agemen taswellasaprovider oft reatme nt.Th efamilysh ou ldparticipateinth eedu cationalprocessas much aspossib le. Inadu lt swith diabet es,involvin gthe spou sein the education alproce sscanbe veryr ewarding ;howe ver, thepatient mustbee ncouragedtoaccep tresponsibilityu nlessthe rear emitigat in gcon dit ions.Th ein it ialgoalsof edu cationar etoh elpthe familyun derstandth ebasicpathophysiologyofd iabetesandth edifferen ces bet we ent heinsu lin-de pende ntandnon-insu lin-de pende ntforms. Patient swith type1diabete sandt heirfamilieslear nbasicskillsne cessary forth epatie nt'ssurvival. Such nece ssaryskillsinclude (a)insulinadministrat ion;(b)SMBGandte stingforurineg lu coseand ket on es;(c)adjust in gin sulin dosagean dfoodintakeforexer cise;and(d)sick-daycare andpr even tion ofk etoacidosisan dtre atment ofhy poglycemia. Patient swith type2diabete saret augh tsimilarskills,alt hought heemphasisisver ymu chonth e nu trition alprog ramand we igh tcontrol.Itisimpor tan tfor p atient stor ealiz ethatth elossofe ven small amount sofweight(10t o20lb)canbe verybe neficialforoverallglucosecontrol.Theabilitytoselfmon itor bloodglucosealsoisimportantinth esepatients. Exer cise helpsob esepatie ntslose weig ht,andifthe y req uestmorethanasimple exer cisepr escription ,itisappropriateforth ephy sician tore ferth emt oan exe rcis ephysiologis t.Caresh ouldbet aken in prescribingvigorou sexer cise progr amstoolderpatie nts, espe ciallyth osewith diabeticcomplication ss uchasneu ropath yorr etinopath y.The reisalsoth eissueof coron ary d iseaseandsilen tischemia.Ifaqu estionarisesabou tth eprese nceofcoronaryartery disease an dwhet here xercisecanbeu ndert aken wit hsafe ty,th epat ie ntshouldber eferre dtoacard iologistfor app ropr iatete stin g.Astu dyin 1999byJan and-Delenn eetal. (37)of203p atient swith type1or t ype2 diabet esnotedt hat 20. 9%ofmalepatie ntswitht ype2d iabetesh adsile ntmyocardialisch emiawith significantlesion son cardiaccathe terizat ion. Th eau thorsth usre comme ndedrout in escree ningforme n withtyp e2diabe tesofmoreth an10ye ars'duration ore venlessforthosewithmor ethanone car diovas cularriskfact or. Onceth epatie ntiscle are dforanexe rcise program,he orsh eshouldexe rcise th reetofourtime saweek foratle ast30min ute sforth eprogramtobeofany benefit. Thosepatie ntswh owillbere ceiv in goralh ypoglyce micthe rapy must becomek nowledge ableab ou tthe act ionofthe seme dication sandt heiradv erseeffe cts.The yalsomustu nde rstan dthatmanypatient swill failtore spon dtothese agen tswithtime and willn eedinsu linth erapy.Wh enmedication ispr escribed, it isessen tialn ot onlytoinstru ctpat ien tsonhowtotake thepillsbu talsot ocoun selt hemon when to stoptak in gthe mtoavoidpote ntiallyseriou sadve rsesideeffect s.Thisisve ryimportant, becau sethe nu mbe rofn ewme dication sfordiabe teshasin creasedrapidlyand,formanyofthe m, we don ot k now th elong-t ermeffects. P. 591
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Atth ein it ialvisitit alsoisappr opriatetodiscu ssbrieflyther ation aleforglu cose con trolandth e poten tialforcomplication s.Atth istime,th ephy sician 'sinte rpret ation and u nde rstan dingoft hecu rren t lite rat ureonth erelationsh ipbe tween the con trolofdiabete sandcomp licationsan dfamiliaritywithth e standardsofcareset b ythe ADAwillb eextr eme lyimport ant .Ifthe physicianisvagu ean dnoncommittal inprese ntingt hisissu e,th epat ien tmayassume thattightcont rolisn ot nece ssary. Byin dividu alizing th erap yand b uildingonasolidfoun dationofb asicskillsacquire dbythe patient ,th ephysicianisina un iqu eposit iontoguideth epatie nttowar dimprovedcontrol.
CLINICAL GOALS
Itiseviden tfromthe ear lierdiscussionth atth etype ofdiabet esinflu enc esthe formofth erapychosen . Int hepatie ntwithn ew-onsetdiab eteswh oh asacu telydecompe nsatedtype 1diabe tesorin the p atient withpre viousdiag noseddiabete swhoisinpoor con trol,t hegoalswillin clu de(a)e limination ofket osis; (b)eliminationofsymptomsofh yperg lyce miasu chaspolydip sia,polyu ria,vagin it is, fatigue, and v isu al blurring ;(c)restorat ionofnormalbloodch emistr yvalues; (d )regaining oflostwe igh t;an d(e) rest oration ofsen seofwe ll-being. Atthistime ,the emph asisfor patien tswith previouslydiagnosed diabet esisonr estorin gthosebe hav iorsth atwillimprovediab etescontr olan dthatwillallowthe mto onceagainfullypart icipat ein the ircare. Glucosecontrolatth ist imeisd ire ctedtowar dgettingpatient s tomonitorthe ir b loodgluc ose, toimprov eadh eren cetoprescr ibed medicat ions, tobe comemore confidentatad ministeringinsu lin, and t ogathe rdataon the patte rnsofglu cose testing. Thisin formation becomesveryimport ant when on eisworkingwitht hepatie nttoplan t hech ang esin in sulin dosagean d timingt hat wille nsur ethatth egly cemicgoalssetwillbeachieved. Once theinitialgoalshave been met ,on ecan proceedtoworkon the planne cessar yforlong-ter m succe ss.Theg ener alaimisthe maint enanceofhealt han dwell-be in gthroug hcon trolofth edise ase. It isimpor tan tnottofoste ralife stylethatiscompletelydominatedbydiab etes. Pat ien tsshouldcontrol th eir diabete sandfollowtheirde sire dlifestyleasmu chaspossible .Thisisn ot alwayseasyto accomplish, especially in patien tswith very u nstableor brittletype 1disease .Aminorityofpatien ts ar esever elyin capacitated, and caremustbe take ntosetre alist icgoalsan dpromotebeh aviorthatis notself-depr ecat in g.Forman ypatien tsan dpare ntsofyou ngch ildren ,wor kin gwit hacoun selor, psych olog ist, orpsy chiatristcanhe lpalleviat efeelingsofg uiltanddep ression . AsdiscussedinC hapt er42,foryoung ch ildre nth egoalsareth emainten an ceofn or malgrowthand deve lopment. Again,t helife styleshouldbeasc losetonormalasposs ible,without diabete sbecoming th efocalpointofthe family'sex iste nce. Ideally,children shouldbecomfortableatschool,particip atein sports,andsocialize with theirpe erswit houtbe in gmadetofeeldiffer ent . Marry in gand h avingafamilyisimpor tan tfor you ngad ultswit hdiabet es.Helpingwomen whowisht o havech ildren achieve asucce ssfulpregn ancy isav eryimportantaspectofdiabet escare .Un less t he phy sician hasconsider ableexpe rie nceinth isarea,itispr eferable forth epatie nttobere ferred toa multidisciplinaryte amskilledinmanagin gthe sehigh-riskpre gnancies.However, allph ysiciansshould edu cate you ngwomen wit hdiabet eson appropriat ebir thcontr olme thodsan dthe impor tan ceofgood glycemiccontr olbeforeconcept ion. Un derlyingallthe segoalsisth edesiretocontrolt hediabe tesoptimallysothatlong-t ermmicrovascu lar an dmacrovascu larcomplication scanbe minimized. Sin cethe recur rent lyisnowaytopre dict wh owill deve loplon g-termcomplication s,itseemsprude nttoset agoalofoptimalglycemiccont rol,withinth e limit sofsafe ty,forallpatien ts. Beforeprocee din gwith the rapy, it isuse fulfort heph ysician tod iscu sswith patien tsthe differ ent leve ls ofsu ccessth atmaybe achiev edin the treatme ntofdiabete s.Inge neral, the g oalsofther apycanbe refe rredt oas minimal, average, andint ensive. Th egoalsasdefine dbythe ADA(38)follow. Minimal goals 1. HbA 1 c ,11%to13%;ortot algly cosylat edhemoglobin(HbA 1 ),13. 0%to15. 0% 2. Many SMBGvalues ofhighe rthan300mg/dL 3. Testsforur in aryglucosealmost alwaysposit ive 4. Int ermitt ent ,spon tan eousket on uria Average goals 1. HbA 1 c ,8%to9. 0%;or Hb A 1 ,10%t o11.0% 2. Pr eme alSMBGof160to200mg/d L 3. Testsforur in aryglucoseinte rmitte ntlyposit ive m 4. Rareket on uria Intensive g oals
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1. HBA 1 c ,6. 0%to7.0%;orHbA 1 ,7%t o9%
2. Pr eme alSMBGof70to120mg/dLandpostme alSMBGoflessth an180mg/d L 3. Testsforur in aryglucoseesse ntiallyneve rpositive 4. Nok etonur ia Int hemost r ecen tstan dard sofglycemiccontr ol(38a), t heADAr ecommendsanHbA 1 c oflessth an 7%, apr eprandialplasmaglu cose lev elof90to130mg /dL,an dapostprandialplasmaglucosele velofless th an180mg/dL . Assessment ofth ele velofdiabe tescontrolisbe staccomplishedby measuringbiochemicalparamet ers. Clinicalin dexessu chasbodyweigh t,frequ enc yofpoly uria,polydipsia,nu mbe r P. 592 ofh ypogly cemicreaction s,fat igu e,andsen seofwell-beingareimportantclin icalparamet ersbut canbe mislead in gaboutth eoverallle velofcontr ol.Itistru ethatpat ie ntswithve rypoorcont roloft encanbe ident ifiedeasilybyth eirsymptoms;howeve r,patie ntswh osefastingglucosele velsare 140to180 mg/dLan dpost pran dialglucoselevelsar e180to240mg/dLcanfeelquitewe llan dpresen tafalse clin icalpictu reofsatisfactorydiabe tescontr ol.Int hepast,dailyur in aryglucosemeasu rement sand randomoffice g lu coset estswere relie don .Howe ver, t heaccuracyofu rin ete stin gcan sufferinth e pre senceofah igh renalt hre shold, r enaldisease,orbladder neu ropath y,an dthe selimitation saren ot eliminat edbyth euse ofadoub le-v oidedu rin especimen.Te stin gfor t hepr esence ofke ton esisstillbest accomplishe dwith aur in esample. Du ringth elasttwodecades,ge neralavailabilityoftwoinn ov ation shasr evolu tionize dou rapproach to th erap y.Thefirstofthe sewasSMBG(39), andt hesecond wasthe developmen tofr eliable assaysfor glycosy latedh emoglobin.
Self-Monitoring of Blood Glucose

Sinceitsdeve lopment, SMBGhasdevelop edin toasophisticated monitor in gsystem.Avarie tyofglucosemon itoringde vice saren owavailablethatgiveadigitalreadou tofthebloodglucoseconcen tration. The devicescont in uetobeimpr ove d,an dthe timere quiredforthe testt obecomple tedisnowasshortas5 seconds. Inadd ition,th esizeoft hebloodsamplesre quiredh asdecre ased, an dmanymeters u sea directactivationsyste m.Some ofth ene westmetersallowblood samp lingbothfr omthe finge ran dfrom th efor earm,th ere byredu cin gtheover useandcallou sin gofth efinger s.These devicesappe araccurate en ou ghforrou tineu sebypatie nts. Forcon ven ie nce, mech anicallanc etdevicesareav ailable for obtainingblood. Someoft hene werglucosemon itorsinclude compute riz edme morytorecordth eblood glucoselevels,andsomecanbeu sedinconjunct ionwithmor eelaborat epersonalcomputer s.Special machine sareavailablefor visu ally impairedpatient s.Oneconce rnabou tSMBGist heaccuracyoft he recordingsascompar edwit hth oseobtain edinth elabor atoriesoflar geclin icsorrese arch settingst hat use moresophisticate din strumen ts.The patien tmayencoun terman yproble mswithSMBGine veryday use ,eve nafte rrece ivingcarefu linstr uction on the t echn iqu ebyadiabetesn urse educator.One such difficu lty in volvesth epatie nt'sabilityt oobtainadropofblood,place it accuratelyonth ereagent strip, an dtimet hemon it orcarefu lly.Newer monitorsthatdonotrequ ire wipingortimingandth atallowthe use ofver ysmallamount sofbloodcan helpminimize thes eerrors.Astu dyper formedbyJovanovicPe tersone tal.(40),inwh ich four met ersyste mswer ecompar ed,de monstr atedt heleastvarian cefrom th econ trolsy stem(aglucoseau toanalyz er)witha no-wipe system.Use ofth issyst em,which eliminat edth enee dforbloodre movalan dtiming, greatly d ecreasedth evar iabilityin test r esults. ForSMBGt obe effective,itsu semu stbeaccompan ie dbyan education alp rogr amthathelpsth epat ien t un derst andt hefac tor saffectinganyparticularbloodglucoselevelan dthatprovidesappr opr iateoption s forcorr ection sor adjustment s.Thisknowledgeispart icu larly neces saryforpat ie ntsinvolv edin in ten sive insulintre atment prog rams. The rehasbeen somediscussion aboutt hevalu eofr ou tin eSMBGinpat ie ntswithty pe2diab eteswh o ar eusingdietororalage ntsforcon trol(41). Alth ou ghth esepatientsr arelywillmaketr eat men t change sont hebasisofin for mat ionfromSMBG,itcan r einfor cedietar yprinciple sandr evealth e ben efitsofex ercisean dme dication .Patie ntswitht ype2d iabeteswh oarerece iv in gin sulin should definitelyuse SMBG.Hypoglycemiaoccu rsbot hinpat ien tsbeingt reat edwithsulfonylure adru gsand th oser eceivinginsulin;inthisset tin gSMBGcan con firmalowglucoseleve landmayhe lpt heh ealthcare provideradju stthe rapy on amoret imelybasis.The freque ncyofmonitorin gcan easilybeadju stedto th ein div idu alpatien t'sn eedsandcircumstances.SMBGisth ereforeanex tremelyvaluable toolfordaily diabet esmanagement. There centint rodu ction ofasu bcut ane ou scon tin uousglucose-sen sin gmonitor th atcanobtaina3-dayprofileofbloodglucoselevels(240r eadings)canbe avery usefultoolin selecte dpatien ts.Such datacan bevery impor tan tin assessing t hedoseofpreprandialinsulin,in ident ifyingu nre cogn ize dhypoglycemia,an din revealing thedawneffect .Rapidadvan cesinne wg lu cose mon itoringsyst emsareex pected over then extfe wy ears.
Glycosylated Hemoglobin Assays
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Int helastde cadeanu mber ofstu die son g lu cosecont rolan ddiabeticcomplication shavebee n complete d,an dallu seHbA 1 c asasu rrogat emarker forrisk.Th estan dar dsofcar eoft heADAwe re rev ised basedonth efast in gbloodglu cose lev elaswellasont heHbA 1 c fromth esest udies.Cu rren tly, laborat oriescanme asu reeithe rthe tot alglyc osylat edhemoglobinorthe A 1 c fraction .Thelat teristhe test usedinth elarge ou tcomestu die s.Howe ver, theassaysh ave n ot been stan dardized, and becau se commerciallaboratoriesuse differ entmeth od s,the refere ncerange svary, makin gitdifficultforthe clin ician tou seth eresu ltsifth eyvar ycon stan tly.Cliniciansshoulduse thesame laboratorytome asur e A 1 c in the s ame patien tov ertime . Inn or mogly cemicsubject s,acarbohydratemoiety isattach edtoasmallpr oportionofh emoglob in A, th uscreatingwhatiscalled g lycosylate dorglycat edhe moglobin(42).Th eglycosylat edhe moglobincan bese paratedintoth reedistinctfraction s,whicharedesignatedA 1 a ,A 1 b ,andA 1 c .Becauseof electr oph ore ticb ehaviorofthese minorhe moglobins,t heyarere ferred toasfast h emoglobin. Th eA 1 c fractionisthe mostreactivesiteofthe N-valine termin aloft heB-chain,whichaccou ntsfor60%ofth e bound g lu cose. Incondition sofsu staine dhyper gly cemia, suchasin diabete smellit us,th eproportion ofhe moglobinth at isglycosylate din creasessubst ant ially(43).Thisglycos ylation isth eresu lt ofposttranslational modification ofhe moglobinAmolecu les;t hebindingofglucoseisanonen zymaticprocessth atoccurs continu ou slydu ringth elifeofthe r edbloodcell. Thus, theamoun tofglycosylated h emoglobin reflects th egly cemiccontrolofap atient duringt he6-to8-weekpe riodbeforet hebloodsamplewasobtain ed, givent heaveragelifespanofared b loodce llof120days(44). Th eamount ofglycosy latedh emoglobin correlat eswellwithfastin gan dpost pran dialbloodglucoselevels.C urre ntly,t heglycosylatedh emoglobin can bemeasu redbyion-exch an gehigh-pe rfor manceliqu id c hromatog raph y(HPLC ),affinity chr omatography, andimmun ologicmeth ods. Inth eDC CTstud y,an ion-e xchan geHPLCme thodwasu sed, an ddat afromth isst udyhavebe enadopt edasth erefe rence stan dardforassessin gglucosecon trol. Arece ntstu dybySchn edletal.(45)n ote dthatthe rearemore than700kn own varian tsofh emoglobin th atmayaffectth ecurr entlyus edassaysforg lycosylate dhemoglobin .The yevaluatedt heeffe ctofth e followingh emoglob in v arian ts:HbGr az, HbSh erwoodForest, HbOPadova, HbD,andHbS.Th eynoted th atth eHPLC bor on ateaffin it yassaylackedth eresolution nece ssaryt oseparat eoutth evar iantsand th atth eimmunoass aysres ultedinfalselylowlevelsofHbGraz.Itisthe reforerecommen dedth at laborat oriesest ablish an dvalidateassaysforth elocalpopulationtomakeallowancesforan y he moglobinvariant s.Theglycosylatedh emoglobin assay ispre sentlyoneofthe mostwidelyapplie d test sin theman age men tofdiab etes. Itisu sefulfor theassessmentofglycemiccontr ol inpat ie ntswithty pe1diabe tesandinpat ien tswithty pe2diabe tes. Glycosylate dhemoglobinvalue smu stbeass essedwithcaution in patien tswit hun stablediabe tes. L evels ofb loodsu garint hese p atient sflu ctuatefromve rylowtovery h ig hon an almostdailybasis,asitu ation th atcanleadtoun want edsymptomsofhyper gly cemiaanddanger ou sepisodesofhypoglycemia(38).A stu dybyBrewe retal.(46)su ggeste dthatusingapie -shape dgrap hofSMBGd atawith definedtarget rangeparamete rscan aidpatien tsan dtheirfamiliesattaint hede sire dHbA 1 c g oals.Th eau thorsset t he targetr ange forSMBGv aluesfordiffe ren ttimesofthe dayandth ende termin edth enu mber ofvalu es th atn eededt obe with in orabov ethatrangetoach ie veth edesiredHbA 1 c .Foryou ngadults17to35 yearsofageu sin gatargetrange of70to150mg/dl, atleast 38%ofthe v aluesn eeded tobe in t he targetr ange andn omor ethan48%aboveth erangetoach ie vean HbA 1 c oflessth an8%. Th eas sayof glycosy latedh emoglobinsh ou ldbe don eeve ry3to4month s,wit hthe goalofadjust in gthe rapyt o obtainth elowest valuet hat doe sn ot placepat ie ntsatund ueriskforhypoglycemicre actions.In p atient s whohavereache dagoalandareve rystable, the testcanbedone e very6mont hs.However ,it is importantth att heinformation obt ainedfromthet estbecommun icatedt oth epat ien ttouset oimpr ove adh ere ncetoth eprescribed t reatme ntplan .Atprese ntt heHbA 1 c ist hebe stsurr ogatemarke rwehave forsettinggoalsoftreatme nt. Effor tsare unde rwaytostandardiz ethe proce dure formeasu ring glycosy latedh emoglobin. Ultimat ely ,thiswouldresultinacertification processforman ufacture rsan d th usen surest andardizat ionofther esultsuse dbythe healt hcar eprofessionalinse ttingglucosecontrol goalsfort heirpat ie nts. P. 593
INITIATION OF THERAPY
Formostadu ltpatient s,in it iation oftre atment issafely accomplish edinth eou tpatie ntset ting.Ver y young childre nan dpat ien tswithdiabe tick etoacidosisorsever e,un con trolleddiab etesu suallyrequ ire hospitalization.Although the d ecisiontouseinsu linu suallyismad ebyth ephysician, itisext remely importanttoexplain t heration aletopatien tsan dtoinclude the minth edecisionpr oces s.Manyh ave an un derst andablefear ofinjection san dofte nregardth isth erapyasanindicationoft hepre sence ofa more severe formoft hedisease.Insu lint herapyne edstobepre sente dasanyother treatme ntoption , an dpat ien tsshouldbemade tou nder stan dthaton e,two,orth reeinjectionsper daymaybe n eede d, depe ndingonth eirresponse .Theph ysicianalsosh ou ld r eviewthe issu eofcont rolan dcomplications and deve lopinitialg oalswithth epatie nt. Atth eJoslinClinic,th edecisiontostartinsulinth erap yisfollowedbyar eferralt oad iabetesn urse
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edu cator,wh owillinstru ctth epat ien torafamilymemberonth etech niquest hat willbe requ ire d. Patient swilladminister theirfirstinjectionat t histimeu nder superv ision .Thisalsoprov ide san oppor tun ity t ote achp atient saboutth etype sofinsu linavailable and t heirch aracteristicpeak sand dur ationsofactivit yand t ore vie wstrat egiesfor dealingwit hhy poglycemiaan dhype rglycemia.The pre sentavailabilityofvery-fast-actin ghu manin sulin an alogu es,aswellasanonpeakingbasalh uman insulinan alogu e,h asincre asedt hene edtoemphasize t opatientst heimportance ofcoordinatingth e timingofme alsan din sulin in jec tionaccor din gtot hety peofinsu linu sed.Th etech niquesformixing reg ularwithinte rme diate-actinginsulinsmaybere viewediftheph ysicianbelievesth att heseare app ropr iateinsulinformu lation sforaspecificpatie nt. Premixedinsu lin[70%neu tralprotamine Hage dor n(NPH)an d30%cr ystallin ezincinsulinor75%n eut ralprotamin elispro(NPL)and25%lispro] can beuse din it iallyinpat ien tswhomaynotbeable tomast erth emixingofin sulin s.Thissimplifiesth e tre atment program,espe ciallywhe npat ie ntshavepr oblemsunde rstandingan dperformin gthe mixin g mane uver s.Fu rth ermore ,th esepre mixedinsu linsarenowavailab leinpr efilledsyringe swith asimple dose-dialin gme chan ism.In manycase s,limit ation sin mixinginsu linsaredue topr oblemssuchas cat aracts,deg ener ativejoin tdise ase, previouscere brovascu laraccident s,orsever eneu ropath y. Most n ewpat ie ntswhoreq uireinsulinwillreceiveh umaninsu linofrecomb in ant DNAorigin.Allergyand lipoat roph yar euncommonwithh umaninsu lins. Beefinsulinan dmixedbe ef-porkin sulinshouldbe av oidedu nlessthe rear especificindicat ionsforth eir useorifh uman insu linisnotavailable .Thes e latte rin sulinsare nowbein gphasedoutinth eUn ite dStat es.Patient salsoareinstru ctedonSMBGat th istimean dareaskedtomaintain closecontactwit hth enur seedu cator,wh ointu rnre vie ws adju stme ntsininsu linth erapyan dthepatient 'sprogresswith t heph ysic ian.In mostpat ien ts,t heblood glucoselevelscan beexpe ctedtobebrough tun dercontr olov era4-to6-week period. Th epatie ntoften isseense veralt imeswit hinth isinte rvalsothatthe physiciancanmonitorprogress, modifyther apy, and rev iewanyinte rimproblemsorconcer ns. Most p atient saren ot start edon an in tensiveman agemen tprogramat t histime, asitisn ecessaryto allowth epat ie nttoadjust tot heemotionalandlife stylechangest hat followadiagn osisofdiab etes. Int ensiveth erapywit hmultipledailyinjectionsor con tin uoussu bcutaneousinsu lininfu sionisusedfor women whoplanapr egnancy, patien tswhocann ot c ont rolth eirglu cose lev elsb ycon vent ional th erap ies, orp atient swhos elifesty lesorcomplication s,espe ciallyh ypoglycemicunaware ness, demand th egreaterflexibilityandcontrolthatin ten sive prog ramsoffer (47). Patient swith knowndiabet esinpoorcontr olor with complicationsofdiabet eswillunde rgoasimilar evalu ationan dphysicalexamination .Atte ntion isfocused h ere ont hepatient'sgen eralapp roachtothe disease ,wit haparticular focusonth epatie nt'saccept ance ofth edisease anditstr eatmen t req uirements. TheJoslinC linicoffe rsan out patien tprogramcalledDOIT, in whichpat ie ntsareseen byateamoverape riodofthre ean dahalfdays.Th isprogramallowsacompreh ensive r eviewoft he pat ie nt'sprob lemsan dfor t hese problemstobeadd ressedonanindividu albasis.Th isprogramh as becomenece ssarybe cau se,withth echangingh ealth care-insu ran ceen vir on men t,th eoldinpatient edu cationprogramsar enolonge ravailab leinman yin stitutions.Man ypat ien tshaveanov erwhe lmin g fearofh ypog lyce mia.Some willd eliber atelyavoidusingr apid-acting insu lin orwillomitthe ir e ven in g injection s,whichpr edictablyres ultsin hype rgly cemia. Othe rswillover compen sateandtr eat any symptomsasasignofpote ntialhypoglycemiaand somewillstart tomonitor g lu coseleve lswith exce ssive frequ encyinanefforttodiscove rlowervalu esinth ehopeofavoidingse vere hypogly cemic reaction s.Itisimportan ttoreviewth enu tritionalp rogr ams,exe rcise habits, alcoh olin tak e,an d psych osocialst atu softh esepatients. Even somepatie ntswithdiabetesoflongdu rat iondonot app ropr iatelytime t heirinsulininjection totheiringe stionofcalor ie s.Also,some patien tsmaketh e mistakeofregu larly in je ctin gin sulin ath ypert roph ie dsit es,withre sultan tun predictabilit yofinsu lin abs orpt ion. In gen eral,n oacutech an gesinthe in sulin prog ramare mad eataninitialv isit,bu tth e pat ie ntfre quen tly isaskedtomonitorbloodglucosethr eetofou rtimesadayforth enex tmont h,with th efocu sbeingonth enu tritionalpr ogr am. Change sofinsulinth erap yaremade byteleph on eor at fut urevisits.Patien tswit hmajorpsy chologicalp roblemsare referr edtoapsych ologistorpsych iatrist. Un le ssthese issu esar eaddre ssed,diab etescontr olwillcon tin uet obeaproble m. Somepatientswillre quirehospitalization.Att heh ospital,t hefocusofthet reat men twillbeedu cation an dclosemon it oring t oiden tify p ote ntialproble mssu chasn octu rnalh ypoglyc emiawithr ebound hy perglycemia,hy poglycemicunawaren ess,orinh eren tly unst ablediabet es.Ev enth ou ghth eprese nt economicclimate ismakingitmor edifficulttohospitaliz ethe sepat ien ts,t here isn oway ofsat isfactor ily add ressingsome ofth eseproblemsint heoutpatient se tting. I ft hepatientishospitaliz ed,itisimpor tan t toatt emp ttor eproducet hepatient'snormallifestyleascloselyaspossible, in clu din gthe timingan d conten tofmealsandex ercise.Complicat eddiabet esrequ ir esin div idu aliz edthe rapyt hat isbothcomple x an dtime-c ons uming .Forappropriateindividualizedcaretobeprovidedforpat ien ts,spe cificissu esth at mayinte rferewithoptimalc ont rolmustbe iden tified andaddresse dcare fu llyandsympath etically. Solut ionsth atoffert hepatie ntth egre atest opportu nityforasu ccessfulou tcomesh ou ldbe sou ghtin consultationwith t hepatientandth epatie nt'sfamily.Ver yofte nindivid ualswit hun stab leglucose controlwilln eedtohaveth eirgly cemicgoalschangedtoav oiddan geroush ypoglyce mia,de spit eearlier
P. 594
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en cou rage men ttomain taint igh tcon trol. Patient swith type2diabete smayrequ ire in sulin wh en t heyarefirstsee n,particularlyifthe yarev ery symptomaticandh avelostweight. Insomeinstance s,in sulin can bediscon tin uedwh encont rolis ach ie vedandadh ere ncetodiethastak eneffe ct(48).Howe ver, man ypat ie ntswillrequ ir ein sulin indefinitely;th isbe comesobviouswh ent heybe comeket on urican dhyper glyc emicwit har educt ionin insulindose. The b asisofth erap yin type2diabete sistopromotelifestylechange swith anu trition alprog ram designe dtor educe caloriesanden cou rage weig htloss. An exer cise progr amisanessen tialpart ofan y efforttoloseweigh t.Glyce miccon trolcanoften beimprovedby c aloricrest rict ionalone, even before significantweigh tlossoc curs.Att hesamet ime,itisalsoimp ort ant topaycloseatten tion tot herisk fact orsformacrovascu lardisease .Thisme anscontr ollin glipidsandh ypert ensionan dcou nselingon smokingce ssationan dthe v alueofglu cose con trol. Pat ien tswithty pe2diabe tesalsoare t au ghtSMBG, an dthe freque ncyoftestingisindivid ualized.SMBGisalway sthepr eferre dme thodofglucose mon itoring, with urinet estingbeing u sedonlyin specialsit uat ions. The d ecisiontouseoralantidiabeticth erap iesisgen erallymadeafterat rialofnu trition alther apyu nless th ein it ialrandomgluc oseleve lishigher than350mg/dL.In gene ral,a4-to12-weektr ialpe riodofdiet an dlifesty le modificat ionisreason able,andift hefastin gglucosecon cent rat ionre mains h ig hert han 140 mg/dLor postp rand ialvalu esar ehigher than200mg/dL,t reat me ntwithoralpharmacologicagen tsis initiated. Mu chhaschangedint hisareasin ceth elastedition ofth ist extbook .Thelast 5yearshave see nthe in troductionnotonlyofn ewsulfon ylu reasbutalsoofn ewnonsu lfonylur eainsu lin secre tagogu es.The latterdr ugsar eoft enmor erapidactin gthanth esulfon ylureasan dmaybever ywell suited in t reatin gpost pran dialh yper glyce mia. Th ebiguanideme tfor min,wh ich hasb eenavailablein manyp artsofthe worldfordecade s,wasint rodu cedintothe United St ate sr elativelyrece ntly.Th eglucosidaseinhibitorsoffer anoth eroptionforcontr ollingbloodglucoseleve ls,e speciallyaftermeals. A totallynewclassofor almedication, thet hiozolidine dione s,alsoisav ailable .Dru gsinthisclassar e novelinsulin-sen sit izingagent sthatwor kthrough specificn uclear recept ors. The p hysiciannowispresen tedwithanumber ofchoicesan dtriesclin icallytomatchth epre sume d un derlyingabnormalityinth eindividualpat ie nttoaparticularph armacologicappr oach.Bec ause type2 diabet esinvolve saduald efect, t hee arlyuseofcombinationt herapymaybeve ryad vant ageous. Cu stomarily,t hepatie ntwillstartwithas ulfony lu reaoranin sulinsensitizer .Itisveryimp ort ant forth e he althcareprovidertobeawareofthe con train dicationst oth euse ofeachdru gaswellthemon it oring req uirementst oavoidseriousadv ersere actions.Failureofcon trolwith asin gledrugwillre sultin the use ofacombin ationregimenth atcantakead van tageofthe diffe rent mech an ismsofaction. Subst itu tion ofdru gsfromoneclasstoan ot herisrarelysuccessfu l;h owe ver,t headdit ionofadru gfrom an ot herclassoften improvesglucosecontr ol. The r ecen tly c omple tedUK PDSd emonst rate dthatmanyofthe oralmonother apieswillfailtocontrolthe bloodglucosele velsforlonger t han 5ye ars(3).Muchofthe failu reisduetoth eprogression ofth ecelld efect, with con tin ued r educt ionininsulinproduct ion. Somepatien tswhofailt oobtaincont rolwit h th emaximaldoseoforalmedicationmayben efitfromth ecombinedu seofinsu linandoralmedication . Usu ally abedtimedoseofinte rme diate-actinginsulinorabasalin sulin analogue (48a)isgive n,witht he oraldrug b ein gcon tinue d(49).Ifthe patien thash ig hbloodglucosele velsfollowingsupp er,amixtu re ofashort-actingan dan int ermediate -actinginsu lincanbegiven beforesupp er.Itisoftenu sefultouse apr emixed in sulin (70/30h umaninsu linmixture or75/25lis promixture )in patien tswhohav edifficulty withmixing oradju stinginsulindose.Sev eralstu die sofcombinationt herapyhavebe encomplete d. Gene rally ,pat ien tswhohaveresiduale ndogen ous insu linse cretionrespond b est,alt houghpatient s' resp on sesvar ygreatly andt reat men tsmustbeindividualized(48). Fore verypatient ,diabete smanage me ntmustinclude acar efulnut rit ionalassessmentandth e implement ation ofarealisticdiet arypr ogr am.Thegoalofn utr itionalth erapy in type2diabete sisth e controlofbloodglucoselevels,normaliz ation oflipidleve ls,andmainte nan ceofide albodywe igh t.For young childre nwithdiabe tes,t hegoalshouldbeth emain ten an ceofn ormalgrowthanddev elopment ,as wellasofareasonablebod yweig ht. Inge ner al,the die tit ianwillprescribeame alplanbase don the in dividualp atient 'stype ofdiabe tesan d modeoftre atment .Patientsr eceivingexogen ou sin sulin mu stpayparticularatte ntion tot hetimin gof mealsan dsnack stopr even tun duefluctu ationoft hebloodglucoselevels.Th eme alplanis individ ualizedwithre specttoweightgoals,pe rson alfoodpre fe ren ces,an dexe rcise habits. Manyobese pat ie ntswithdiabe tesmayre quirespec ialweight -lossprogramsan dbehaviormodificationth erap yto maintain we igh tloss. U nfortu nat ely ,mostpatientsdonotsucc eedinth eir effor tstoloseweightandto maintain we igh tlossforprolonge dperiod s. Diet ther apyoften isre fe rredt oasthecorn erstoneoftre atment ,par ticu larlyin type2diabete s.Fort he pat ie nttoben efit maximallyfromthisasp ectofpatient manage me nt,ateamapproach, whichin cludes th eservicesofaskilledr egistere ddie tit ian,isrecommen ded.Althoug hthe seskillsar enotalways av ailable in p hysician'soffices,th eyareoffe redinlocalcommun it yhospit alsand bysomedietitian sin privat epractice .Adetaileddiscussiononthiscompone ntoftreatme ntisprese nte din C hapter36on
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nu trition alther apy. Exe rciseplaysan importan trole in diabete sman age men t.For patien tswit htype 1diabet es,ex ercise shouldnotbet hought ofast hemajorwayofimprovin gglucosecon trolbu trather aspar toft heoverall app roachtomain taining ahe althylife style.Physicalactivitycanben efit thep atient byloweringt he bloodglucosele velifoverallcontrolisgood .Howe ver,caremustbe take ntoin stru ctthe p atient on the possibilit yofph ysicale xerciseprovokin ghypoglycemicr eactionsorworse ningcontr olwhen unde rtaken inth eprese nceofhigher b loodglu coseleve lsandket on uria. Fur the rmore, patien tswit hthe complication s ofr etinopath yan dneu ropath ycan p lacethe mse lve sin jeopardywit hexce ssive exer cise. Inge ner al,pat ien tswhoare freeofcomplicationscanen gage in anyt ypeofexercise. Cert ainact ivities, such asscu badivin g,h avetobeassessedinlightofthece rtification requiremen tsissuedbyappropriate organ ization s.Patient soften mayben efit fromaconsu ltation with ane xerciseph ysiologist.In patien ts withtyp e2diabe tes,anindividualizedex erciseprogramshouldbepartoftheover alltr eatmen tplan. Exe rcisehelpspromote weigh tloss, optimize glyce miccon trol, an dreduce cardiovascu larrisk.The se pat ie ntsn eedtobescre ened forearlyneu ropath yor peripher alvascu lardise asebe fore they start an exe rcis eprogram.Silen tischemiais morecommon in patien tswit hdiabet esthaninth egen eral population,andap prop riatepatie ntssh ou ldh ave astre sst estbeforest arting thee xerciseprogram. Routine screen in gofmenwith type2diabete soflon gerth an10ye ars'duration orlessifthey have more thanon ecar diovascularriskfact orisrecommen dedbe cause ofth ehighpr evalen ceofmyocardial ischemiawit hsignificantlesion samon gmen wit htype 2diabet es(37).The progr amshouldbedone th reetofourtime saweek tobe effective, with appropriat ewarm-ups, settingt arget exer ciseleve lswith mon itoringofpulseratean dcoolin g-down time. Afu rth erdiscussion ofth isimport ant areaappe arsin th eeditorialby Ne sto(50)inth eissueofDiabe tes Careth atpu blishe dthe abovestu dy[refer ence (37)]. P. 595
FOLLOW-UP
Acriticalpartofdiabet esmanag eme ntisregu larfollow-u pofpatie nts. Th isisbase don the g oals establish edwit hth epat ien tinthe in it ialmanagement plan.Ate achv isitth ereafter, thepatient 's progressisrev iewe dand ong oingproblemsareaddresse d.The fr eque ncyofvisitsdep endsonth e individ ualpat ie nt,t ypeofd iabetes, goalsofcon trol, an doth ermedicalcon dit ions.Pat ien tsstarting insulinth erap yneed tobe seenfr eque ntlyin it ially,bu tonceth eircon dit ionh asstabilized,t heycanbe see nthr eetofou rtime sayear.In addition ,patien tsar eencour agedt omaintain telephone con tactwith th eot hert eamme mbe rs.Somepatientswith t ype2diabetesn eedt obese enonlyeve ry6mon ths. Aspar tofth isfollow-upprocess, aninte rimhistoryisobt ained, resu ltsofglucosemonitoringar e rev iewe d,an dnewpr oblemsorilln essesth ataffectdiabe tescontrolareaddresse d. Acompre hen sive physicalexaminationisdoneannu ally .Atin ter imvisits, previou sly abnormalfin din gs ar eree valuat edan dheigh t,weight, an dblood p ressur eare deter mined .Foryoun gerpatie nts, an asse ssme ntofsexualmat urationsh ou ldbe don e.Acomplete ,dilatedey eexaminationby an ophth almologistshouldbepe rfor medann uallyin allpatientsolderth an30ye arsandinpatie nts12to30 yearsoldwh ohaveh addiabet esfor moreth an 5years. Atest forglycosylatedh emoglob in sh ou ld b edon eat leastqu arte rly in p atient swith type1diabete sand semiann uallyin thosewithty pe2diabe tes. Th epat ie ntwithadult-on setdiab etesalsomayben efit from havingeithe rafastin gor postp ran dialglucoselevelche ckedasame ansofjudgingoverallglycemic control.Adete rmination offast in glev elsoftriglycerides, cholest erol, andh igh -den sity lipop rot ein (HDL) cholester olshouldbeper formedannu ally andmor eoft eninpatie ntswithdy slipidemia.Urinalysisdone at leastyearlyisu seful.Afte r5yearsofdiabetes, patien tsshouldbete stedformicroalbuminuriay early. Ifproteinu riaispr esen t,th epat ien t'scr eat in in ean dblood u reanitrogenleve lssh ou ldbe closely mon itored ;inaddition, aggre ssiv ean tih ypert ensiveth erapyan dproteinrest rictionsh ou ldbe con side red. Ateachvisit theover allman agemen tplan, includ in gthen utr itionalprograman dthe exer ciseplan ,is rev iewe dand modifiedasrequ ire d.Inaddit ion, theover allemotionalst atu softh epat ien tisreviewed. Thistype ofcompre hen sive care isex tremelyimportan tfor patien tswit hach ron ic, life-lon gdise ase such asdiabe tes.Th isch apte rhasr eviewedth egen eralprinciplesofman agemen tofdiab etes. Manyof th edetailswillbefoundinothe rchaptersint histextbook.Sinceth elasteditionthe reh avebe enman y importantadvan cesinthe unde rstandingofthepathophy siologyandtr eatmen tofdiabe tes. Ne w diagn osticcriteriah ave been developed,andne wgoalsoftreatmenth ave b eende fin ed.Man ystud ies demon stratingth evalue noton lyofglucosecon trolbu talsoofriskfact orre ductionan dcardiovascu lar disease hav ebeen publish edandincorpor ate din tot herout in eapproac htodiabete sman age men t.In add ition,th erapeut icch oiceshaveincre asedg reat ly, andt herapycan nowbebase don the u nde rly in g pat hophysiologicmech anismsofdisease .The p rimar ygoalintr eat in gpatien tswith diabete sistohe lp th emavoidsh ort -termproble msandlon g-termcomplication s.Arecen tstu dyofadultswit htype 1or type 2diabe tesinvest igatedcognitivere presen tat ionsofillness,se lf-re gulationofd iabetes, quality-oflife, and behavioralfactor s.Theauth orsfoun dthatindividu als'u nder stan din gofdiabe tesandth eir per ception sofcontr olove rthe dise asewer ethe mostimportantpr edict or sofoutcome (51). This
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reinforcest hen eedtocontinue top rovideongoingself-edu cationfor patient sand t opr ovideth emwith th eeviden ce,nowavailable ,thatcontrolofdiabet esisp ossiblean dthatcomplicationscanbe avoide d. Tot hepracticin gphysician, diabete soffer sthech alle ngeofprovid in goptimalpatien tcare atev eryvisit . Itallowst heph ysician the opportu nityan dprivilege top racticen otonlyth escie ncebu talsotheartof medicin e.
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16.American Diabet esAssociat ion. St and ardsofmed icalcareforpatien tswit hdiabet esme llitus. Diabetes C are2000;23[Su ppl1]:S32S42. 17.R andomised trialofcholester olloweringin4444patie ntswithcoronaryhe artdisease:th e Scan dinavianSurvivalStu dy(4S). Lance t1994;344:13831389. 18.SacksFM,PfefferMA,Lemue lA.Th eeffectofpravastatinon cor on arye vent safter myocard ial infar ction inpatient swith aver agech oleste rollevels.N En gl J Med1996;335:10011009. 19.Tightbloodpr essure con trolandth eriskofmacrovascularandmicrovascularcomplicationsin typ e2diabe tes(UK PDS35):U KProspect ive Diabe tesStud yGroup .BMJ1998;317:703713. 20.HanssonL,Zanche ttiA,Carrut hersSG,et al.Effect sofinte nsivebloodpressu relowe rin gan d low-doseaspir in inp atient swith hype rten sion:principalre sultsofth eHyper ten sionOptimal Treatment(HOT)randomized trial:HOTStu dyGrou p.Lancet1998;351:17551762. 21.C ollaborativeover vie wofrandomisedtr ialsofant iplat ele tth erapy -1:pre vent ionofdeat h, myocardialin farct ion,andstr oke byprolonge dant iplat ele tthe rapy inv ariou scate gor iesofpat ien ts. Ant iplat ele tTrialists'Collab oration .BMJ1994;308:81106. 22.E ffectsofr amipr ilon cardiovascu laran dmicrovascu larou tcomesinpe oplewithdiabe tesmellitus: re sultsofth eHOPE StudyandMICR -HOPESu bstudy:He artOu tcomesPreve ntionEvalu ationStud y In vestigators. Lance t2000;355:253259. 23.GressTW, NietoFJ,Shahar E,et al.Hypert ensionan dant ih ypert ensiveth erapyasriskfactor sfor typ e2diabe tesmellitus. N E ngl J Me d2000;342:905912. 24.Kn owlerWC ,PettittDJ,SavagePJ,etal. Diabet esincidence inPimaIn dians:cont ribu tion of obesityan dpat ernaldiab etes. Am J Epidemiol1981;113:114156. 25.Die hlAK,Ster nMP.Specialhe althpr oblemsofMexican -Amer icans:obesity,gallbladder dise ase, diabe tesmellitusandcardiovasculardisease.Adv Int ern Med1989;34:1356. 26.FujimotoWF. Backgroun dand recru itmen tdatafor theU SDiabet esPre ven tionProgram.Diab etes Care2000;23[Supp l2]:B11B13. 27.Ke nny SJ ,Auber tRE, GeissLS.Prevale nceandincidenc eofn on -in sulin -depen dent diabetes .In: Har risMI,C owieCC ,Ster nMJ,eds.D iabete s in America,2n ded.Bet hesda,MD:Nat ionalIn stit ute of DiabetesandKidn eyDiseases,1995:4767;NIHpu blicat ion95-1468. 28.Minak erKL. W hat d iabetologistsshouldknowabout elde rlypatien ts.Diab etes C are1990;13[Su ppl 2]:3446. 29.Th ivoletC, elFar khJ,PetiotA,etal. Measuring v ibr ation sensation swith agraduatedtu ning fork:asimpleandre liablemeanstodetect diabeticpat ien tsat risk forn europat hicfootulceration . Diabetes C are1990;13:10771080. 30.DyckPJ,Me lt on LJ3rd, O'BrienPC,e tal.Approach estoimproveep idemiologicalstu diesof diabe ticn eur opathy:insight sformth eRocheste rDiabe ticNe uropath yStud y.Diabe tes1997;46[Suppl 2]:S5S8. 31.PerkinsBA, Olaley eD, Zinman B,etal. Simple screen in gtestsforper iph eraln europat hyinth e diabe tesclin ic. Diabete s Car e2001;24:250256. 32.HaffnerSM,Leh toS, Ronne maaT,et al.Mortalityfr omcoronaryh eart dise aseinsub je ctswit h typ e2diabe tesan dinnon-diabe ticsu bjectswithandwithoutpr iormyocardialin farction.N En gl J Med1998;339:229234. 33.Mogense nCE .Pr edict ionofclinicaldiabet icn ephr opathyinIDDMpat ie nts:alte rnativ esto micr oalbu minu ria?D iabete s1990;39:761767.
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34.Mogense nCE .Microalbuminur iapredictsclin icalpr ote in uriaandearly mortalityinmatu rit y-on set diabe tes.N En gl J Med1984;310:356360. 35.ZieglerAG,ZieglerR,VardiP,e tal.Life-table analysisofprog ression todiabe tesofant i-insu lin autoan tibody-positiv erelat ive sofindivid ualswit htype Idiabete s.Diabe tes1989;38:13201325. 36.Kr isch erJP,SchatzD, Riley W J,etal. I nsulinan disletce llau toantibodie sastime -depen dent covariatesinth edevelopme ntofin sulin depen dent diabetes. J Clin Endocrinol Met ab1993;77:743 479. 37.Janand-Dele nne B,SavinB,Habib G,BoryM,et al.Silen tmy ocardialische miainpatientswith diabe tes:whotoscreen .Diabe tes C are1999;22:13961400. 38.Physician's guide to in sulin -depe nden t (type 1) diabet es: diagnosis and t reat men t.Alexandria, VA:Ame ricanDiabete sAssociation ,1988:18. 38a. Amer icanDiabetesAssociation .Stan dar dsofmedicalcareindiab etes. Diabet es Car e2004; [Supp l1]:S19. 39.American Diabet esAssociat ion. Te stsofglycemiaindiabet es.D iabetes C are 2000;23[Su ppl 1]:560582. 40.Jovan ov ic-Peter son L,Pe tersonC M, Dud ley J D,e tal.Iden tify in gsou rcesoferrorinself mon it oringbloodglucose. D iabete s Car e1988;11:791794. 41.Alle nBT,Delong E R,Feu sserJR. Impactofglucoseselfmon itoringonn oninsu lint reat edpat ie nts withty peIIdiabet esme llit us:randomizedcont rolledtrialcomparin gbloodand u rinete sting. Diabetes C are1990;13:10441050. 42.Bu nnHF,Han eyDN,Gabbay KH,etal. Fu rthe ride ntification ofth enatur ean dlinkageofthe carboh ydrateinhe moglobinA 1 c .Bioch em Biophys R es Comm1975;67:103109. 43.R ahbarS.Anabnormalhemoglobin in redcellsofdiabe tics. Clin Chim Act a1968;22:296298. 44.Koen igR J,Pe tersonC M, J one sRL.C orr elation ofglucosere gulation an dhemoglobin A 1 c in diabe tesmellitus. N E ngl J Me d1976;295:417420. 45.Sch nedlWJ,Kr ause R,Halwach -Bau mannG,et al.Evalu ationofHbA 1 c de termin ationme thodsin patie ntswithh emoglob in opathies.D iabete s Car e2000;23:339344. 46.Bre werW,C hase HP,Owe nS,etal. Slicin gthe pie .Correlatin gHbA 1 c valueswithaverageglucose valu esinapie-ch artform.Diabe tes Care1998;21:209212. 47.American Diabet esAssociat ion. Con tinuoussu bcutane ou sins ulin infu sion. Diabet es Care2000;23 [Supp l1]:S90. 48.Gen uth S. Insulinuse in NIDDM.D iabete s C are 1990;13:12401264. 48a. Riddle MC ,Rosenst ockJ, Ger ich J,on beh alfofth ein sulin glargine2002stu dyinvest igator s. Randomized additionofglargine orh umanNPHinsu lin t ooralth erap yoftyp e2diabe ticpatient s. Diabetes C are2003;26:30803086. 49.R iddleMC.E ven in gin sulin .Diabe tes Care1991;13:676686. 50.Nest oRW. Screen in gforasymptomat iccoronar ydise aseindiabe tes. D iabete s Car e 1999;22:13931395. 51.WatkinsK, Con nellCM,Fitz geraldJT,e tal.Effect ofadults'se lf-re gulationofdiab etesonqu ality of-lifeoutcome s.Diabe tes Care2000;23:15111515.
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Chapter35 Education in the Treatment of Diabetes

Ric hard S. Beaser Katie Weinger Lisa M. Bolduc-Bisse ll Thisbuildin ggiv enbyth ou san dsofpatientsandth eirfriendsprovidesanop port unity formanytocon trolt heirdiabe tesbymeth odsofteachinghith ertoavailab let oth e privile gedfew. Ch ise led in st on eon the fron toft heJoslinC linicBuild in g,ere ctedin1955,th eaboveinscr ipt ion reflect edElliottP. Joslin'sconv ictionth atedu cationwasn ot ju stapartofd iabetest reat men t,itwast he tre atment .Dr .Joslin'scon cernabou tedu catingboth patien tswit hdiabet esan dtheirfamiliesbe gan more than100ye arsago, wh ensu chinstr uction wasconsidere dbymanytobealu xury. Overth elast twodecad es,th eimportanceofeducation hasbe comemore widelyre cogn iz ed.Asth eWor ldHealt h Organizationcomment edin1980,Ed ucat ionisacorne rstoneofdiabeticthe rapy andvitaltoth e integ rationoft hediabe ticint osocie ty(1). Thisgrowin grecognition ofth evitalrole ofedu cationin the treatme ntofdiabete sle dtot he deve lopmentandpe riodicupdatin goft heNat ionalStandardsfor Diabet esEdu cation byth eNation al DiabetesAdvisoryBoardin1983(2, 3,4).Thiswasfollowedbyth edeve lopmentofare cogn it ionprogram fordiabete seducation b ythe American Diabe tesAssociation(ADA)(5)andofacertificationprogramfor diabet esedu catorsbyth eAme ricanAssociation ofDiabetesE ducator s(6)nowadministere dbya separat eor ganization, the Nation alCert ificationBoardforDiabe tesEd ucat ors. Pr ogr essin makin gedu cation alprogramsavailable t oev eryonewith diabetesh asbee nslowe dbythe reluct ance ofth ir d-part ypaye rstoreimbu rseforeducation alservicesinth eUn ite dState s(7).Th isis nowchanging. In 2001,th eCen terforMedicareandMedicaidServices(C MS)be ganpayingforMe dicare pat ie ntstoat tendgr ou pdiabete seducation p rogr amsandformedicalnut rit ionth erapyvisits. Many privat ein sure rsfollowed s uit.Howe ver, diabetese ducationpr ogr amsarestillatrisk,withman yclosing th eir doorsbecauseofpoorr eimbur seme nt. Onen ation wide studyfoun dthatmoret han 60%ofpeople withdiabe teshavere ceiv edlitt leorn odiabe tesedu cation(8, 9).U nfortun ate ly ,littlee vide ncesu ggests th atth isischanging. Despitet heobstacles, however, healt hcar eprofession alswh ot reat people with diabet escontinue the ircommitme nttopat ie ntedu cationth rou ghth edev elopmentofne wp rogr amsand rese arch in tomoreeffect ive met hodsofte aching t hepr in ciplesandpractice ofdiabe tesself-car e.
WHY IS SELF-MANAGEMENT EDUCATION IMPORTANT IN THE TREATMENT OF DIABETES?

The impor tan ceofimpr ove dgly cemiccontrolin delayingth eon setandprogre ssionofseriou s microvascularcomplicationsis n owclear(10,11).Tre atment ofdiabet esleadingt oimpr ove dcon trolisa 24-hour- a-day activityan dofte nincludesimport ant chan gesinlifest yle ,mostofwhichper son swith diabet esmu stprovidefor themselvesonadailybasis.These effort srequ ire carefu lbalancingofvar ious lifest yle funct ionsandact ivitiesth atareinte gralpart softh edailyroutine. Thus, thegoalofd iabetes self-managemente ducat ionisnotsimplytoin creaseknowledgeabou tdiabete s,but rath ertosupp ort individ ualswit hdiabet esan dthe irfamiliesint heireffortstoin cor poratediab etestr eat men tin totheir lifest yle s.Ofcou rse, themoreth atpeoplewithdiabe tesun derstandh owtomaketh esere quiredch an ges an dwhatthe r ationaleisbehind t hem,th emore successfu lth eywillbeinth eirdiabete sselfmanagement . Diabetesse lf-man agement education prov ide sman yben efit s.Edu cationallowspeoplewithdiabe testo takecontrolofth eircon dit ion,int egratin gthe daily r ou tin esofself-monitor in g an ddisciplineintothe ir lifestylerathe rthanper mittingth isconditiontoove rwhelmtheman dcon trol th eir lives. Education in d iabetesse lf-man agemen ttrain sp eop let otaketh ene cessary action sto improvet heirmetab oliccont rol,wh ich helpsmain tainh ealth andwe ll-beingandre ducesth eriskof diabet iccomp lications.Th ewell-ed ucat edpersonwithd iabetesmayalsodecr easet hecostsrelatedto th econ dit ionbot hth edir ectcostofmedicalcare and t heindirect costsr elatedt olost in comeor product ivity(12). Diabetese ducat ionisbot han art andafle dgin gscie nce. Onlywith in the sepast 20ye arsh asre search begu ntoexamine t herolean deffectiven essofe ducationindiab etesself-management ,an dfutu re rese arch isn eeded tofu rthe revalu ateandclarifyoptimalmeth odsforth isedu cationalprocess(4).In P. 598
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add ition,inth islitig iousage,ast hevalu eofeducation g ainscrede nce, thepr ovision ofproper e ducation topeople with diabete sbyah ealthcareprovidermayh elpredu cethe risk ofmalpract icesu it s. The e volut ionofthe s cien tificcompone ntofdiabete seducation h astr aveledalongandsome what bumpy road. Initialst udiesexaminingdiab etesed ucat ionwer edifficulttodesign, perform, and e valuate,and whe nthe ywerecomple ted,t heirvaliditywasoften t hesu bje ctofcont rov ersyamonghe althcare profession als.One reasonforth isdisagr eement wasthe assumptionbyre search ersstu dyingdiabe tes edu cationth atitwasanintegr alcompon en tofcare.Th us,th eusu alstudy desig ncontrastedinte nsive edu cationwit hless-inten siv eedu cation rat hert han with noeducation oraplaceboformofeducation . Somesmallst udiescomparin gthe setwoformsofe ducationsh owed nod iffere ncesinglycemiccon trol bet we engr ou ps.Fore xample ,atr ialcomp aringmin imalvers usin ten sive education showedsimilar improvemen tin the twogr ou ps(13).Goodcon trolwasrelated toth edu rationofsch ooleducation , abs enceofan xie ty,andqu ality ofcontrolandde gree ofself-con fide nceu pon ent ryin tothest udy. A similarstu dy,withadmitte dsocioe con omic b iasaffectingsomeofth esefactor s,showedth ate ducat ion ledtoimprovement sin k nowledg ean dbehaviorbu tnotinimprovemen tsin me taboliccontrol(14). Howe ver, duringth elasttwodecades,man yran domizedclin icalt rialsandsmalle rstud iesh ave examine dthe e fficacyofdiabe tesedu cat ion(4),an dseveralwe ll-donemeta-analyses(15,16,17, 18,19) th atev aluat edthe qualityofeducation summar ize dthe resultsofresearchindiabe tesedu cat ion.Th ese meta-analyse s,alongwithmore recen ttrials(20,21,22, 23,24),provideconvincinge vide nceth at diabet esedu cation ise ffectiveinsupport in gpatien ts'effortstoimproveand/ormaintain physiologicand quality-of-life out comes. Cu rren tly,rese arch in diabete se ducationh asmove dbeyondth eque stion ofwhe ther itisimportantand isbeginningt ofocusonth escie nceofedu cation ,add ressingqu estion sthatclarifyeducation al outcome s,dete rmine whichgroupsofpatien tsrespondb esttowhichformofeducation ,an devalu ate whichareth emostefficientandcost-effe ctiv eme thodsofpr ovidingedu cation(25,26,27, 28).Diabe tes edu cationalreadyen compasse sthefamilyandsocialsupport;re sear chersaren owbeginn in gtocon side r pub lic-healt hasp ectsofd iabetese ducationatthe commu nityandpossiblyth enationalleve l(29).
Education Improves Well-Being and Quality of Life

Pe oplewithdiab etesmustmake what someperce iv easbeing over whelming lifestylech ange s,yet t heir failuret oacceptth esech ange smayresu ltininadequ atediab etescontr ol.Emotionsr elatedt oth e psych olog icalbu rden ofdiabet es,su chasanxiety, depre ssion, andpoorself-con fiden ce,h ave been showntobeassociat edwit hpoorcont rol(13,30,31, 32,33).Thu s,apr ope rly designede ducat ionprogram notonlyshouldprese ntfactsbutalsoshouldadd ressth eemotionalresp on sestodiabetes. Edu cationimprovesse lf-carepractices(16,17,22, 34)butamer ein creasein knowle dgeandskillsdoes notgu arantee animprov eme ntinmetabolicparamet ers(14).Sev eralpsych olog icalfactor s,havin gbeen implicatedasbar rie rstoimprovedglycemiccontr ol,playanimportantr oleintranslationofk nowledge an dskillsin tothede sir edme tabolicre sults.The sefactorsinclude e motion -base dcopingst yle s(35, 36), diabet es-relat edemot ionaldistre ss(33) ,an dlackofre adinesst och ange (37).Forindividualstobe willin gan dabletomakeallthe n ecessarylife stylechanges, they must hav eknowle dgean dskillsplusa posit ive emotion alou tlookabout t heirdiabe tes,be lievingt hat t hech ang esthe ymakewillle adtobett er he alth. Aned ucat ionalprogramth atde monst rablyimprovesparamete rsofe motion alwell-beinginadditiont o add ressingself-car epract ice shasbe ensh own t oleadtoimprov edme taboliccontr olthatwassu staine d over6month s(38,39).The aut horsofth esestu diessugge stedth ate motion alwe ll-beingitselfmay contribut etoimprovedself-car e(38).Oth ersconte ndth at,formany patien ts,edu cationabout diabetes an dself-care alon eenh an cesemotionalwell-b ein g(40,41,42), wh ich furt herboostsself-care ability.In th efir stran domizedcontrolle dtrialtode monstr ate anaddit ive effectofpsychologicalin terv entionon glycemiccontr ol,Greyandh ercolleag ues(43,44)de monstr ate dthatadole scent swh or eceivedtr aining incopin gskillsalon gwith me thodsofint ensivediabe testre atmen timprovedglycemiccon trolandselfcar ebeh avior smoreth andidadolescen tswhorece ive don lyinte nsivetr eatmen tin stru ction. Howev er, whe ther emotion alwell-be in gleadstoimprovement in s elf-careorvicevers ahasnotbeen cle arly det ermin ed.Mor erese arch isne ededt oclarifyth eassociation samon geducation ,improvedse lf-care, an dimprovede motion alou tlook.
Education Improves Self-Care Management

Eve naft eroneacceptsth ate motion alwell-beingisacr ucialcompon ent ofth eedu cation alin terv ention, th ecomplexityoft hediabe testr eatmen tregimenitselfoft enleads t oconfu sionandmisun derst and in g th atinte rferes with theabilitytomanageon e'sd iabetes. Diabe tesedu cationcan playan impor tan trole inclarifyingth etreatmentr egimen ,reinforcingth eskillsne cessar ytosu ccessfullymanagediabet es,an d supp ort in geffor tstoint egrateself-managementbe haviorsintoon e's life.Seve ralme ta-analyse sand clin icaltr ialse xamin in gthe e ffectsofdiabete se ducationfoun dthatedu cation le adstoimprovedse lfcar ebeh avior saswellastoimprov edknowledge, andmetabolicand p sychologicalou tcomes (15,16,17, 19,22,34,38, 45).Ru bin andh iscolleague s(45) n ot edadiffere ntialeffectamongse lf-care beh avior s:behaviorsr equiringchange sin lifestylesu chasindietandex ercisewere moredifficu ltt o
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maintain ove rtimet han wereless-deman dingbeh avior ssuchasself-monitorin gofbloodglucose (SMBG).
Education Improves Metabolic Control

The Diabet esControland C omplication sTr ial(DCCT)andth eUn ite dKin gdomProspe ctiveDiab etesStu dy (UK PDS)e stablishedt heprincipleth atimpr ove men tinglycemiccontr olisbe neficialandth atmaint aining glucoselevelsasn eart onormalaspossibler esultsinred uction in the r iskofdeve lopme ntand progressionofse riou smicrov ascularcomplications. Theimportanceofedu cation tothet rainingof pat ie ntswithdiabe tesabou tthe irt reat me ntan dtosupportingth eirself-manag eme nteffortstoimprove th eir glyce miccontrolb ecameapp aren tearly duringth e9-year cour seoft heDCCT(46,47). Moreover , th eimportan ceofamu lt idisciplinaryte amc ons istingofat leastonehe althcarepractition er/edu cator such asar egistere dnur seor n utr it ionistwasde finitivelydocument ed(46,47,48). Th erole sof other teammembe rs,su chasth epodiatrist,psy chologist,ophth almologist,ph armacist, e xercise phy siologist,amongothe rs,arenowbeingre cogn ize daswell(12, 20,21,22, 38, 39,49,50,51). Although initialstu die satte mpting t ode monstr atet hat education improvesdiabet escon trolpr odu ced variable resu lts, again itwasthrough me ta-analyses t hat examinedt hecumulat ive evidence thatthe conclusion canbe drawn thatdiabete seducation canre sultinamode rat etolargeeffect on improvin g glycemiccontr ol(15,16,17, 18,19).Forglyce miccon trol, themagn it udeofthiseffect waspar ticu larly eviden tinstud iest hat we recomplet edafte rme asur eme ntsofgly cosylat edhe moglobin(HbA 1 c )came intowide spreaduse(15). Tr aditionald iabetese ducat ionalsoresu lt edin improvedkn owledge andse lfcar ebeh avior swith asmalleffe cton psychologicalou tcomes(17). Pad gettandcowork ers(16)fou nd th atdietinst ructionhadthe largesteffe ctsiz ewhile relaxationt rainingh adth eweak est. Oth erstu die salsoh aveu nder score dthe impor tan ceofse lect in gthe r igh tou tcome cr it eriafor measu rement. Ifthewr on gou tcomesaremeasu red,e ducationmayn ot appeartoberesponsibleforthe desired improveme nts, bot hwhen lookedat in r elation tovariou sou tcomesoth erth anmetaboliccon trol (52)an dwhen examinedovere xten dedper iods(34,53).Forexample,th eDiabetesE ducationSt udy rep ort edminimaldiffer ence sb etween the education andcont rolgroupsinmeasu rement softh eir kn owledgebu tfou ndn umerous,significant differ ences int heirskillsan dself-care behaviors. Su ch stu die ssuggest thatadu ltlearningth eoryholdstrue :Individualsten dtolearnwh atisimportanttothe m an dwhatthe ycanr elatet oth eirown lifeexpe rie nce(54). Notsu rprisin gly ,disc repan cie smayexist bet we enwh ath ealthc arepr oviders t each and wh atindividualswithd iabetespe rceiveasimpor tan t. The sestudiesalsopoin tou tthe difficultiesofmeasuringth eeffect sofedu cat ionaft erasingle edu cationalinter vent ionth atfocuse sprimar ilyonfactsabou tdiabet esrather thanon behaviorsandth at doesnotincludeongoingfollow-u p(55)ort hat measure sou tcomesinte rmsofselecte dmet abolic par ameter son ly. Su chlimitedstu die softe nfailtode tectallthe pot entiallon g-termben efit sofan ongoin geducation alexper ien ce(56).Oth ersh avemade the impor tan tpoint thatimprovedglycemic controlmaynotbeap paren tun le ssoth ertr eat men tfactors, suchasthe t reatme ntre gimenand individ ualme tabolism,aretakenint oaccoun t(57). Although t hest udiescit edsugg estth atedu cationdoesimprovemetaboliccon trol, moststu dies d onot examine education inisolation .Inanexte nsivere vie wofth ediabete seducation literatur e,C lemen t(58) emphasize dthatne gativestu diesdid notexaminediabe tesedu cat ionth atwasin tegratedintomedic al tre atment .Ther efor e,onemust conclud ethatedu cationalon edoesnotimpr ove met aboliccon trol. This poin twasn icelydemonstratedinaran domizedcontrolled s tudyofnu rsecase manage me ntth atinclude d a12-h ou redu cation program.After 1year,th ecombine dmedical/edu cat ioncas emanag eme ntapproach ledtoagre ater improvementinglycemiccon trolasmeasure dbyHbA 1 c of1.1%ascompared with the controlgrou prece ivingt heu sualcar e(21).These dataan dthee mph asisthatthe DCC Tplacedon edu cationtohelppat ie ntsre achglycemictarge ts(46,48,59, 60,61)supportt hesug gestion thatthe maximalbe nefitofd iabetese ducationisrealizedwh ene ducat ionisin tegr ated int odiabe tescare. P. 599
Education Enhances the Prevention and Early Detection of Complications

Eviden ceisnoweme rgin gthatdiabe tesedu cationplaysanimportantrole in thepr even tion ande arly det ection ofdiabe tescomplication s.Infact,th eRev ise dNation alSt and ardsforDiab etesSelfManagement Education hav ein clu dedpre vent ion, detect ion,andtr eat men tofboth acut ean dchronic complication samon gthe t enconte ntareasfordiabe tesedu cation(4). Acase -con trolstu dyof886subjectswith long-te rmdiab eticcomplicationsand1,888contr olsubject s withoutcomp licationsfoundt hat ,in addition tob ein gmale ,olde r,an dhavin gtype1or in sulin -treated type 2diabe tes,patientswh odidnotre ceiv ean ykin dofe ducationalint erven tion we reatin creasedrisk ofd evelop in gcomplications. Fu rthe rmore, self-manage men tofin sulin ,askillth atisusu allyde pend ent onrece iving d iabetese ducat ion, hadaprotectivee ffe cton the risk ofcomplic ation s(62). Inaran domizedcontroltrialof352patient sandfourh ealth care prov ider pract icet eams,Litzelmanand he rcolleagu es(23)fou ndth atpatient swith type2diabete swhowe reassign edtoane ducational inter vent ionwithpatient ,healt hcar eprovid er,andedu cationalsyste mswer ele sslikelytohaveserious
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footlesion san dmorelik ely t ore por tappr opriat eself-care behaviorsth an we repatie ntsassign edto usu alcare .Inaddit ion, h ealth care prov ide rswhoreceivedpr acticegu ide lines, in format ionalflowsh eets onfoot-re latedriskfactor s,an dwhohadr eminde rnoticesplacedonth eirpat ien tschartswer emore like lyt oex amin epatien ts'fe etan dtor eferpatientsforpodiatryappoin tme nts.
Education Decreases Costs of Care

Whileit isge nerallyagreedt hat education canbe amajorfactor in decreasin gcost sof hospitalization,n otu ntilt hisfactcanbepr ove ncon clu sivelyregardin gdiabet icpatie nts willample money bemadeav ailable forth ene edede ducat ion. Thisstat ementby J oslin 'sDr.LeoKrall(63)op ened t hese ctionine arlie redition softh iste xtth at discussedh owe ducat ioncoulddecre aset hecostofdiab etescare.Finally,inth ised ition,th eeviden ceis beginn in gtoaccru ethat,inde ed,Dr.Kr all'swish fordatamaybe comin gtru e.However, the p ath t oth is conclusion hasfollowedadifficultand c onv olute droute, and t heconclusionhasbeen slowtogain acce ptan ceamongmany, part icu larlythoseresp on sibleforpaying t hebills. In addition ,as K rallp ointe d outatthe J oslin symp osiumheldat the2000In tern ation alDiabe tesFeder ation me etings,froma worldwidepe rspective, economicenvironment svary notallofth emresemblin gthatofth eUn it ed States. Yet, spurre dbythe manag ed-car emovement ,cost-effectiven essandth eimpact on qualityoflifeare nowbeingmeasu red, and slowlyt here cogn it ionth atdiabe tesedu cationisareason ableex pense is beginn in gtogainacce ptan ce.Th istr endisseeingacon flu ence ofen dpoint s.Medicalprofe ssionalsare lookingtoimproveparamete rssuch asHbA 1 c valuesorcomplication rat es,assumin gthatthe good stemmin gfromimprovemen tsin the senu mber sisjustificationin an dofitself.However, thepe oplewh o pay thebillsthe manage d-care execu tiv esin it iallyan d,u ltimately, t heconsu me rsofh ealthcare serv ice sviewpar ame terssu chasd ollarsan dcent sand ,in part icu lar,impactonqualityoflifefordollar spen ttoensu reth atth eben efitsreapedbyaninter vent ionsu chased ucat ionwar ran tthe expen se. De monst ratingt hat education isacostworth b earingh asbe enpromulgate dove rthe lastfewdecades. Howe ver, duringth e1990s,en ou ghmomen tumseemedtohavegat here dfor p eoplet ofinallybeginto acce ptth isprinciple.Priort oth at, atradit ionalen dpoin twasar educt ioninhospitalizations,wh ich may notn ecessar ilyreflect t hee ntirepictur ein thisne wmillen niuminwh ich ou tpat ien tmedicin ean d pharmaceu ticalcostsareafocusofthe cost -con scioush ealthcareinsu ran ceexe cutives.Ne verth eless, hospitalizationsar estillcost lyandser veasareason ableyar dstick. P. 600 Toge tase nseofthebattleth ath asbee nwage d,wesh ou ldlookbackto1981, atth edawn ofth eeraof inte nsiveinsulinth erap yher aldedbyth eav ailabilityofSMBGandHbA 1 c measu rement s.Thisquiet rev olutionindiabet esmanageme ntgaveus t hetoolstotargetn ormogly cemiamor erealisticallyand t o mon itorglucosepattern sin anormalsetting with ou tthe need forh ospitalizat ion,y etincreasin gthe importanceofself-care sk ills ifth esene wtoolswe retobeu sedtotheiroptimale fficac y. Atth attime,edu cationaldeficitswereclearlyacau seforin creasedcost sofmedicalin terve ntions.In 1981,Gelle rand Bu tler(64)judged that27%ofthe hos pitaladmission sfordiab etescomp licationsover a1-yearperiodwereth eresu lt ofedu cationaldeficitsan dthatan additional20%were duetoa combinationofedu cational,psych ological, and socioe con omicde ficits.In a1985edition ofth iste xtbook , Krall(63)recoun tedth eclassic,but notscie ntificallycontr olle d,re port of100patient ssurve yedwho were admitt edtothe Joslin Diabe tesCe nte rwith footinfections.On ly 38%oft hese patien tshad rece ive dan ydiabete seducation .Thesamey ear, Scott etal.(65)fromNe wZe alandsu ggeste dthat edu cationlower sadmission rat esamon gpatien tswit hdiabet es.Ofag rou pof902in sulin -usingpatie nts, 79requ ir edhospitaliz ation ,ofwhom11%hadr eceivededu cat ionpre viouslyan d89%h adn ot. Ina1983r eportfromMaine (66), base don itse xperience sasoneofthe fe wstate sthatatt hat time providedsomer eimbur sementfordiabet esedu cation ,38.5%fe werpeoplewereh ospitalizedand28.3% fewer hospitalizations we rene cessar yamon gpatien tswhohad p articipate din ane ducat ionalpr ogram. The e xperien cein RhodeIslan dreporte din 1985by Fishbe in ( 67)alsodemonstratedaredu ctioninth e nu mbe rofadmission safter atte ndanceinan ou tpat ie ntedu cationprogram. Howe ver, these and oth erstu die sthathaveappe are dove rthe year shadse eming lyn otpr ovided convincingproofthateducation doe ssavemon ey. Critic ismsofvariou sst udies,e xemplifie dbyare vie w byKaplanandDavis(68),typifiedthe dilemma.Rev ie wing st udiesuse dbythe ADAtosupportth ir dpar typay men tforou tpat ien tedu cationan dnut ritionalcoun selin g(69),the seau thorsident ifiedvarious defe ctsin study d esig nsuch asdeficienciesinth euseofcon trolgr ou ps,inpat ie ntrandomizat ion, in costaccoun tin g,andinclearlydemonstratingactualsavin gs.The yalsopointedout thatduration of hospitalstayand r ate ofhospitaladmissioncanbeaffe ctedbymultiplefactorsinfluen cin g hospitalizationpractice sthatare unr elatedt odiabe tesedu cationoreven toactualmedicalconditions . The cr uxoftheargumen tatt hat timewase xpresse dsuccinctlybyAn derson(70)inare ply toth e Kaplanan dDavisr eport(68),poin tingoutth atp atient sappeartonee deducation tofollowtheirdaily
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routine ofdiabe tesself-care .Aswit hth eimpact on medicalparameter scite dear lier, askingth atan edu cationalprogramalonere sultsinredu ction in costwithout con side rin gthe oth ervariablesthataffe ct such ou tcomemeasuresisascr ibingmor epowe rtoeducation alin terve ntion thaniswarrante d. Howe ver, duringth e1990swepassedasignificant mile ston e,asthosewhoviewhealt hcar einthe agg regate,rathe rthanonepatient atat ime,be gan t ore cogn iz ethatpat ien tedu cationwasanimportant componen tofthemultifactorialeffor ttoachieve improvements indiabetescontr olan dredu ctionsin complication san dthu sachieve bette rou tcomes. St udiessuch asth eDC CTan dUKPDSprovideden ou gh moment umt oest ablish the econ omicvalue, albeitin direct, ofpat ie ntedu cation.Although the DCC Thad alreadyproven thatin ten sive the rapyr educe smicrov ascular andn eur opathiccomplication s(7,71), the cost-effective nessofin tens ive t her apyitselfwassub seque ntlydemon strated(72).Implicitly,patie nt edu cationisc entr altoe stablishingasu ccessfulinten siv ethe rapypr ogr am,an dthu spatien teducation contribut estoacost-effect ive out come. Concu rren tly,other studiesex amine dthe costsofcare forpatient swith diabete sin t heman aged-care en vir on men t.In ahe althmainte nan ceorgan ization (HMO)inwhich3.6%ofthe patien tshad diabetes, th esepatie ntsaccou nted formor ethanth reet imesth eir allotmentofcosts,or11.9%oftot alhealth care deliverycosts,attribu tableinsignificantparttolong -terman dshort-ter mcomplications(73).Thisstu dy sugg eststh atre ducingth eoccurre nceofcomplicationswouldgen eratesav in gs,accomplished through disease manage me nt,wh ich in clu destoaconsiderable degree ,ofcour se,patiente ducat ion. Other stu die sfu rth erun derscoret hesee con omicb enefitsofimprovin gdiabet escon trolandpre vent in g complication s(74,75,76),aswellasthebe nefitofaddingqu ality timetoape rson 'slife (77). The ADAhasp articipate din thisargu me ntformanyye ars, stronglyadvocat in gpropersup port for pat ie ntedu cation.E venb efor ethe DCC Tr esultsbecame available, theADAstate dthateve rypat ien thas ar igh ttoaccessiblean daffordablepatie nt-e ducat ionse rvic es(78)and h asissue dapolicystatement th atsu ppor tsan dencouragesre imbur seme ntforou tpatie ntedu cat ionan dnu tritioncoun selin gthat meetacceptable stan dardsforper son swith diabete s(69).Again, in 1990, theADAissu edapolicy statement (79)t hat notedth eomissionofou tpatie nted ucat ionas aben efit in man yinsurance and he althcarefinan cin gplansconst itu tesamajorbar riertothe availabilityandaccessibilit yofth ese serv ice sand su pportedadequ ate reimbu rsement andpayme ntforoutpatie ntdiabe tesed ucat ion serv ice st hat mee tacce ptedstandards.Su chlackofcove rage maybethe resu ltofeithe rthe failur eof insur ance compan ie st oinclude cove rage int heirpoliciesor achoicemadebyemploye rsnottoin clu de such cove rage in theinsu ran ceben efitsthe yoffer theiremploye eswhen arr anging in suranceben efits. More recen tly,th eADAstated(80)th atse lf-man agemen teducation isacrit icalpartofthemedicalplan forpeople with diabete s,such thatme dicaltr eat men tofdiabeteswithout systematicself-management edu cationcan beregarded assubst andardan dun ethicalcare.Th eADAsug geststh atsu chedu cation willultimatelyredu cecosts. Throug hou tth ispe riod,e con omicfactor saswellastech nologicadvancesh avee xerte danincr easing influen ceon the settingforan dscope ofdiabe tespatie nted ucat ion.Th eability tope rfor mSMBGh as eliminat edth enee dtoh osp italizeapersonjust t omon it ormultiple glu cose lev elst hrough ou tthe day. Inpatient educationp rogr amsaren owre strictedtopeoplewit hme dicalcond itionsth atcannotbe ade quatelyaddr essedinanou tpatie ntset tin gan dthu sju stifyhospit alization ;thesh or terh ospitalstays nowmandatedlimitthe exten tofmat erialthatcan betaught (81).Thus, diabete seducation must increasinglybedelivered t hrough ou tpat ien tprograms(82). Ironically ,however ,th eevolu tion fr omin patien ttoou tpat ien tedu cationhasbeen negativ elyin flu enced byeconomicfactor saswell. Inpat ie ntedu cationfrequ en tlywasprovide daspartoft heover head serv ice cover edbyth ecostofh ospitalizat ion.Howeve r,becausee ducationisoft eninadequatelycovered byinsu ran cein manystates, thecostofou tpat ien tedu cationis often bor nedirect lyby thepatient . Thu s,becauseinpatiente ducationisrest rict edan dou tpat ie ntedu cationisunaffordable,alleducation maybeu navailable formos tpatien ts. Out patien teducation doe s,however ,havead vant agesover in patient education .Ther eisflexibilityof timingofth esession s,ext ension ofth eedu cationalexpe rienceover we eksormont hs,abilitytoeducate inan ormallifese ttingrathe rthaninan art ificialinpatient environment ,an dtheopportu nityfor followup sessions.The tren dsofre cogn it ionofboth the qualityan dthe importan ceofout patien teducation hopefu llywillcon tinue ,but u ntilallpe oplewithdiabe tescan havesomeaccesstoin surance-su pported outpatiente ducat ion, thefu llpotent ialcannotbemet. Insu mmary ,wear efin ally reach in gthe pointatwhichmost people acceptt hat patien teducation can improvediabetescont rolan ddecre aseth eriskofacute andch roniccomplicat ionsandth usisa significantcomp one ntofan ove rallman agemen tplan. Th esere sults,intu rn, canleadtor educe dcosts an dimprovedqu alit yoflife .Patiente ducationalone doe sn ot accomplishthis,bu tpat ie ntedu cationas par tofacompreh ensiveman age men tprogramdoes.Thu s,th ecost ofedu cationalser vice sandt he supp liesth atmustaccompan ythe m, suchastestst ripsandmete rs,ar eslowlybeingincludedinman y P. 601
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coverageplansnotun ive rsally,but itishappen in g. The followin gwaswritte ninthe lastedition ofth iste xt:Weh ope thatin the next editionofthis tex tbookth erep ort ont hefinancingofd iabetese ducationwillbequ it ediffe rent ! Well,it is!May beit shouldnotbete rme dquited iffere nt, butitisdiffer ente noughandde fin ite ly evolvin genoug hin the righ tdirectiontobemoste ncouragin g!
Malpractice Protection
Sen sitivitytothe pot entialformalpr acticelawsuitsforallegedn egligen cehasbecome partofthe practiceofmedicin e.Th isconcer nalsoexten dstotheactofconv eyinginformation aboutdiabe tes.Le gal pre ceden tsin United St ates lawe xist thatrequ ire healt hcar eprovid erstobesur ethe irpatient sreceive ade quateedu cationan dthatoutlin eth epot ent ialliabilityforeither noteducatingorpoorlyedu cating th eir patien ts(83). Inlightofthe p rogr essdur in gthelast decade sin demonst rat in gthatimprovedcontr olan davoidance of complication scan b eaccomplishedt hrough education ,the risk ofpoten tiallawsu it ss temmingfrom inade quateorimpropere ducat ionisthe ore ticallysignificant .Alt houghe con omicmotiv ation push es he althcareorgan iz ation stor ecognizeth enee dtosu pportpat ie ntedu cation,t hehu manisticapproach of th ehealt hcar eprovidersth atlead stot here comme ndat ionforsuch education (with ,wehope, some crossov ermotivationinth ebest ofallworlds!), both groupsmaybefu rth eren cou rage dbythe pote ntial forliabilit yofnotdoingso. The refor e,itisprude ntforhealt hcar eprofession alstoe nsur ethatth eir patien tsreceivee ducationof properqu alit y.Un le ssaprogramisknowntome etest ablish edstandar ds,programsre cogn ize dbythe ADAoredu catorscer tifiedbyt heNat ionalC ertification Boardfor Diabet esEdu catorsar ethe most reliablesourcesofpropere ducat ion. He althcareprofession alsshoulden cou ragepatient stoatten dsuch programsan ddocumentinth epatie nt'srecordth atth eydidso.
THE DIABETES EDUCATION PROGRAM

Diabetesse lf-man agement education isth eprocessofprov idingpe oplewithdiabe teswithe xperience s th atfavorablyin flu ence t heirun derst anding s,att it udes, andpr acticesre latedtolivingwellwith diabete s (84).Atitsbest ,an education alprog ramemp ower st hosewit hdiabet estoachiev eopt imalselfmanagement ofth eir con dition(85).Asucc essfuleducation alprogramdoe snotoccu rbyac ciden t;itis car efully planne dbythe healt hcar eteamandth enex ecute dbythatte amwith theindividualwith diabet esasaninteg ralpart ofth eteam. Th emostsu ccessfuldiabet esself-manag eme nted ucat ionis individ ualized(37,61, 86, 87),isin tegratedintomedicaltreatme nt, andaddresse spsychosocialan d beh avior alcomponen tsofcare(88,89). The g oalofany e ducationalp rogr amistohelppatie ntswithdiab etesgain the knowled gean dskillsthat en ableth emt ocar efor themselvesandtodeve lopthe attitu desth atwillen ablethe mtomake beh avior alchan ges. An ationaltaskforce repre senting organizat ionsinte reste din d iabetes(ADA, Vete ran sAd ministration, Cen tersforDiseaseContr ol,In dianHealth Service,American Diete tic Association, Amer icanAssociationofDiabe tesEd ucat ors, Diabet esRese arch and Tr ainingCe nter s)has rece ntlyrev ise dtheNationalSt andardsforDiabe tesEdu cation(4)(Table 35.1). Thesest andardsprovide guidelinesforth eformat ofdiabe tesedu cationan daclear out line ofth econ ten tare asth atsh ou ldbe add ressed(4).The ADAprovid esan e ducationr ecog nitionpr ogramt hat evaluatesdiabe tesedu cation accordingt oth eNationalStan dar dsandce rtifie st hoseprogramsth atmeetorex ceedth estandar ds. TABLE 35.1. National Standards for Diabetes Self-Management Education (DSME)
Standard 1.TheDSMEentitywillhavedocumentationofitsorganizationalstructure,missionstatement,and goalsandwillrecognizeandsupportqualityDSMEasanintegralcomponentofdiabetescare. Standard 2.TheDSMEwilldetermineitstargetpopulation,assesseducationalneeds,andidentifytheresources necessarytomeettheself-managementneedsofthetargetpopulation(s). Standard 3.Anestablishedsystem(committee,governingboard,advisorybody)involvingprofessionalstaff andotherstakeholderswillparticipateannuallyinaplanningandreviewprocessthatincludesdataanalysisand outcomemeasurementsandaddressescommunityconcerns. Standard 4.TheDSMEentitywilldesignateacoordinatorwithacademicand/orexperientialpreparationin programmanagementandthecareofindividualswithchronicdiseases.Thecoordinatorwilloverseethe planning,implementation,andevaluationoftheDSMEentity. Standard 5.DSMEwillinvolvetheinteractionoftheindividualswithdiabeteswithamultifacetededucational instructionalteam,whichmayincludeabehaviorist,exercisephysiologist,ophthalmologist,optometrist, pharmacist,physician,podiatrist,registereddietitian,registerednurse,otherhealthcareprofessionals,and
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paraprofessionals.DSMEinstructorsarecollectivelyqualifiedtoteachthecontentareas.Theinstructionalteam mustconsistofatleastaregistereddietitianandaregisterednurse.Instructionalstaffmustbecertifieddiabetes educatorsorhaverecentdidacticandexperientialpreparationineducationanddiabetesmanagement. Standard 6.TheDSMEinstructorswillobtainregularcontinuingeducationintheareasofdiabetes management,behavioralinterventions,teachingandlearningskills,andconsultingskills. Standard 7.Awrittencurriculum,withcriteriaforsuccessfullearningoutcomes,shallbeavailable.Assessed needsoftheindividualwilldeterminewhichcontentareaslistedbelowaredelivered.

Describingthediabetesdiseaseprocessandtreatmentoptions Incorporatingappropriatenutritionalmanagement Incorporatingphysicalactivityintolifestyle Usingmedications(ifapplicable)fortherapeuticeffectiveness Monitoringbloodglucoseandurineketones(whenappropriate),andusingtheresultstoimprovecontrol Preventing,detecting,andtreatingcomplications Preventing(throughrisk-reductionbehavior),detecting,andtreatingchroniccomplications Goalsettingtopromotehealthandproblemsolvingfordailyliving Integratingpsychosocialadjustmenttodailylife Promotingpreconceptioncare,managementduringpregnancy,andgestationaldiabetesmanagement(if applicable)
Standard 8.Anindividualizedassessment,developmentofaneducationalplan,andperiodicreassessment betweenparticipantandinstructor(s)willdirecttheselectionofappropriateeducationalmaterialsand interventions. Standard 9.Thereshallbedocumentingoftheindividual'sassessment,educationalplan,intervention, education,andfollow-upinthepermanentconfidentialeducationrecord.Documentationalsowillprovide evidenceofcollaborationamonginstructionalstaff,providers,andreferralsources. Standard 10.TheDSMEentitywilluseacontinuousqualityimprovementprocesstoevaluatetheeffectiveness oftheeducationexperienceprovidedanddetermineopportunitiesforimprovement. Copyright2000AmericanDiabetesAssociation.FromMensingC,BoucherJ,CypressM,etal.National standardsfordiabetesself-management.Diabetes Care2000;23:682689.Reprintedwithpermissionfromthe AmericanDiabetesAssociation.
The Educators
Int heye arsaft erth ediscove ryofinsu lin, Dr. Joslin wasamongth efir sttorecognizeth atth e resp on sibilityofpat ie ntcar elaymainlywith the patien tsthe mselves. Thepatient ishisownnu rse, doctor'sassistantandch emist, hewroteint hefirstcompr ehen siv eguidetoself-care ,A Diabet ic Manu al for t he Mut ual Use of Doctor an d Patie nt, in 1924(90), shortlyafter thediscoveryofinsulin. Rec ogn izingt hen eedforpatien tedu cation ,Joslinsh owe dhisnurse showtogiveinsu lin, calculate the diet,andbalanceinsu linr equiremen tswith thatdiet.Th esen ursest hen v isitedpatient sin theirhomes th rou ghoutNewE nglan d,somet imesstayin gwit hfamiliesfor weeks,t ote achpatient sandfamiliest o planmen us,pr epar efood,andadministerse veralinjectionsdaily. The r oleofthe teach in gnu rseh assinceev olvedandexp ande dand n owinclude soth erh ealth care providerswithspe cialdiabe tes-re latedskills. Diabet esedu cators,asthey aren owcalled, includ enu rses, nu trition ists, socialworkers, exerciseph ysiologists, psychologists,ph armacists,andph ysic ians.The ir expe rtiseindiabet escare and e ducationmay q ualifythemtotak eane xamin ationtobecome C ertified DiabetesE ducator s(CDE s)or Boar d-Cer tifiedAdvancedDiabet esManagers(BC-ADM) . The sediabete seducatorsformth ebasisoft hete amapproach tod iabetese ducat ion(91). Working togeth erinbothinpatientandoutp atient settings, each member ofth eteamprovidesth epat ie ntwith specializedexp ertser vice s.Fore xample ,nu rsesh elppatient smasterth eskillsne cessar ytoinject insulinan dmonitorbloodglucosele velsandadapt these skillstot heirlifest yle ,nu trition istsworkwith pat ie ntstodeve loprealisticme alplans,andpsych ologist sandsocialwork ersfocu son coping mechanisms. Th epersonwith diabetesandke yfamilymembe rsare nowrecognizedasimpor tan tplayers inth eteamwhomustbeinv olvedinth eedu cationalprogram(92,93,94). Thismultiface tedte ame ffort , whichinclude sthepatient andt heph ysician ,providesth emostcomplet eapproachtodiabete se ducation an dcare (12,20,22,39, 50).
The Setting for Education

Edu cationfordiabete scaremay b eprovide din avarie tyofs ettings, suchasclinics,h ospitals,e ducation
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cen ters, aphy sician 'soffice, ort hepatient'shome (95) .Theprogramcanbeformalize dand presen tedin aclassr oomse ttingorprovid edin aone-t o-onefashion .Itmaybe presen tedinacarefu llyplan ned edu cationalsession or mayarisespontaneouslyfromr espon sestoque stionsaskeddu ringarout in e officevisit(96). Ine ducat ionalse ssions, t hesizeofthe grou psmayvar yan dtheformsofinte ractionuse dmayin clu de, but notbelimit edto,discussion ,lectu re,andinte ractivelearningactivities(97, 98,99).Inn ov ative edu cationaltech nique s,such asprogramsincorpor ating compu ters, theIn tern et, andoth erau diovisualmedia,canen hanceth eedu cationalprogram (99,100,101, 102). Availabilityofstaff, then eedsofpat ien ts,t hesub je ctmatter ,an deconomicfactorsoftendictateth e choiceofse tting.Forexample,ge neralinformationabout thev ariou skin dsofinsu linandth eir resp ectiveact ivitypatte rnsmigh tbepre sent edin agroup se tting. Howeve r,th eteachingofspecific skillssuch asdrawin gin sulin in tot hesyr in geisbestcar rie dou ton an in dividualb asisorinsmallg rou ps th atarenolarger thansixpeople .Thissmallsiz eprovid esthe health care profe ssionalwith t he oppor tun ity t oh elp each patient in div idu allylearnth etech nique snecessaryforcarr yin gou tth ese esse ntialactivities.Similarly,gen eralinformation aboutmonitor in gglu cose lev elsmightbe p resen tedin agr ou psetting, butt heac tuallear ningoft heskillsh ou ldtakeplace in asett in gin whicheve rypat ien t can bene fit fr omthe ind ividualatte ntion ofth ehe althcareprofession al.Howe ver, wemu stalsok eepin min dthatreimbu rsemen tguidelin esoft endictateth edetailsofsuche ducat ionsessionsan dthe ir stru ctur e. Inaddition, aswithmany oth ersch oolsettings, the e ducationale xperien ceisn ot limited t oformalize d instru ction alsession s;much ofdiabe tesed ucat ionoccursth rought heinte ract ionsamongpatie ntsth at takeplaceindiabe testr eatmen tun itsandcamp-ty pesett in gs(103,104).Informationan dun derstanding gaine dthr ou ghth esharin gofpe rson alexpe rie ncescanhe lppatientsimprov ebot hself-managementand copin gskillsin waysn otpossible with moreformalize din struct ion. Anex ample ofsuch aprogramisthe Diabet esOutp atient Inten siv eTreatme nt(DOIT) p rogr amatJoslin DiabetesC ente r(Table35.2).Thisbeh avior modificat ionprogramh asevolvedfromt hehistoricDiabe tes TreatmentU nit,anin pat ien tprogramorig in allyint ende dfordiabe tesedu cationan dtre atment .Becau se ofcu rre ntre imburse men tforthisedu cation ,th eDOITprogrampe rmitsth esamemedicalmanage me nt, withaccompan yin geducation and g rou pcoh esivene ssbutonanoutpatie ntbasis. Du rin gthis3. 5-day program,patient saree valuatedbyaphysician, nurse ,dietitian, exer ciseph ysiolog ist, and men talhe alth profession al.Aftert heinitialassessmen t,th eremaining3daysconsistofmed icalcarean dedu cation . Freetimeisalsoav ailable forsocialin teractionamongpatient s.Follow-upsh ort lyaftercomplet ionof th eprogramis r ecommende d,bothviat ele phoneandofficev isits,t oen sure thatpatien tsare ableto app lywh atth eyhavelearneddu ringth eprogramtothe ire verydaylive s. TABLE 35.2. Schedule for 3-Day Program of the Diabetes Outpatient Intensive Treatment (DO-IT) Program of the Joslin Clinic P. 602
Activity Lab
Times 7:30 8:00a.m. 8:00 9:15a.m. X
Tuesday X
Wednesday X
Thursday
Breakfastandselfinstructionalcomputer modules
Check-in Choosefrom breakfastbuffet Computertime DiabetesKnow-how
Check-in Choosefrom breakfastbuffet Computertime Exercise:Moving TowardBetter Control RespondingtoHigh BloodGlucose Levels
Check-in Choosefrom breakfastbuffet Computertime BloodGlucose Interpretation
Class1
9:15 10:00 a.m. 10:00 10:45 a.m. 10:45 11:00 a.m. 11:00 12:00
Class2
FoodforThought
UnderstandingFats
Break
Class3
UnderstandingYour DiabetesMedications
HealthyFood Choices
StayingonTop: InvestinginYour
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p.m. Lab 12:00 12:15 p.m. 12:15 1:00p.m. 1:00 2:00p.m. X X
Health X
Lunch
Choosefromlunch buffet Exerciseclass
Choosefromlunch buffet Exercise Class/familysupport group SkillsTraining(as needed) Check-outwithcase manager
Choosefromlunch buffet BringingItall Together
Class4
2:00 2:45p.m.
SkillsTraining(as needed) Check-outwithcase manager
Finalcheck-outwith casemanager
Since1992,th eJoslin'sDOITprogramhasbeen are cogn ize deducation prog ramasper ADAstan dard s. One crit erion nece ssarytoach ie veth isre cogn it ionistoprov ethe effectiven essoft heprogramasit relat esbothtoclin icalaspectsofdiabete scareandtothe qualityoflifeoft hese personswithdiabe tes. The seou tcomesdatah ave shown an aver agede crease in HbA 1 c ofle velsof1.5%overa3-to6-mon th per iodfollowingth epar ticipationint heDOITpr ogr am.Atten deeswh oseHbA 1 c levelswere greaterth an 10%we resh ownt ore duceth elevelbyanave rage of2.5%dur in gthesame timepe riod.In aclin ical sur veycondu ctedaft erth eprogram,participantsofthe programreporte da38%improvementinth eir per ception ofth eirdiabete s-relate dproble ms.In addition ,programevalu at ionhasshownade creasein emerge ncydep artmen tvisits, hospit alization s,an dlosttime fromwor kor sch oolforpatients aftert heir par ticipationint heDOITp rogr am. P. 603
Who Should Be Educated

The Nation alSt andardsforDiabe tesEd ucat ionre cogn ize sthatdiabete seducation isanintegr al componen tofdiabetescare(4),an dthe ADArecommen dseducation forallpeoplewit hdiabet esatt he time ofdiagn osisan datre gularint ervalsth roughout theirlife time(5).These stan dardsr ecog nizeth e rightofeachpersont ou nderst and then atu reofhisorh ercondition ,tobegiventh etoolstomanage an dcon trolt hecondition ,an dtohave thisin for mationu pdate droutinely. U nfortun at ely ,wear efarsh ort oft hat goal. Howeve r,inasu rvey of2,318pe rson swith diabete s,59%ofth osewith type1diabetes , 49%ofth osewith in sulin -treatedty pe2diabe tes,and24%ofth ose with type2diabet esnottre ated withinsulinhadat tende daclassorprogramabout diabetes atsomet imedur in gthe c our seoft heir illne ss(8).The challenge fort hete amistogainaccesstothe patien tatre gularint ervalsandtome et th enee dsofeachpatientt hrough assessment ,implement ation ,an devalu ation .
Patient Assessment
Assessment ofth epat ien t's andfamily 'sreadinesstolearn ist hefirstste pin thee ducat ionalpr ocess (37,105).Concu rren tillnesse s,ne wdiagnosisofdiabete s,or psychosocialproblems may affecta pat ie nt'swillingn essorability tolearn.Apatientwh oh asjustre ceivedadiag nosisofpan creat ic car cin omamayn otbe readytod iscu ssin sulin admin istr ation .Similarly,apatient recoveringfrom sur gerymaybe moreinte reste din start in gon solidfoodthanlearn in gself-monitorin gtech niques. The key t oassessmentiscommunicat ionwitht hepatie nt. Ife ducationst artswh ent hepatie ntisemotionally an dexpe rie ntiallyread y,th ereisabet terch anc eofen gagingh imorher int heen tireedu cational process(106). The e motion alresponset odiabe tescan havean impact on t hepatient'sability toh ear andabsor b information .De nialmay bethe patien t'sfirstre actiontothediagnosisofdiabete sandcanimpair hisor he rabilityt olear n(107). Theh ealthcarepr ovidercanassistt hepatie ntby r ecognizin gthisresp on seas den ial, ackn owledgingth atitmaybe astag ein the longprocessofadaptingtoach ron icilln ess,an d supp ort in gthepatient 'sefforttocop ewit hthe dise ase. Involve me ntinsup port grou psan din div idu al th erap ymayhelpth epatien tmovefr omdenialtosuccessfu ladapt ation . Assessment ofkn owledge, skills,an datt itu desabou tdiabete sisanongoin gprocessthatstartswithth e initialch art reviewan din terv iew. Manypatientsdonotre callmedicaladviceandsomer eportne ver havingrece ive dspecificse lf-carerecommen dat ions(108, 109,110).Assessmen tofth eper son 's kn owledgeofhisor h eractualtr eat men tprescr ipt ionisasimportantforth osewith diabetesoflon g dur ationasforthosewithn ewlydiagnoseddiabe tes.U seofacon versation alstyle,rathe rthana que stion -and-answer session ,helpstoestablishr apportandtogiv ethe health care profe ssionalsome ideaofthe patien t'slife style(111). Th ehe althcareprofession alshouldle arn tolistent oth epat ie nt,t o besympathet icandun derst anding, and toacceptth att hepatient'sprioritiesmayn otbe the same as
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th oseofthe healt hcar eteam. It isimp ort ant t ore me mber thatdiabete sisanintru sionintodailylife, th atmost p eop lewillstillh avesignificant gapsinth eirknowle dgeabout diabete se ven afterh avingt he condition for20years,andth atitisultimat elythe p atient whomak esthe fin ald ecisionsab ou thowhe orshewillap proachth edisease (94,112). Recognizingan daccep tin gthe serealitieswillallowth e he althcareprofession altosetreason able, achievable ,an dmu tuallyacce ptab legoals.Th ein it ial asse ssme ntshouldbeclearlydocu me ntedint hech artandu pdate don aregu larbasis(4,113, 114,115). Becauseth ebackgroundsofthe teammemb ersmaybeve rydifferen t,many differ entassessment stake place. Ar egistere ddie tit ian,forexample, mayassesst hecu rren teat in ghabitsofsomeonen ewly diagn osed with diabete sandpr ovideth atpe rsonwit hamealplan ascloset oth isaspossible.An exe rcis ephysiologis tmayteachape rson wit hdiabet eshowtocorre ctlyadjusth isorhe rin sulindoseto pre vent h ypogly cemiadu ringexe rcise.Anu rseedu catormayassessapatient'sskillsan dgene ral diabet esknowledgeandprovidehimorh erwithth ene cessary in formation.In someinstitut ions, CDE s ar eseen asjustt hat :d iabetese ducator s. P. 604 Usingt hisrationale, anyC DE canmeet thediab etesed ucat ionn eedsofapat ie nttoacer tainex tent .For example, ifap atient need stolearnhowtoself-admin iste rinsulinan dnonur seeducatoris availableto dothis,asaCDE,aregistere ddie titianorexe rcise physiologist cou ldte acht hisskill.Then ,at alater dat e,th epatie ntmayfollowu pwit han urse educator tor eviewtech niqueaswellasacquireoth er ne cessar yin format ionre latedtoin sulin.Patien tsstar tin gexer cise p rogr amscanr eviewgene ralin sulin orfoodadjus tme ntwithanurs eeducatoran dthen sched uletoseean exer cise p hysiologistformore det ailed adjustmen ts. Atth eJoslinClinicin Boston, educatorsuseateamap proachtopat ie ntasse ssme ntandedu cation.A n ewpatien ttothe clinicwills eean educatorsolelyforane ducationalassessment ( i.e .,todet ermin e th epat ien t'scu rren tlevelofdiab eteskn owledge andsk illsandtosche duleappointment swith appropriatee ducator sbasedonth isassessment ).Thisserve stwopu rposes:Iten ablesth epatien tto recogn ize d iabetese ducator sasapartofhisorh erhe althcarete amandallowsaneffe ctiv ean defficien t wayt ore cogn ize and addre ssthen eedsofthe patien t.Thep rimary goalistoide ntifyan dfocu son t he edu cationalne edsoft hepatie nt. The assessment proce ssprovide sanopportu nityfor thepatientandfamily toe xpressth eirhealt hcar e beliefsan dtheiragendafort hat visitandtoexpre sspart icu larnee dsorg oals(116).Theinformation gaine dnotonlyprov ide stheh ealth care t eamwit hdat aab out education alneed sbutalsoguidesth e teaminman agemen tissu es.Th eteamh asth eopp ort unitytoan swerqu estion s,providepositive feed back, ande ncourageproperself-car ebeh avior s. Inadditiont oass essin gthe patien t'sre adinesst olear n(37)an dstage ofadaptation t odiabe tes(117), th ehealt hcar eprofession almu stobt aininfor mationont hepatie nt'seth nicorcu lt uralbackground, occupation, socioe con omicst atu s,support sy stems,personalityt ype,andh ealthbe liefsbe forelookingat th epat ien t'sk nowledg eofdiabe tes(118) .Othe rfactorsth atmayh ave animpactonlearn in ginclude age ,gen der, literacylevel,andlevelofe ducat ion(119).Thisin format ionisin valuable in gettingasense oft hepatientandth eap proachtoedu cation an dtreatme ntt hat wouldbemost helpfulan dreason able forthatpat ien t. Anev aluat ionoffunct ionalabilityhe lpsth ehe althcareproviderplan howtote ach s killssu chasSMBG an din sulin admin ist rat ion(120) .Thepatient'sdext eritymaybeaffectedby arth ritisorne uropat hy. Visionchange sduetoret in opathymay beeviden tatarelativelyyoun gage. Somepat ien tshavea difficu ltt imeadmittingtothe ir visiondeficit ,soitisimportan ttoassess t hepatient'sskillin the se ar easatthe in itialvisit andagainatregu larinter vals.Re lativ esor closefriends sh ou ld d efin it ely be includedint hispartofthe assessmen tprocesstodeter minewh eth erth eyar ewillin gandable toassume somer esponsibilityfor c areofthe patien t. Rep ort ededu cation alle velappe arstobeap oorpred ictorofread in gability, becau seape rson 'sactual readinglevelmaybesignificantlylowe r.Neve rthe les s,it maybehe lpfu ltoaskaboutedu cational expe rience(121).Int hiscon text, aqu estion con cerningh owt heper son learnsbe stwillprovide some guidelinesfordecidingwhe ther tou seau dio,video,orwritten materialsoraone-on-one orclassr oom sett in g.Re centr esear chsug geststh ath ealthliteracy,th eabilit ytou nder stan din stru ctionandh ealth information ,mayimpacthowwe llindivid ualsmanageth eir diabetes (122).
What Is Taught
The e ducationalplanisd evelope dbyth eteam addre ssin geducation alnee dsandt reat men tgoals ident ifiedbybotht hepatientandth eteam. Education beginswithsu rvivalknowledge(i.e. ,th e information absolu telynece ssaryforap ersonwit hdiabet estohav etofunct ionindepe nden tlyan dsafely at home). Forsome, thismaybeassimple asident ifyingwh entocallthe h ealth care prov ide r.For other s,SMBGan duse ofinsulinan dglu cagonmaybe survivalskills.E veryone with diabete smu stalso havesome gener alknowle dgeabout diabete stou nder stan dwhen itisne cessary tocallthe healt hcar e providerforhelp. The e ducationalassessment sdon ebyvariousdiabe tesed ucat orspr ovideth ebasisforthe
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individ ualizationoft each in g.Hav in gdeter minedt hepatient'sknowle dgeabou tdiabete s,psych osocial history,attitud esaboutdiabetes, ande atingandex ercisehabit s,the educatorcan then formulat ean edu cationalplant hat reflectsth epat ien t'ssp ecificne eds. Asou tlin edbyth eNationalStan dar dsforDiabete sSe lf-Man age men tEdu cation(Table35.1)(4), the act ualconten toft hediabe tesed ucat ionprogramisbase don assessed n eedsofth ein div idu alor individ uals.Diabete seducation p rogr amsdon otn eedtobest ructu redinth emodelofame dicalor nu rsingcourseondiab etes(89)bu tin steadshouldbestru ctur edinawaythatprovid esmaximalben efits forpatien tsin termsofh ealth ou tcomes. Manyedu cationprogramsbeg in with areasid entifiedbyth e pat ie ntasp riorities.Addre ssin gthe patien t'spre ssin gissu esth enallowst hepatie nttobemor e at tent ive tot heissue st hepr oviderh asident ifiedasimpor tan t(89). The Nation alSt andardsre comme ndth atth ecur ricu lu minclude ane xplanationofdiabet esdise ase processandtre atment optionstohelpindividualsmakeinformedtre atment choice sandfacilitate selfdirecte dbehavior. Anexplan ationoft reat me ntmodalities,including t heu seofinsu lin, in sulin delive ry syste ms, oralantidiabet esme dication s,the mealp lan,andexe rcise ,ar eimportantasp ectsoft he cur ricu lu m. Other keycompone ntsofawell-r ou ndede ducationalpr ogramaremeth odsforincorpor ating nu trition almanage me ntan dphysicalactiv ity int oone'slifest yle .Thegoalsofmonitor in g;the t ypes, descr iptions,andlimitationsofmonitor in gdevices;an dinstru ction int heu sean din terpr etat ionofSMBG resu lt sare als one cessar ypart sofinitialandongoingedu cation. Patient salson eedinformation aboutth erecognition,tr eatmen t,andprev entionofacut ecomplication s such ashy perglycemia,h ypoglycemia,andke toacid osisan dthepr even tionofchroniccomplication s th rou ghrisk-re ductionbeh avior s(footin spectionan dcare ).Thee ffectsofilln essondiabet esan dsickday rulesar eacriticalpar tofanydiabe tesedu cation.Guidelin esformonitorin gbloodglucosean durine ket on es,formodifyin gfoodintake,andwhe ntocallt heh ealthcarete amaree ssent ialskillsforthe pat ie nt.E quallyimportantcompone ntsofcare in clu dehe lpingpatientsse trealistic,achievablegoalsfor th eir diabete scareanddiscussionoft hepsych osocialadjustmen ttodiabetes .Finally, p atient smaynee d specialtye ducat iondu ringspecific t imessuch aspre con ceptionor pregn ancy ,the on setofcomplicat ions, orthe in itiat ionofnewtr eatmen ts. The se ction onp reven tion ,treatment ,an drehabilitat ionofchroniccomplication sshouldin clu de strategiesforcopin gwith the physicalchangesandlosse sthatcomplications may brin g.Itisext remely importanttostre sstheb enefitsth atbloodglucosecontr olcan have forboth thesh or t-and long-te rm. Focu sin gon thepr even tion ofcomplication sthroug hriskredu ction isav italpartofthissection.A discussion ofpe rson aladaptat iontolifewithachronicdiseaseandth eimpactofdiabetesonth efamily willalsoh elppatien tsun derstandsome ofth eir feelin gs. Careofthesk in ,tee th,andfee tisp artofthe hygiene segmentofadiabe tesedu cationprogram.Se lfcar eme asur esthathe lppr even tcomplication s,addr essthe nee dforre gularch ecku ps,an dou tline the effect sofsmoking, alcoh ol,anddru guseareaddressed int hissection .Theclass ont hebe nefitsan d P. 605 resp on sibilitiesofcare e xplore sthepatient -profe ssionalpartn ershipinplan ningcar ean dhelpsthe pat ie ntdev elopsh ort -andlong-ter mgoals.E xplorationofthe useofhealt hcar esystemsan dcommunity resour cescan helpth epatien tfin dsupportandser vice sin thecommun it y.
Educational Methods
Diabetese ducat ionh asben efitedfrompr in ciplesofadultlearning(54)an din stru ction ald esig n(123). The u seofbasiceducation alprin cip lesasguidescanincreaseth esucce ssofadiab etesed ucat ion program,r egar dless ofitssetting .Howe ver,cont in uedev aluat ionofthe applicabilityan dusefu ln essof principlesborrowe dfromedu cationalth eor yisimp ort ant forth econtinu edimprovement ofedu cat ional programsindiabet es(119). Forexample, theactiveinvolv eme ntofthepatient in allaspectsofthe edu cationalen deavor, in clu din gdecisionsabou tthe treatmentpr ogram, isone su chprincipleth atisnot un iv ersallyrecognizedasbeingimportantforsucce ssfuldiabete se ducation. Un fort unately,man ydiabete seducation prog ramsfrequ entlyfostertoopassivear oleforthe patien t (124). Manyed ucat orsh ave s uggest edthatwhe npat ien tsparticipateindecision saboutth eircar e(86), improvemen tsare seen in measure sofbothclin icalcond itionan datt itu desabou thealt h-relatedquality oflife.In acon trolledst udy, Gre enfieldan dassociates(125) metwith patient sbeforeasch eduledoffice visit with the irph ysicianstoreviewpastme dicalconce rnsan dtofocu sandimprov epatien ts' information -seekingskills. Pat ie ntsre hearsedne got iationsk ills, addr essin gob stacles,su chasfe elin gsof embar rassment orintimidation ,thatstood int hewayofth eirgaininginformation fromth ephysician. Patient ssocoach edweret wiceaseffectiveasthoseinth econtrolg rou pate licit in gin format ionfromt he phy sician .Improv eme ntsinlevelsofHbA 1 we resignificantlygre ater in these in dividu als,aswer e red uction sin factorssuch asdayslostfromworkasaresu lt ofillne ss. Oth ersalsohav eemphasized ther elation shipbetwee ntre atment adh eren cean dthe waysinwhichth e phy sician andt hepatientr each treatme ntde cision s(126, 127,128,129). Comment in gon someoft hese stu die s,Simsan dSims(130)concluded thatpatien tswilladhe retothe ir t reatme ntplan smore consisten tlyifth eyfeelase nseofown ershipoftheplan s.Today, e mph asisisplace don the influe nceof
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pat ie ntpriorit ie sont hat person'sabilitytomanageth eself-care t asksre quiredforth eir diabetes tre atment .Eachindividual's p rioritiesan dlifeissuesmustbe con side redwhe nth ediabet esteam, includingth epat ie nt,se tsgoalsandt arget s(112,131).The s elf-caregoalsthatar esetsh ou ldbe concret e,re alist ic,andmeasu rab le(132,133). Astud yofadolescen ts(134)inasummer -schoolprogramfor you ngpeoplewit hdiabet esdemon strated an ot herimport ant principle: E ducation andlearningaremore effectivewhe npeoplehavean opp ort unity toactivelyaddressth eque stion sandpr oblemsthatactu ally affectt hem.One grou pofparticipant swas randomlyassigne dtoasoc iallear ninginter vent ionapproacht oident ifysitu ation sin whichsocial pre ssuresmade itdifficultfor t hemtomain tainth eirtreatmentr egimen ,an dthe yreh earse dappr opriat e resp on sestothese situ ations.Th esecondgroupofadolescent sund erwen tamore didactic,fact -orien ted diabet esedu cation program.Sub seque ntHbA 1 valu esweresign ifican tlyloweramongth eadole scent sin th esocialskillsinte rvent iongr oup .Variablessignificant lycorre latedwithgoodmet aboliccon trol includedse lf-re por tedad here ncewithadiabete sregime nan datt itu destoward se lf-care. Ofcou rse, prov idingcomplet edidacticinfor mationt hat ispe rson ally conn ecte disalsoimportan tan dis associate dwith higher patien tsatisfact ion.L eyetal. (135)providedpat ie ntswithaddit ionalph ysician visit sthatwerede sign edtoasse sspreviou spatien tedu cation an dunde rstandingan dtoclarify areasof misu nders tan din g.These patien tsshowedsignificantlymore satisfactionwithth eircare thandidthe controlgrou p.In areviewofthissubject ,Tabak(136)concur redth atpatients 'sat isfactionisclearly relat edtothe amoun tofin formationav ailable thatcon tribute stot heirun derst andingofth eir con dition an dthatth eycan useincarin gfor themselves. Itisalsoimportantth att heprovisionandacquisitionof information sp anareason abletime p eriodifpatien tsare tor eme mbe ran duseit.For example,astudy ofadietedu cationprogramgivenover eit her3daysor11week sshowedthatth elonge rprogramwas associate dwith sign ifican tlygreaterimp rove me ntsindietarybeh avior s(137).Th enee dtop acebotht he provisionanduse ofinformation hasbe ende monstr ated b yoth ersaswell(109). Rein force men tan drepet it ionar ealsoimpor tan tcomponen tsofanedu cationalprogram(108). Often, th isisaccomplishedt hrough thepr epar ation ofwritte nmater ialsforpat ie nts.U nfortun ate ly, the reis frequ ent lyamismatch betwee napatient'sreadin gskillsan dtheleve lofcompreh ensionreq uiredto un derst andt hemate rials(138,139). Inone study(140),only28%ofthe patient shad r eading sk ills atoraboveth enint h-gradelevel:59% readat t hefifth-t oeight h-gradelevelan d13%h adreadingskillsbelowt hefifth-gr adeleve l. By contrast,anevalu ationofthee ducat ionalmate rialsusedwitht hesepatient sshowe dthat87%we re written att hen in th-gradelevelorabove,13%at thefifth-t oeigh th-gradelevel,andnone belowth e fifth-gradelevel.Th ismean sthat87%ofthe materialswere compreh ensibletoon ly28%ofth e pat ie nts, 13%were unde rstoodby 87%,andn on ewerer eadable by13%! Formulash ave b eend evelope dtodeter minet here adinglevelofe ducationalmat erials (141, 142,143,144,145). Ty pically,re commendationsforre adab ilit ysugge stthatedu cation almaterialsbe gearedtowar dthesixth -grad ereadin gle vel.Howe ver, mat erialsshouldbeselecte dbase don asse ssme ntsofther eadingleve lsofthe targe tedpopulat ions. He lpfu lstr ate gie sareavailablefor deve lopinghe althe ducat ionmate rialsforlow-literacygroups(146). Mostword-processingpr ograms havere adab ilit ystat isticsfun ction ssuchasthe Flesch-K in caidgrade le velthatwilld eterminere ading level.E ducat ionmate rialssh ou ld als obeavailablein the primar ylangu ageofthe targ etedpopulat ion. The Nation alI nstitut eofDiabete sandDig estivean dKidney Disease softh eNation alInstitu tesofHealth maintain sanu p-to-date Websit e(ht tp://www.niddkk. nih.g ov/h ealth /diabete s/diabete s.htm)th at providesdiabet eshealthinformation ,aswellasrev iewsofdiabet esin format ionpu blicat ions, in e asy-t oreadfor mats.The sereviewsareav ailable in b oth Eng lishandSpan ish .Joslin'sWebsite (ht tp://www.joslin.org)isan oth ersource ofuse fuldiabete sinformation. Fin ally, asucce ssfuleducation prog ramprovide spatien tswit han opportu nitytoexplorethe ir attitu des towardt hemate rialb ein gtau ghtandtoun derst anditsimplicationsfor day-to-dayliving.Fact orssu ch ast hepatie nt'sfamilial,social,andcu ltu ralen vir on men ts;socioeconomicstat us;other healt hproble ms; an dov erallpsychologicalan demotion alwell-be in gprovide framesofr efere ncefromwh ich patien ts app roachdiabe tescar ean dthe irparticip ation in it(149).The goalsfordiabet esedu cation developedby th eADAack nowledg ethe impor tan ceoft hesefactors(92).Ande rson etal.(147)sugge stamean sof adaptinganedu cationalprogramtothe patien t'sframe ofrefe rence through activitiesth atstimu latean explorat ionofthemeaningofd iabetest oth epat ie ntan doft hepsych ologicaladapt ation srequ ire dfor th epat ien ttocope with hisorh erconcep tofth edisease . Clearly ,the impleme ntationofthe education alprinciples d iscu ssedaboveismoste ffe ctivewhen the he althcareprofession alhasreceivedt raininginte achingsk ills(124,148,149, 150,151,152). Un fort unately,man yhealt hprofession alsin volved in d iabetese ducationarenotadequatelytrain edin th eseskills.Su chtrain in gisst ron glyencouraged.
P. 606
When Education Should Take Place

Edu cationfordiabete scareisan on going, life-lon gun dertaking.However ,the rear eid entifiablestages
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inth eprogression ofdiabe teswhe nedu cationalinter action sare part icu larly recommende d.The ADA ident ifieddiabet esedu cationgoalsforindividualsandth eir familie satdiagn osisan dthr ou ghoutth eir life(92, 96).
DIAGNOSIS STAGE
Uponr eceivin gadiagn osisofd iabetes, manypeoplear eov erwhe lmedbothbyt hecondition it selfandby th eide aofallth einformation t heyt hinkth eymustabsorb .Ther efor e,peoplewit hne wlydiagn ose d diabet esshouldstartbylear ningth eminimumbasicskillsrequire dforsu rvival.The yshouldle arnt o maintain reasonablysatisfactoryman agemen toft heirdiabet eswhile carry in gou tessen tiald aily act ivities.Th eyshouldbecomefamiliarwithth emedicalnutr it ionalprinciplesth atth eywillbefollowing an dbeablet och oosefoodsinth ecorrectamoun tstofollowthe ir mealplan .Patient sshouldbetaught SMBG,andsome nee dtolearnhowtoin je ctinsulin.Thisinitiale ducationpr ovidedatoraroun dthe t ime ofd iagnosiscanoccuroverse veraldays,particularlyift hepe rson ish ospitalized, orinsmallinc rements oversev eralday sorwe eksfor thosewhoare ou tpat ien ts.
ONGOING STAGE
Once patien tshavemaster edthe essen tial survivalskillsofdiabete smanage me nt,t heysh ou ld progresst oamorein-dept hprogramofon goingdiabe tesed ucat iontohelpth emb ecomeev enmor e sufficientatself-care andt here fore atpre ven tin gcomplication s.Thech alle ngeforpat ie ntsinth isstage istolearnandfollowacomple xan ddemanding r egimen when the b enefitofpreve ntingcomplicationsis distan t(117). Keyissuesconce rnadaptingdiab etesse lf-management towork, s chool,social, andfamily sett in gswhile copingwithmoretypicallifeissue sandcr ise s.Self-manage men tedu cationprogramsar e av ailable in man yedu cationcent ers,clinics,hospitals,andcommun ity p ublic-h ealth p rogr ams.These programs,su chast heDOITprog ramatth eJoslinC linicdescribede arlie r,n otonlyprovideinfor mation, kn owledge, andsk illsb utalsosupportpatie nte ffortst oincorporate self-caret asksintoeve ryday life (Table35.2). Pe riodicedu cation alupdatesareext remely impor tan tafte rpatien tscomplete t heinitialin -depth train in g toenablethe mtome etchangingn eedsatdiffe ren ttimesofthe irlives.People canlearnn ewwaysof managin gdiabet es,dev elopskillsth aten ableth emtoadapt t heirmanagement prog ramtoch an gin g ne eds,andfamiliarizet hemselveswithn ewresource sandadvan cesavailable fordiab etescare.
ONSET OF COMPLICATIONS AND OTHER MAJOR POINTS OF CHANGE

Timesofmajorlife andh ealth chan gescansig nalth enee dforr evisionsindiabe tesmanagement and oftenmake supplement aryed ucat ionalex posu rene cessar y.Throug hou tth ecou rseofapre gnan cy,for example, nut rit ionaln eedswillchangeandinsu lintr eatmen tprogramsmaybecome moreinte nsifie d,an d pre gnan twomen mu stle arn tomake thes echangesproper ly. Anothe rmilestoneatwhichsu pple men tar yeducation isn ecessaryisatth eappe aranceofear ly symptomsorsignsofamajorcomplication.Thisistypically atimewh enpatient su nde rgoe normous an xietyandfearand ofte nseek d iabetese ducationtohe lpimprov ethe irglycemiccon trol(117).Because improved c ont rolcan slowth eprogression ofmajorcomplications(7),diabe tesedu cationprogramsfocus onhe lpingindividualsmake lifestylech ange stoint egratemore successfu lself-management practices. Fore xample ,pat ie ntscanle arn tomak echangesinth eirroutinet hat ,ifinst itu tede arlyen ou gh,may slowdownth eprogressionofkidn eydysfun ction .Howe ver, even formot ivatedpatients, lifesty le change sc anbe difficultan dfrustr ating.
MAXIMIZING THE EFFICACY OF EDUCATION

Aspoin tedoutpre viously, k nowled gedoe snotequ aladhe ren cetot hese lf-carerecommen dat ionsofthe tre atment plan.Nonadher enceisnotun iq uetodiabet esnorisitanewproblem.Infact,th erearelow ratesofadhe renc ewith recommen dedtre atmen tin avarie tyofch roniccon ditions.Olderst udiesshow th atonly50%ofpat ien tsar ecompliantwithlong-te rmmedicationan dthatonly25%arecompliant whe nthe con dit ionisasymptomatic(153).In studiesspecificfordiab etes, 80%ofthosestu die d administere din sulin in anu nacc eptab leman ner ,58%gaveth ewrongdose,and75%did n ot follow dietaryrecommen dations(83).Oth erre cent st udiesreflect similar r esults(154,155, 156). Difficultywithfollowingt heth erapeut icre comme ndationspr esent sasubs tan tialobstacle toth e ach ie vement ofme dicalt reatme ntgoals,diminishe sthepote ntialbene fit softh etreatmentr egimen ,an d makese valuationoftreatment e fficacyin accu rate (157).Th ereisnocommonpr ofile ofan on adh eren t pat ie nt.Age ,sex, education ,in come, orpe rson alit ytypecann otpr edictapatie nt'sabilityt osu ccessfully self-managediabet es.Also, p atient smaybenonadher ent inone areaan dnotin ot hers(158). The p atient 'sab ilit ytoman age diabetesisaffe ctedbyanumberoffactors. Th efirstistheindividual's kn owledgeofthe self-man age men trecommen dations.With athorough assessmen tofth epatie nt's kn owledgeofdiabete sand ofself-managementr ecommendations, diabete seducation canaddresst his bar rierbycorrect in gmiscon ceptions,de termin in gpat ien tprior it ies, and e ncouragin gchangesin beh avior byhelpingpatientsse tach iev ablean dme asur ablegoals.Acknowle dgme ntofthe imperfect ions
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an dfrust rationsoft hetr eat men tplanh elpstopr epar ethe patien tfort heinev itablesetbacks(159). The se con dfactorth atimp actsself-managementb ehaviorsisthe p atient 'sbeliefsabout h ealth care .The he alth-be liefmode llooksat wheth erth epat ie ntbelievest hat h eorsheh asdiabe tes,t hat itisserious, th atth etre atment isbe neficial, and t hat the b arrierst ocarear eou tweighed byit sb enefits (160, 161,162,163,164). He althbe liefscan becomplicated andint errelat ed;th us,modificationofsome he althbe liefsalonemayn otr esultinimproved p hysiologicoutcomesofdiabe tescare(163, 165,166).For example, health belie fsaboutth eseriousne ssofdiabe tesof79p articipant sweren otr elatedt oclin ic at tend ance ,dietar yin tak e,weight loss,orfastingglucoseleve lsbu tdid p redictredu ction sin bodymass indexafter1year(166). In addition ,th erealitiesofaperson'slifeandth eprioritiesth eindivid ualhold s maydifferfromt hose ofth ehe althcareprovider. Forexample, amoth ermaypu tmoreemph asison child-care dutiesorfamilyre quirements t han on her ownh ealth carer equiremen ts.Thistype ofbarrieris difficu ltt oovercome.Insomecases, the rape uticgoalsandre comme ndationsmayr equirer estru cturing sothatthe ybette rfit thepatient 'sprior itiesandachieveatle astsome improvementinglyce mia.Ot her app roachesmay inv olveth ehe lpofsocialserv ice sandofme ntalh ealthpr ofessionals. The ch aracter isticcopin gstylesofapatien tmayalsobefactorsth atde termineadhere nce. Thos e pat ie ntswhotypicallyuseaproble m-focused copingsty lemay b ebett erabletoself-managethe ir diabet esthanth ose whoe mployamore emotion -focu sedapproach(35,36). Den ialofdiabet eswillnot allowth epat ie nttoent erintoan aggre ssive treatme ntre gimen .Onth eother han d,th ose p atient swho ten dtobeobsessive/compu lsivemayn eedtobegiven permissiontodolessrathe rthanen cou rage dto domore. Anothe rimportantfact oristh etreatment r egimen it self. Thegre ate rthe c omple xit yan ddurationofthe reg imen, themorene gativeisit simpact ont reatme ntadhere nce(158).Themoreweaskpatien tstodo an dthe longe rweaskt hemtod oit,th elesslikelyth eywillbeable tosu staincomp lian ce.Inastudy of pat ie ntswithty pe2diab etestr eate dwit hor almed ication, Paesetal. (156)fou ndth atpatient staking onepillper daywer eadh eren ttothemedicat ionpre scriptionon79%ofdays,h owev er,th ose taking t wo orthr eepillsperdaytook medicat ionsasprescribedononly66%and38%ofdays,re spectively. The h ealth care teamcan helpmodifythisad here ncebarrier. Asimp lifie dand t ailoredr egimen designed tome etindivid uallifest yle need sismore likelytobeimplement edsucce ssfullyt han isonet hat focus es onme taboliccontr olalon e.C le ar,sp ecific,simp le, and concr eteinformationan din struct ionsina diabet esedu cation programwillgofartowardre ducingth eperce ive dcomplexityoft reatme ntand improvingth erateofadhe ren ce(108,167). Afin alcriticalfactorin the p atient 'sabilit ytoself-man aget heirdiabe tesistheh ealth carepr ovider .He orshecanlist entothe patien tan dmodify thet reat men treg imenand/oralter hisorh erre lationsh ip withth epat ien tasn eede d.Infact,th ehe althcareprovidermaybe one ofth emostimp ort ant factors influen cin gadhe ren ce. The r elation shipbetwe enth ehe althcareproviderandpat ie ntitselfcan h ave aposit ive orn egat ive effect oncompliance. Impe rson ality,inabilit ytolisten ,an dlackofwarmt hinth erelationshipbet ween t he he althcareproviderandth epat ien tcan adve rselyaffect patien ts'adhere ncet otre atmen t(168).On the other han d,th ehe althcareprovider'suseofself- disclosu reandposit ive nonver balcommu nication,su ch assmile, touch, ande yecontact,can haveapositiv eimpacton compliance.Alth ou ghtime forproviders isapreciouscommodityint oday'sstr in gent health care environment ,tak in gafewmin ute st och eck whe ther patien tsund erstandth eirself-manage men ttasks,toaddr essan ticipateddifficu lt ieswith t he tre atment regime n,ortoan swe radditionalque stionscanbe q uiteben efic ialtobothth epat ien t'ss elfmanagement b ehaviorsandtothe h ealth care prov ide r/pat ien trelat ionsh ip. Inadditiont oworkingonapositiv erelationshipwithth epat ie nt,t heh ealth carepr ovider cansimplify th efor moftreatme ntandsupp ort thepatient'seffortstomanagehisor hercare.
P. 607
ASSESSING OUTCOMES
Ou tcomere ferstothe hoped-foreffectofan education ale ffort on diabetesman age men tan dove rall qualityoflifeforpeoplewit hdiabet es.Assessmen tsofed ucat ionaloutcomehavetradit ionallyfocusedon phy siologicimprovement s,whichareth echangesmost easilymeasure d.Today,t hese assessment s at tempttodeter mineh owch ang esin knowle dgean dskillscon tribut etobette rself-carebe havioran d improvemen tsin bloodglu cose le vels,decre asedcomplications,r educe duseofhealt hcar eservices, and improved q ualityoflife(20,24,55, 147,169,170). Howeve r,assuggest edearlier, healt hcar eprofession als ar erecognizingth atassessingoutcome sbyexaminingonlyth eknowle dgeacq uiredan dthe skillsle arn ed ast hesole factorsinvolve din effectingbe neficialself-carepracticesan dme taboliccontr olist oonar row afocus(57, 70). There areman ystepsbe tween an e ducationale ncount eran damedically or economicallyvaluable ou tcome, with mu ltiplefact orsinflue ncingth eprocessalongth eway. K nowled ge an dskillsare on lyt wofact orst hat in flue ncese lf-carebeh avior,an dself-care b ehavior,alt houghcr ucial forsuccess, isonlyonecompone ntofafavorable ou tcome. Fore xample ,improvemen tsin self-carep racticesareun likelytooccurun le ssthe p atient isalsohelped toactivelyinte grat ehisorh erth erapeut icre gimen int oth emany facetsofdailylife.Ifth epatie ntis
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expe ctedtoassu me on lyapassiverolein dete rminingt here gimenorinper formingtasksan difhisor he rpersonalvalu esan dne edsare ign or ed,notru eprogressislike ly(78). The u lt imate purposeofassessing out comesofeducation aleffort sistojustifyth ecost andt oen sure th atth edesiredgoalofimprovedhe althisreached. Howev er,measuringth eefficacyofeducation has bee nlimit edbyth edifficultyorimpr acticalityofde monstr atingadir ectlin kbetwee nedu cational inter actionan ddesiredoutcomewhile cont rollin gfort heothe rvar iable s.Ther efor e,beforebe neficial outcome scanbe measure d,edu cationalprogramsmustbe d esig nedtoadd ressth emu lt iplefact orst hat en cou rage activepatie ntparticip ation in self- caret hat u lt imat ely brin gaboutanassociate dimprovement inmetaboliccontr ol,overallhe alth, andqu alit yoflife (89).Forex ample ,on eprogrammadeaneffortto he lppatientsd evelopamoreacceptingandpositiv epersonalre spon setohavin gdiabete sandt oits tre atment (147).An oth erprogramsu ccessfullyaffecte dself-carepatte rns,leve lsofHbA 1 ,an demot ional well-b ein gbyspecificallyaddressingt hese issu es(38).Joslin'sDOITprogramalsodemons trat ed improvemen tsbothinth eglucosecon trolparamete rsan din quality-of-lifemeasu rement s.Cu rren tly , th erefore, assessment sofoutcomelookbeyondkn owledgeandskillsandfocusonbeh avior s. Iden tificationofabout t hree specific, desiredbeh avior alchan gesdu rin gthe education alencoun ter per mitssubse quen tevalu ationbase don wheth erth esech ang eshaveoc curre d. The ch allenger emain stodesignoutcome assessment sthattracethe furth erprogre ssionfrom edu cationalinter vent ion, t hrough behavioralch an ges,todesiredout comeinter msofmeasurable medicalparamet ers,improv eme ntsinqu alit yoflife ,or econ omicparamet ers.Todete rmine thee xact effect ofedu cation,h owev er,one must con trolforthe oth ervariablesth ataffe ctthe ou tcome, a challen geth atre main sformid able.Fin ally ,asse ssmen tofallasp ectsoft hepr ocessofedu cation isas importantasassessingout comes(4, 171).
CONCLUSION
Diabetese ducat ionprogramst hat aree volvingas p artofmu lt ifaceteddiab etesman agemen teffor ts providedbyskilled health care teamscan helppatie ntsre achh igh erleve lsofadhe ren ce,metabolic control,an dsatisfact ionbyleadin gtot heireve nmore activeparticipation in self-care. With such models ofe xcelle nceandth egrowin grecognition ofth ecost-effectiven essofeducation alin terve ntion ,th ese edu cationalprogramsshouldber ecogn iz edast hebargainth eyarerather thanasanad ditionalfinan cial bur denonsocie ty.Diabete spatien tedu cation servicesmustbe comeacce ssiblet oallpeople with diabet esasanimportantcompone ntofthe effort toe xten dqualitymedicalcare t oall.Tocon tin ueDr. Krall'sp atte rnoflook in gforward,wet rustt hat bythe n exte dit ionofthistext book,t hehoped -for un iv ersalav ailabilityofpatient e ducationwillbeclosertoare alit y. P. 608
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Febiger, 1924:21. 91.SatterfieldDW ,David son JK .Thet eamappr oachtoevaluation ,edu cation,andtre atment .In: DavidsonJK,e d.Clin ical d iabetes mellitu s: a problem-orient ed app roach.Ne wYork:Thieme, 1986:128141. 92.FranzM,etal. Goals for diabetes e ducation. Amer ican Diabe tes Association Task Gr ou p on Goals for Diabe tes Edu cation.Alexandria, VA:American Diabet esAssociat ion. 1986. 93.An dersonRM,Fun nellMM,But ler PM,etal. Patie ntempowerment :resultsofarandomized contr olle dtrial.Diabe tes Care1995;18:943949. 94.WilliamsGC ,Freedman ZR,DeciEL.Sup port in gaut on omytomotivate patien tswit hdiabet esfor glucosecontrol.Diabe tes Care1998;21:16441651. 95.U rban AD,R earsonMA,Murph yK.Th ediabet escent erhomecare nur se:an in tegralpartofthe diabe testeam. Diabet es Edu c1998;24:608611. 96.Brink S, Simin eriaL, Hinn en- He ntze nD,etal. D iabete s education goals. Alexandria:VA: AmericanDiabete sAssociat ion,1995. 97.Pie berTR, Br unn erGA,Schn edlWJ,etal. Evalu ation ofastruct uredout patien tgroupedu cation programforin ten siv ein sulin treatment. Diabet es Care1995;18:625630. 98.HellerSR, ClarkeP,DalyH,etal. Gr oup educationforobesepatientswith type2diabetes : gre ate rsuccessatlesscost .Diab Med1988;5:552556. 99.GlasgowRE,Toob ertDJ,HampsonSE,e tal.Abriefoffice-basedinte rven tiont ofac ilit ated iabetes dietaryself-management. Health E duc Re s1995;10:467478. 100.Glasg owRE ,Toobert DJ,HampsonSE .Effect sofabr ie foffice-base din terve ntiontofacilitat e diabe tesdietaryself-manageme nt. Diabete s Car e1996;19:835842. 101.LewisD.Th eInte rne tasar esourceforhe althcareinformation .Diabe tes Edu c1998;24:627630, 632. 102.LewisD.C omput er-basedpat ien tedu cation:use b ydiabete seducators.Diabe tes E duc 1996;22:140145. 103.Managementofdiabet esatdiabe tescamps. American Diabe tesAssociation .Diabe tes Care 1999;22:167169. 104.Misur acaA, DiGe nnaroM,LionielloM, etal.Su mmercampsfordiabet icch ildren :ane xperien ce inCampania, Italy.D iabetes R es Clin Pract1996;32:9196. 105.Rugg erioL. He lpingp eoplewithdiabetesch ang ebehavior:fr omthe oryt opractice.D iabetes Spect rum2000;13:125132. 106.Redman BK.The p roce ss of patie nt ed ucat ion, 6th e d.St.L ouis:Mosby ,1988:2148. 107.HamburgBA, In offGE. Cop in gwith predictable cr ise sofdiabet es.D iabetes C are 1983;6:409 416. 108.LeyP.Satisfact ion, complian ce,andcommun ication .Br J Clin Psych 1982;21:241254. 109.PageP, Verstraete DG,RobbJR,e tal.Patient recallofself-car erecommen dationsindiabet es. Diabetes C are1981;4:9698. 110.Rugg ier oL, GlasgowR,DryfoosJM,et al.Diabe tesself-management .Self-reported re comme ndat ionsandpattern sin alarge popu lation .Diabe tes Care1997;20:568576.
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111.McL eodB. Program dev elopment for diabe tes.Toronto:Canadian Diabe tesAssociation, 1988. 112.Glasg owRE ,Ande rson RM.Indiabe tescar e,moving fr omcompliancetoad here nceisnot en ou gh. Somethinge ntirelydifferen tis n eede d.Diabe tes C are1999;22:20902092. 113.Lie senfe ldB, He eker enH,Sch adeG,et al.Qualityofdocu me ntationinmedicalreportsof diabe ticpatient s.Int J Qu al Health care1996;8:537542. 114.Midwest Med icalIn suranceCompan yRis kManag eme ntC ommitte e.Medicalrecord document ation isyoursah elpor ahindrance in alawsuit?S Dakota J Med1998;51:5152. 115.Gr ebeSK, SmithRB. Clin icalauditan dstan dardisedfollowupimproveq ualityofdocumen tation indiabe tescar e.N Z Me d J1995;108:339342. 116.ReslerMM.Teach in gstrategiesth atpr omot eadh eren ce.Nur s Clin North Am1983;18:799811. 117.JacobsonAM, Weinger K .Psy chosocialcomplication sind iabetes. In:LeahyJ, C larkNG,Cefalu WT,e ds.Medical manage men t of d iabetes. NewYork:Mar celDekk er,2000:559572. 118.Rosenst ockIM.Un derst and in gande nhancingpatientcomplian cewit hdiabet icre gimen s. Diabetes C are1985;8:610616. 119.WalkerE A.Ch aracteristicsofth ead ultle arn er.D iabetes E duc1999;25[Supp l6]:1624. 120.AlognaM. Assessme ntofpatien tknowledgeandperforman ce.In :St ein erG,Lawrence PA,e ds. Ed ucat in g diabetic pat ien ts.NewYork:Springe r,1981:146153. 121.Barr P,HessG,FreyML. R elation shipbetwe enre adinglevelsan deffective p atient education . Diabetes1986;35[Supp l1]:48A(abst). 122.SchillingerD,Grumbach K,Pie tteJ, e tal.Association ofhe althlit eracywith diabete sou tcomes. JAMA2002;288:475482. 123.Gagn R M, Brig gsLJ,Wage rWW.Principles of instru ction al design.For tWor th:Harcou rtBrace Jovan ovichC ollegePublish ers,1992. 124.Lor enzR A.Teach in gskillsofh ealthp rofe ssionals. D iabete s Educ1989;15:149152. 125.Gr een fieldS,KaplanSH,WareJEJr .Patients'par ticipationinmedicalcare :effectsonblood su garcontr olan dqualityoflifein diabete s.J Gen In tern Me d1988;3:448457. 126.RostK.The in flu ence ofpat ie ntparticipation onsatisfactionan dcompliance. Diabete s Educ 1989;15:139143. 127.RoterDL.Patient participationinth epatien t-providerinte raction:th eeffectsofpat ien tque stion askin gon theq ualityofint eract ion, satisfactionan dcompliance. Health E duc Mon ogr 1977;5:281 315. 128.Rother tML ,Talarcz ykGJ. Patie ntcomplian cean dthede cision-makingprocessofcliniciansand patie nts. J Compliance He althcare1987;2:5571. 129.Stewar tMA. What isasuccessfu ldoctor-pat ie ntinte rview?Astu dyofin teractionsand outcome s.Soc Sci Med1984;19:167175. 130.SimsDF,SimsE AH. Comment ary. Diabet es Spectru m1990;3:227228. 131.Lutfe yKE, Wish nerWJ. Beyondcomplian ceisadhe renc e.Improvingth eprospectofdiabete s care.D iabetes C are 1999;22:635639.
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132.DavisM,E schelmanE R,Mckay M.Th e relaxation and st ress re duction wor kbook.Oakland,C A: NewHar bin gerPublication s,1988. 133.Strech erVJ,SeijtsGH,KokGJ, etal.Goalsettingasastrategy forh ealthbe haviorchange . Healt h Edu c Q1995;22:190200. 134.Kaplan RM,Ch adwickMW,SchimmelLE.Sociallearningint erven tion topr omot eme tabolic contr olin typeIdiabe tesmellitus:pilot e xperimentr esults.D iabete s Care 1985;8:152155. 135.LeyP,BradshawPW,Kince yJA,etal. In creasin gpat ien ts'satisfaction wit hcommunicat ions. Br J Soc Clin Psychol1976;15:403413. 136.TabakER. Th erelat ionsh ipofin for mat ione xchan gedu rin gme dicalvisitstopatien tsatisfact ion: ar eview.Diabetes E duc1987;13:3640. 137.Campbe llLV,Bart hR, Bosper JK,et al. Impactofint ensivee ducat ionalapproacht odietary ch ange in NIDDM.D iabete s C are 1990; 13:841847. 138.Hose yGM,Free manWL,Str acqualu rsiF, etal.Designingandevalu atingd iabetese ducat ion mate rialforAmericanIn dians. D iabete s Educ1990;16:407414. 139.Overlan dJE, HoskinsPL,McGillMJ,et al. Lowliteracy:aproblemindiabetese ducat ion. Diabet Med1993;10:847850. 140.McNe alB, Salisbu ryZ,Baumgardn erP,etal. Compre hen sionassessme ntofdiabete seducation programparticipants. Diabet es Care1984;7:232235. 141.Dale E,Ch allJS. A formula for predicting re adability.Columbus:OhioState Univer sity Press, 1948. 142.Flesch RF.Anewre adab ilit yyard stick .J Appl Psychol1948;32:221233. 143.Fr yE.Are adab ilit yformulat hat savest ime.J Re ading1958;11:513578. 144.McL augh linGH.SMOGgr adingane wr eadabilityformu la.J Re ading1969;12:639646. 145.DoakC C,DoakLG,Root J H. Teach in g patien ts wit h low lite racy skills. Philadelphia:JBLippincott Co,1985. 146.PlimptonS,R ootJ.Mat erialsand s trat egiesthatwor kin lowliter acyh ealthcommu nication . Public Healt h Re p1994;109:8692. 147.Ander son RM, Nowace kG, Richar dsF. Influ en cin gthepe rson alme aning ofdiabet es:rese arch andpractice .Diabe tes E duc1988;14:297302. 148.Bou lt on C ,Gart hRY.Stu dent s in learning gr ou ps: active learning th rou gh conve rsation.San Fran cisco:Jossey-Bass, 1983:7381. 149.Fink elDL,Mon kGS.Teach ers and learn in g groups: dissolut ion of the atlas complex. San Fran cisco:Jossey-Bass, 1983:8397. 150.IstreSM.The art andscien ceofsu ccessfulteachingcontinu in gedu cation credit.D iabete s Educ 1989;15:6776. 151.Lor enzR A.Trainingh ealth p rofe ssionalstoimprovet heeffe ctiv eness ofpat ie ntedu cation programs. Diabete s Educ 1986[Su ppl];12:204209. 152.Sanson-Fisher RW,Campb ellEM,R edmanS,e tal.Patient -prov ide rin teraction sandpatient P. 610
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outcome s.Diabe tes E duc1989;15:134138. 153.Sacket tDL. Themagn itu deofcomplianceandnon-comp lian ce.In :Sackett DL,Hayne sRB,eds. Complian ce with th erapeutic re gimens. Baltimore:The Joh nsHopk in sUniver sity Press, 1976:925. 154.Hayn esRB,McKibbonKA,KananiR.Syste maticr eviewofrandomized t rialsofinter vent ionsto assistpatient stofollowprescription sfor medicat ions. Lance t1996;348:383386. 155.Hayn esRB,McKibbonKA,KananiR.Syste maticr eviewofrandomized t rialsofinter vent ionsto assistpatient stofollowprescription sfor medicat ions. Lance t1996;348:383386. 156.PaesAHP,Bakker A, Soe-Agn ie CJ.Impact ofdosagefre quen cyonpat ien tcompliance .Diabe tes Care1997;20:15121517. 157.SpeersMA,Tur kDC .Diabe tesselfcar e:knowle dge,be liefs, motiv ation an daction .Patient Coun s Health Educ1982;3:144149. 158.ErakerSK, BeckerMH.Improvin gcomplianceforth epat ien twithdiabe tes.Pract ical D iabetol 1984;3:611. 159.Westbe rgJ,Jason H. Buildingahelpfulrelat ionsh ip:t hefound ation ofeffe ctiv epat ien t edu cation.D iabete s Educ1986;12:374378. 160.Becker MH.Th eoreticalmodelsofadhe rence andst rate gie sforimp rovin gadhe renc e.In: Shu makerS,e tal,eds. The h andb ook of h ealth be hav ior change. NewYork:Spr in ger,1990. 161.BradleyC .Health belie fsandkn owledge ofpatie ntsanddoctorsin clinicalpractic eand research. Patient Educ C ou ns1995;26:99106. 162.BradleyC .Measu resofperceived cont rolofdiabetes. In:Bradle yC,e d.Han dbook of psy chology and diabet es.GreatBritain:HarwoodAcade micPu blishing, 1994:291331. 163.WooldridgeKL,WallstonKA, GraberAL, etal.Th erelationshipbet weenh ealth beliefs, adhere nce, andmetaboliccon trolofdiabete s.Diabe tes E duc1992;18:495500. 164.Maiman LA,Becke rMH. Theclin ician 'srolein patien tcompliance. Trend s Pharmacol Sci 1980;1:457459. 165.Coate sVE ,Boore JR.The in flu enceofpsych ologicalfact orsont heself-managementofinsulindep ende ntdiabe tesmellitus. J Adv Nu rs1998;27:528537. 166.PolleyBA, JakicicJM,Ven dittiEM,etal. Th eeffect sofhe althbe liefsonweightlossin individualsat highriskforNIDDM.D iabete s Car e1997;20:15331538. 167.StrowigS.Pat ien tedu cation:amode lforau tonomousdecision -makin gan ddelibe rate action in diabe tesself-management. Me d Clin North Am1982;66:12931307. 168.HarrisG.Filling thegapsbetwe enpatientsandprofession als.D iabetes E duc1987;13:133136. 169.TillyKF, Belton AB,McL achlan JFC .Continu ou smonitoringofh ealth stat usou tcome s:experien ce withdiabe tesedu cationprogram.D iabete s Educ1995;21:413419. 170.TildesleyHD,MairK,SharpeJ, etal.Diabete steachingout comean alysis.Patient E duc Coun s 1996;29:5965. 171.O'C on norPJ,R ushWA, Pet ersonJ,et al.Continu ou squalityimpr ove men tcan improveglycemic contr olforHMOpat ie ntswithdiabe tes.Arch Fam Med1996;5:502506.
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Chapter36 Medical Nutrition Therapy

Kare n Hanson Chalme rs
A BRIEF HISTORY OF NUTRITION AND DIABETES

More than50yearsago,E lliottJoslin state d: The d iet in health ismade upchieflyofcarbohydr ate;t hedietindiabe tesbeforet he discove ryofin sulin wasmadeup ch ie flyoffat. Insulinhaschangedallth is.Th etaskof th emodern diabeticisnotsomuch tolearnh owtolivecomfort ablyuponless car boh ydratean dmorefat,bu trat hert obalanceth ecar boh ydrateinhisdietwith insulinsothathecanut iliz eit andt husk eephisur in esugar-free .(1) LittledidDr. Joslinrealizet hat h is g uidelin eswou ldst illh oldtru eat thebe gin ningofthe21st centu ry. Patient shave ide ntifie ddietason eofth emostch alle ngingaspectsoftheirdiabe tesre gimen. Howe ver, cou ntlesseve ntsh aver esultedinpositiv echangesinn utrition scie nceasit r elatest odiabe tes. Fromth erigidlycontrolle d,semist arvation diet sin ancien ttimes t oth epre sent all-foods-can-fit, we havearrivedat nut rit ionscience aswekn owittoday me dicaln utritionthe rapy . One ofth eearliestr efere ncestoaso-calleddiabet icdietwasnotedinamedicalwritin gasfarbackas 1550B.C. ,alth ou ghforthe first3,500y ear sofdiabet eshistory,n ocleardist in ctionwas P. 612 madebe tween type1and t ype2diabetes. Thewritingsre comme ndedadie thighincarbohydrates, whichinclude dfruit,wh eatgr ain,andswee tbeer tost opth epassing oftoomuch urine. Aretaeus, a followe rofHippocrate s,fir stused t hen amediabet esin the firstce ntu ryA.D.todescribeth emeltin g downofflesh andlimbsintoth eurine (2). He con clu dedth atdiabe teswasadise aseofthe stomach an d shouldbet reat edwit hmilk,gru el,cere als,fru its, andswe etwines. Milk ,wate r,wine, andbe erwer e use dasth emain flu idst ore lievee xcessiveth ir stunt ilthe secondcen tury A. D. ,when diabete swas th ou ghttobeadise aseofthe k idn eys.Att histime, restriction offluidswasre comme nded. Bythe sixt h cen tury ,diabet eswasth ou ghttobedirect lycaused b yove reatin gan dthough ttobeadiseaseofswe et ur in e(3). Littleinformation aboutdiabe tesan dfoodismen tion edagain unt ilthe late1600s,wh enth esugge sted diabet icdietr etur nedtofoodsh igh erincar boh ydrates,su chasmilk, bread,an dbarleywater. Also,at th istime,opiu mwasin troducedasastaple ofth ediettodecre aseappetite, asphy sician srecognized th atth ose peoplewith diabeteswh oateth eleastfoodlivedth elon gest. Int helate 1700s, aFren chphys ician began prescribingu ndern utr itionorsemistarvationdiet s, inter spersed with freque ntpe riodsoffasting, forth ose with diabete s.Fin ally, aphy sician fr omEn gland relat edcar boh ydratestohighglucoselevelsan dexcessiveu rinat ion. Again ,th edietrev erte dbackto lowcarboh ydratesan din cludedmor efatandprote in int heformofmilk,bu tter, suet ,an dran cidmeats. Low-carbohyd rate veget ableswere addedonlywhe nth eurine becamecomplete lysu garfr ee.Although fat in t hediabe ticdiet wasfurt her liberalizedt oad denough caloriesforsur viv al,mostpeoplewith diabet escouldnotadh eretoth eextr eme lylimitedqu an tit yoffood. Thosepeople with diabete swho were thin d idn otsu rvive,wh ereasthosepeoplewithdiabe teswhowere fatimp rove d. Int heearly1900s,Dr .Fr ederickM.Allen ,inth eUn ite dState s,deve lopedh isstarvationdiet andwas oneofthe firstt otailorfoodsindietstohispatien ts'pr efere nceswhilestillprovidin gon ly1,000 calorie saday.Alt houghman yofh ispatient swe remalnourished ,heiscred ite dwith helpingmany sur viv ebeforeth ein troductionofin sulin t her apyin1921(3). The st arvation die tdisappearedwitht hediscov eryofin sulin .Thepr escribeddiabe ticdiet wasstill4% car boh ydrate,21%protein,and75%fatallmeasuredandweigh edtoexact amou nts.Althoug hno consisten tfoodlistswer eavailab leatth etime, the carbohydr atefoodswerecategorizedaccordingt o th eamou ntofcarbohy drat eeach foodcon tain ed,e. g.,5%, 10%, and20%vege tables. Ve getable swe re cooke dthre etime s,the water chan gedeachtimetoremove asmu chcarboh ydrateasp ossible .Eve n aft erinsulinwasinitiate d,Dr .ElliottP.Joslincontinu edtouseahigh-fat ,car boh ydrat e-rest rict eddiet forhissever ediabet icsandn ote din hisfirst p reinsulinDiabe tic Manualt hat oliv eoilformsan exce llen tlu nch forad iabetic(1). Dr. Joslin grad uallyin creasedhisdietformilddiabeticsto23% car boh ydrate,15%protein,and62%fat. Int he1940s,itbecame evident t hat the rewasagreatnee dtode velopconsisten tan dstan dar dize dfood valu esan dtode sign asimplemeth odforplann in gthe diabeticdiet.Th eAmer icanDiet eticAssociat ion, th eAme ricanDiabetesAssociation ,an dthe diabete sbran choft heU .S.PublicHealt hServicede velope d ameth odt hat becamewhatwekn owtoday asthe exch ange system.Sixcon ven ien tsamplemealplans were developedth atdet aile dthegr amsofcarboh ydrate,pr ote in ,an dfatforvar iouscalorieamounts.
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The seplanswer edeve lopedtobeu sedbyth ehealt hprofession al,whowou ldmodifyt heplan tosu it the par ticularne edsofthepatient .Alth ou ghth emealplanswer enotmean ttobedistribute dtopatient s, th eysoon b ecamewidelyavailable. Int heearly1970s,the sample mealplan swerebe in gusede xten sive ly .These preplan neddietsdidnot focuson nu tritione ducationoronfollow-u pbyare gist ereddiet itian .Patient squickly lostth eir motivationt oad here tot hesed iet s,an dthe irint erestinn utr itionquicklydiminished .A1973pu blication byKe llyWest, Diet The rapy of Diabe tes: An An alysis of Failur e,ex amin eddete rren tstosuccessfu ldiet th erap y,whichinclude dlackofph ysic iansupportinpr omot in gadequ ate nut rit ioncarean doft hird-par ty reimburse men tfor die tary ins truct ionforou tpat ie nts(4). Int he1970s,th ehigh -carbohydr ate d iet wasrediscovere d(5,6),andth eofficiallyre comme ndedd iet wash igh erincomplexcarbohydrateandlowe rin fatandproteinth an mostoft heearlie rdie ts.The at tit udet owardsucroseandother sugar sbecamemore liberal.TheAmerican Diabet esAssociat ionbe gan emphasizing then eedfornu trition e ducationabou tth eexch ange system.Thiseve ntu allyledt oth e pub licationin1971ofth eAssociation'sPrinc iples of Nu trition and D ie tary R ecommend ation s(7). Th e exch an gelistsformealplann in gwerere visedin 1976,1986,an dagain in 1995;e ach r evisionplace dan increasingemphasisoncarboh ydrates.Th esech ange sreflectamovefromth emainfocu son the let hal effect sofshort-t ermcomplications(k etoacidosisan dhypoglycemia)toanewfocus:conce rnab out longter mcomplications. The e xchangesys temc ont in uedt obet aug htan duse dandwasperceive dasth ediabeticdietun tilth e 1980s.However, surve ysfromdietitians wh opr ovidedn utritionedu cation for p atient swith diabete s ident ifiedan eedforavarietyofme al-plann in gmet hodstobe usedinaddit iontoth eexch ange system. In1987, t heDiabete sCare and Education Practice Gr ou pofth eAme ricanDiet eticAssociat ionpromote d th econ ceptofthe in dividu alization ofth eme alplanning approach todiab etesn utritionalcare with new nu trition resourcesfordiabe tesmealplann in g(8). Moreandmore p eop lewith d iabeteswe reseek in ga dietitian'scare and coun selin gfor u pdat in gthe irmeth odsofme alplannin g. Cu rren tme dicaln utr itionth erap yrecommend ation sforover allh ealthofpersonswith d iabetesareth e sameasthoseforallh ealth yAmer icans,asseen int heU .S. Dietary Guidelin es2000(9). Th ese guidelinesinclude thefollowin g: Aimforahe althywe igh t Ch ooseav arietyofgrain sdaily, especiallywhole g rains Ch ooseav arietyoffruitsandveg etablesdaily Ch oosead iet thatislowinsatur ate dfatan dchole sterolandmoderateintotalfat Ch oosebev erag esan dfoodstomoderateyourint akeofsugars Ch ooseandprep arefood with le sss alt Ifyoudrinkalcoholicbe verages,dosoinmod erat ion.
The v olumeofr esearchonissuesofnu tritionanddiabe tesan dthe number ofchangesinn utr ition recommen dat ionsoverre cent year saren owgre ate rthaneve r.The evolu tionofnewk nowledge is rapidlyaffe ctingth emanag eme ntofdie tfor t hepatientwith d iabetes. There fore ,the 2000Dietary Guidelin es,whicharepu blishe dever y5yearsbyth eDepart men tofHe althandHuman Services(HHS) an dthe Department ofAgricultu re(USDA),are curre ntlyinth eprocessofr eviewin light ofrece nt scient ificevidence tode termineifrevision isne ededinth e2005six thed ition.The USDA'sFoodGu ide Py ramid, whichwasint rodu cedin1992,isalsou nder review.Prominen texpe rtsinnu trition andh ealth ar enowproposingarevisedfoodgu ide pyramidthatclearlyemphasiz esthe bene fitsofhealt hyfats, dailyexer cise ,an davoid ance ofexce ssiv ein tak eofcalories.Re comme ndationspr omot ehighfiber, he althyandu nprocessedcarbohydr ates, aswellasade quat econ sumption offre shfruits an dvege tables.He althysour cesofpr ote in aree ncouraged,su chasn uts, leg umes,fish,poultry, an d eggs, where asre dmeat,bu tter ,refine dgrains, p otatoes,andsugarar eminimize d. The availabilityofagre ate rvariet yin thet ypesoforalantidiabet esage ntsandinsulins,t oget herwith th eavailab ilit yofte chnologyfr omself- monitor in gofbloodglucosetocon tinuousbloodglucosesen sor s an din sulin pumpthe rapy ,hasallowedincreasedflexibilityinmealplann in g.Acon tinue dresearchfocus onth egly cemicresp on seofth enu trient scarboh ydrate,pr ote in ,an dfat isgr aduallych anging h owwe th in kaboutdietindiabetes. The d iet aryman agemen tofty pe2diab etesisnowrecognizedtobequ it ediffe rent fromthatoftype1 diabet es.Ou rknowle dgeab ou tthe t reatme ntofobe sity ind iabetesalsohasin creased.In addition , at tent ionisbeinggiven tot hespe cialconsideration srequire damong differ entsu bgroupsofpeople with diabet es,spe cifically then eedsofeth nicminoritygroups, p regnantwomen,gr owingch ildren an d adolescen ts,andth eelderly.E mph asisisplace don p rov idingindividualized, flex iblemealplanst hat peopleare willing andable tofollow.Dr amaticchangesinourmeth ods ofdiabet esedu cation havealso P. 613
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bee ninstitut edin rece ntyears.Newst rate gie s,knowledge, andt echn iqu esfor teach in gan dimproving th eov erallmanage me ntofdiabetes, aswellasdietar ymanageme nt, we reclear lyde monstr ate din the 1993publishedre sultsoft heDiabete sCon trolandC omplicat ionsTrial(DC CT)for thosewithty pe1 diabet es(10)an dthesmallerStockholmDiabetesIn terv entionStud y(11)ofsimilardesign. These stu die srecognizedth eimportanceofacoord in ated t eamappr oachtothe achieve men tofn utr itiongoals. The d iabetest eamusedint heDCCTconsistedofthe patien tan dfamilyasth eprimaryparticipants, a diabet esnu rseedu cator, aregister eddietitian, abeh avior ist ,an dthediabetologist.Today, e xercise phy siologistsalsohav ebeen in clu dedasimport ant member softh ediabete steam.Th eDC CTalso providedspecificin formationab out importan tnu tritionint erve ntion strat egies,basedfirmlyonscientific eviden ce.In 1994, shortlyafte rpublication ofth eDCCTclin icalfindings, the American Diabe tes Associationpu blish edare vise dsetofnut rit iongu ide lines, refocusingonanindivid ualizedap proachto nu trition self-man age men tthatisappropriat efort hepe rson allife-sty leanddiabe tesmanagement goals oft heindividualwithdiabe tes(12). The r esultsofanoth er20-yearlandmar kstudy, the UnitedK in gdomProspect ive Diabe tesStud y(UKPDS) (13),forthosewitht ype2d iabetes, werepu blishe din 1998andfu rthe rcon fir medt hat theint ensiveu se ofp har macologicth erap y,togeth erwithdietandex ercise,wouldhaveclin icalben efits.In 1996, recr uitme ntbe ganforamorerece ntrandomize dclinicaltrial,The Diabet esPr even tionProgram(DPP) (14).The DPPwasde sign edtotest strat egiestopreven tordelayglucoseconcen trationsandimpair ed glucosetole ran ce(IGT). Thismajorclin icaltr ialcomparedint ensivelife stylein ter vent ion(dietand exe rcis e)wit hme tfor mintr eatmen tin 3,234people with impaire dglu cose t olerance. Life style inter vent ionworkedaswellinmenandwomen an din allet hnicgroups, reducing t heriskofgetting t ype 2diabetesby 58%.It alsoworkedwellin peopleage60an dolder ,redu cin gthe irde velopmen tof diabet esby71%.Metforminwasalsoeffe ctiv ein me nan dwomenandinalleth nicgrou ps,re ducingth eir riskofge ttingty pe2diabe tesby31%,bu tnotase ffe ctiveinthe olderv olunt eersandinth ose wh o were less over weig ht.Th etrialend edaye arearlybecauseth edat ahadcle arlyan swered themain rese arch quest ions. Th isisth efirst majortrialtoshowthatdietan dexer cise canpr even tor delay diabet esinadivers eAmer icanpopulationofover weig htpeoplewit hIGTandamajorste ptoward rev ersingth eepidemicoftype 2diabet esin the UnitedStates. Ar ecen tly launch edtrial,t heLook AHE AD (Action forHe althinDiabetes)st udy, willex amin ehowdie tan dexerc iseaffecthe art attack,str oke ,an d car diovas cular-disease-relat eddeathinpeoplewit htype 2diabe tes. Diet stillremainsth ecor nerst on eofdiab etesself-management ,but additionalr esearchisnee dedto improvet hecontr ibu tion t hat die tcan mak efor effectivediabe tesself-management.
GOALS OF MEDICAL NUTRITION THERAPY

Tod ay,t here isn ooned iabeticdie t.Th ecurr entn utr itionrecommen dationscan bedefine dsimplyas anutr it ionpre scrip tionbasedonasse ssme ntandtre atment goalsandoutcome s(15).The 1994 Ame ricanDiabete sAs sociationnu trition r ecommendation sredistribute dthe caloriespr ovidedfromthe variousmacronu trien ts(12),an dthe serecommen dationsstillholdtrue today.Table 36. 1givesa historicalperspe ctiv eofn utrition recommen dations.The Amer icanDiab etesAssociation recommend st hat th edis tribution ofcaloriesfromcarboh ydrateandfat b ebase don n utr itionalasse ssme ntandonblood glucose,weigh t,an dlipidgoals, wit hcon tinue demphasisonadietwith fe werth an10%ofcaloriesfrom sat uratedfat sand with 10%to20%ofcalorie sfromprotein(lean ). TABLE 36.1. Historical Perspective of Nutrition Recommendations for People with Diabetes
Distribution of calories (%)
Year Before 1921 1921 1950 1971 1986 1994
Carbohydrate
Protein Starvation diets 10 20 20 1220 1020
Fat
20 40 45 <60 Basedonnutritionalassessment andtreatmentgoals
70 70 35 <30 Basedonnutritionalassessmentand treatmentgoals;<10%ofcaloriesfrom
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saturatedfats Copyright2001AmericanDiabetesAssocation.FromtheAmericanDiabetesAssociation.Nutrition recommendationsandprinciplesforpeoplewithdiabetesmellitus.Diabetes Care2001;24:S47.Reprintedwith permissionfromtheAmericanDiabetesAssociation. The g oalsofmed icaln utrition the rapyaresu mmarizedinTable 36. 2,wh ich ou tlin esthe mostrece nt recommen dat ionsoftheAmerican Diabe tesAssociation(15)andar ediscussedinmor edetailbelow. TABLE 36.2. Goals of Medical Nutrition Therapy
P. 614
1.Attainandmaintainoptimalmetabolicoutcomes,including
Bloodglucoselevelsasnearnormalaspossibletosafelypreventorreducetheriskforcomplicationsof diabetes Optimalserumlipidprofiletoreducetheriskformacrovasculardisease Bloodpressurelevelsthatdecreasetheriskformacrovasculardisease
2.Preventandtreatchroniccomplicationsofdiabetesby
Modificationofnutrientintakeandlifestyleforpreventionandtreatmentofobesity,dyslipidemia, cardiovasculardisease,hypertension,andnephropathy
3.Improvehealththroughhealthyfoodchoicesandphysicalactivity 4.Addressindividualneeds,suchas
Personalandculturalpreferencesandlifestylewhilerespectingtheindividual'swishesandwillingnessto change
Copyright2003AmericanDiabetesAssocation.FromAmericanDiabetesAssociation.Evidence-based nutritionalprinciplesandrecommendationsforthetreatmentandpreventionofdiabetesandrelated complications.Diabetes Care2003;26:S51.ReprintedwithpermissionfromtheAmericanDiabetesAssociation.
Goals in Type 1 Diabetes

The p rimar ygoalsofthe rapyforper son swith type1diabete sareasfollows: Pr ovision ofan in dividu aliz edme alplanbasedon usu alfoodin tak eand lifestyle. Th isplan isu sedas th ebasisfor in tegratinginsulinth erapy in tot heu sualeatin gan dexercisepatte rns.
Consisten cyofcarbohydr ateint aket oallowth esyn chronizat ionofmealt imeswithtimesofinsu lin act ionforpersonsr eceivin gfix ed in sulin regimens.
De terminat ionofpremealinsulindosean dpost pran dialbloodglucosere spon sebymon itoringof bloodglucosele velsan dadjustinginsu lindosesforth eamou ntoftotalcarbohy drate con sumedfor per son sr eceivinginten sive in sulin the rapy.
Pr even tion ofweightgainisde sir able,withatten tion ther efor epaidtototalcalor icintakefrom car boh ydrate,pr ote in ,an dfat, forper son swith improvedglycemiccon trol. Adjustmen tofrapid -orsh ort -actinginsu linfordeviationsfromusuale atingandexe rcisehabitsis th eprefe rredch oiceforpreve ntion ofh ypog lyce mia. Add itionalcar boh ydrat emayben eeded for un plann edexe rcise .
Goals in Type 2 Diabetes

The p rimar ygoalsofthe rapyforper son swith type2diabete sdepen don body we igh tan dle velof glucosecontrol. Emphasisonlife stylechanges t hat resultinre ducedcaloricin tak ean din creasedene rgyexp enditu re
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th rou ghph ysicalactivit yfort hosewhoare ove rweightandinsulinresistant
Achieve men tan dmain ten ance ofglucose,lipid, andbloodpr essure goalsby reduct ionindietary intakeofcarbohydr ate, satu rat edfat, chole sterol, and s odiumwhen nece ssary Mainte nan ceofmoderatecaloricr estriction and anu tritionallyadequatemealplan with aredu ction ofcarbohydr ateandtotalfatesp eciallysaturatedfatt oget her with anincre aseine xercisefor th osewith e xcessiveweight
Incr ease ofact ivityandex ercisetoimproveglycemia,decr ease insu linr esistan ce,an dredu ce car diovasc ularriskfact ors
CALORIES
The d iet ofth ediabet icpatie ntsh ou ldcontainthe minimu mn umberofcalorieswh ich th enormalin dividualwouldreq uireun dersimilarcondition s.Ifthe patien tisallowed more thanthe minimu mamoun toffood t her eisfarmorelikelih oodthataportionwill belos t,un assimilate d,an dappearassu garint heu rin e.(1) Pr escribin gen ou ghcalorie s(kilocalories, orkc als)toachieveandmaintain adesirable we igh tshouldbe car efully con side red.C aloricreq uirementsforper son swith diabete saren ot differ entfromthosefor per son swith ou tdiabete s,assu mingt hepe rson with diabete sisn otlosin gcaloriest hrough glycosur ia. Caloricnee dsvary with apat ie nt'sweigh t,age,ge nder ,activitylevel,andgen eticback grou nd. Th e recommen dedcaloriele velisbasedonth eweightth att hepatientandh isorhe rhealt hcar eprovide r ack nowledg easonet hat canbe achieve dandmaint ained, forboth thesh or tterman dthe longte rm. Thismaynotbet hesameaside albody we igh t. Pe rsonswit htype 1diabet esar eofte nth in when thediag nos isisfirst made,andth edie tshouldinclude en ou ghcalorie stoe nsur enormalgrowt han ddeve lopme ntandtosustain the usualleve lofphysical act ivity. Forinfan ts,ch ildren ,an dadolescen ts,caloricint akesh ou ldmaint ainconsistent growt hcur ves bas edon ene rgyne edsdur in gperiodsofgrowthand P. 615 sexu almatur ation .The p rescribedcaloriesmu stbeadjustedonaregu larbasis.Ifdiabe tesisnot properlycontr olle d,growthmaybe retardedandth ehe igh tpot ent ialmayn otbe reached. An yabn or mal orune xplainedde viation in growt han dweightdeman dsan assessmen tofdiabe tescontr ol,eatin g pat tern s,an dcalor icintake, aswellasin sulin dosage. Pe rsonswit htype 2diabet esar eofte noverweigh twhen thediagnosisisfir stmade.Amode rate weig ht loss(5to9kg),irre spectiveofthepatient 'sstartingweight ,ispe rhapsthe mostimportantaspectof medicalnutr it ionth erapyand isassociate dwith an improvementinlipids, bloodglu cose ,an dblood pre ssure(15, 16,17,18,19). Weig htlossleadstoaredu ctionininsu linr esist ance and h aslon g-ter m effect son themaint enanceofredu cedbloodglu cose le vels.Overwe igh tan dobe sepat ien tswithty pe2 diabet esshouldbeen cou rag edtoattain are asonableweigh trat hert han att empt in gtoachieve t he traditionallydefine ddesirableoridealbodyweight.Se ttinginte rme diateweight goalsmaybe usefu l whe napatientbe comesoverwh elmedby themagn it udeofhisor h ern ecessaryweightloss.Weight management als oshouldincludebe havioralmodification toe ncouragehe althye atingbe hav iors,toget her withincre asedph ysicalactivity.Amode rate reduct ionincaloriesofapproximat ely250to500kcalpe r day lesst han the aver agedailyintake(calcu latedfromafoodhistory)can resu ltinlossesof2to4kg per month ,arateth atisconsiderede xcelle nt. Seve raldiffe rent meansofestimatingdesirable b odywe igh tan dcaloricne edsar ein clu dedinTable36. 3. The r ecommende dcalorieleve ln eednotbe absolu telyprecisebu tshouldbeconsidere dastartingpoin t forfin e-tun in gdur in gfollow-upu ntilale velhas b eene stablishedt hat willh elp t hepatientachieve h isor he rgoals forweight andbloodglucoseleve ls. TABLE 36.3. Estimating Caloric Intake and Desirable BodyWeight for Adults
Estimating caloric intake Basalcalories:10kcal/lbdesirablebodyweight Addcaloriesforactivity Ifsedentary,add10%ofestimatedbasecalories Ifmoderatelyactive,add20%ofestimatedbasecalories
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Ifstrenuouslyactive,add40%ofestimatedbasecalories Adjustmentsa Estimating desirable body weights from frame size Women100lbforfirst5ftplus5lbforeachadditionalinch Men106lbforfirst5ftplus6lbforeachadditionalinch SmallframeSubtract10% LargeframeAdd10%
aAdjustmentsareapproximate;weightchangesshouldbemonitoredandcomparedwithcaloricintake.
AdaptedfromVinikA,WingRR.Nutritionalmanagementofthepersonwithdiabetes.In:RifkinH,PorteDJr, eds.Diabetes mellitus,4thed.NewYork:Elsevier,1990.
The reise vidence t osu ppor tthe useofbody massinde x(BMI)(Table 36.4)inriskassessmentforth e diagn osisofdiabe tesorresponse towe igh tloss.Th eBMIpr ovidesamoreaccurate P. 616 measu reoftot albodyfatthandoesassessme ntofbody we igh talone. Measure me ntofwaist circumferen ce(20)isparticular lyh elpfulwhen patien tsare c ategorizedasnormaloroverwe igh t.Men whosewaistcircu mfere nceisgreater t han 40in chesandwomen whosewaistcircumfere nceisgreater th an35inch esare ath igh risk ofdiabet es,dyslipide mia, hyper ten sion,andcardiovasculardisease becauseofexce ssabdominalfat.The relation shipbetwe enBMIan dwaistcir cumfe ren cefor d efin in grisk isshownin Table36.5.
TABLE 36.4. Body
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
Height (in.) 58 59 60 61 62 63 64 65 66 67 68 91 94 97 100 104 107 110 114 118 121 125 96 99 102 106 109 113 116 120 124 127 131 100 104 107 111 115 118 122 126 130 134 138 105 109 112 116 120 124 128 132 136 140 144 110 114 118 122 126 130 134 138 142 146 151 115 119 123 127 131 135 140 144 148 153 158 119 124 128 132 136 141 145 150 155 159 164 124 128 133 137 142 146 151 156 161 166 171 129 133 138 143 147 152 157 162 167 172 177 134 138 143 148 153 158 163 168 173 178 184 138 143 148 153 158 163 169 174 179 185 190 143 148 153 158 164 169 174 180 186 191 197 148 153 158 164 169 175 180 186 192 198 203 153 158 163 169 175 180 186 192 198 204 210 158 163 168 174 180 186 192 198 204 211 216 162 168 174 180 186 191 197 204 210 217 223
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69 70 71 72 73 74 75 76
128 132 136 140 144 148 152 156
135 139 143 147 151 155 160 164
142 146 150 154 159 163 168 172
149 153 157 162 166 171 176 180
155 160 165 169 174 179 184 189
162 167 172 177 182 186 192 197
169 174 179 184 189 194 200 205
176 181 186 191 197 202 208 213
182 188 193 199 204 210 216 221
189 195 200 206 212 218 224 230
196 202 208 213 219 225 232 238
203 209 215 221 227 233 240 246
209 216 222 228 235 241 248 254
216 222 229 235 242 249 256 263
223 229 236 242 250 256 264 271
230 236 243 250 257 264 272 279
Tousethetable,findtheappropriateheightintheleft-handcolumn.Moveacrosstoagivenweight.Thenumberatthetopofthecolumnis
FromNationalInstituteofHealth,NationalHeart,Lung,andBloodInstitute,NorthAmericanAssociationfortheStudyofObesity.Thepracti
TABLE 36.5. Classification of Overweight and Obesity by Body Mass Index, Waist Circumference, and Associated Disease Risk
Disease riska relative to normal weight and waist circumference
BMI (kg/m2) 18.5 18.524.9 25.029.9 30.034.9 35.039.9 40
Obesity class I II III
M<102 cm (40 in.) W<88 cm (35 in.) Increased High Veryhigh Extremelyhigh
M>102 cm (>40 in.) W>88 cm (>35 in.) High Veryhigh Veryhigh Extremelyhigh
Underweight Normalb Overweight Obese Extremelyobese M,men;W,women.
aDiseaseriskfortype2diabetes,hypertension,andcardiovasculardisease.
Increasedwaistcircumferencecanalsobeamarkerforincreasedriskeveninpersonsofnormalweight.
FromNationalInstitutesofHealth,NationalHeart,Lung,andBloodInstitute,NorthAmericanAssociationforthe StudyofObesity.Thepracticalguide:identification,evaluation,andtreatmentofoverweightandobesityin adults.NIHpublicationno.00-4084,October2000.
CARBOHYDRATE
The d iet ofth enormalanddiab eticin dividu alsdiffer sverylittlethe sedays ,chiefly
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becauseofthe discover yofinsu lin.At one timemyhospitalpat ien tsdidnothaveover 30gramsofcarbohydr ate sperday ,or thee quivalen tofabou ton eounce ort wo table spoonsofsugar.Todaynopatie nth aslessthan150g ramsofcarboh ydrateorthe equ ivalentof10tablespoonfulsofsu garor10slice sofbread.(1) Caloriesfromcarbohydratearevariable and shouldbein dividu aliz edon the basisofn utrition al asse ssme nt,diabetest reat men tgoals,other medicalissues, andt hepatient'seat in ghabitsandre spon se ofb loodgluc oset ocarboh ydrateintake. Ifproteincontr ibu tes10%to20%ofcalories, carbohydr ateandfatcan b edist ributed b etween the remaining 80%an d90%ofcalorie s,afte rthe bloodglu cose andlipidleve lsaretakenint oacc oun t(21). Although c arbohydr atefoodsvary int heabilitytopromotegoodh ealth ,th etotalamou ntof car boh ydrateconsumedismoreimport ant thanthe sou rceorthe typeofcarbohy drate .Eve nsucr ose contain in gfoodsmaybesu bstitute dforothe rcar boh ydrat egramsan dare accept ableaslongast hese foodsarewithinth econ tex tofah ealth yme alplanandme taboliccontr olan ddesirablebodyweightare maintain ed. Anu tritionpr escription (basedonn utr itionalasse ssme ntan dtre atment goals)mayre sultinare duction incar boh ydrat ean ddie tary fatparticular lysatur ate dfatwh ich in tur nredu cescar diovasc ularrisk. Although t her eare supportivestu die sin dicatingth ath igh -carbohyd rate mealplansimproveglucose tole ran cean din sulin sensitivity(21,22,23, 24),the reisstillsomedisagr eementabou twhatconstitut es th eopt imalperce ntageofcarbohydr ateforper son swith diabete s(25, 26).Although s omerese arch ers ar econ cern edabout high-car boh ydratedietsandth eir pote ntialfor in flu encingglucoseandlipid metab olisman dbloodpressu re(27,28,29, 30,31,32),oth ershavedemonstratedt hat thelimited elevation inlipidscanbep reven tedifcarbohy drat eand fiber in thedietareincre asedinparallel (33,34,35). JoslinDiab etesC ente rhasrecen tly updatednu trition recommend ation sforpe oplewitht ype 2diabeteswh oareoverweight andobese .Alt houghadditionalr esearchwillbere quiredtodefinet he maximu mn utrien tsthatpromoteb oth bloodglu cose c ont rolan dweightlosssuccess, we curre ntlyasse ss eachpat ie ntindividuallytodeter mineanapprop riatemealplan composition based onr educingcalories toach iev ean egative caloricbalan cean dusingth egu idelinesbe low:
Carbohydrates
Nomoreth an40%oftotaldailycaloriein tak eshouldcomefromcarbohydr ates, whichshouldbemainly low-glycemic -in dexfoodssu chasve getable s,fruits, andwh olean dminimallypr oce ssedgrain s.Refined car boh ydratesorprocessedgrain san dstarch yfoodsu chaspasta, bread,cere al,an dwhitepotat oes shouldbeavoided orconsu medinlimitedqu an tit ie s.
Protein
Tomaint ainmusclemassan dener gyexpe nditure ,30%oftotaldailycalor ie int ake sh ou ld c omefrom protein. Pre fe rablepr ote in sou rcesincludefish, p articular lycoldwater fish su chassalmon,t una,or sar din es,andchicken ,tu rkey, and oth erpoultryandsoy,rathe rthanre dorpr ocesse dme at. Furth ermor e,datasu ggestth atpr ote in aidsin the se nsationoffulln essan dthatlow-proteinmealplan s ar eassociatedwith in crease dhun ger. Th us, prot ein mayserve tor educe appet ite and assiston ein ach ie vin gan dmain tainingt hedesire dlowercaloriele vel.
Fat
Oftotaldailycalor ieint ake30%shouldcomefromfat,wh ich shouldbemainlyderivedfrom mon ou nsat uratedan dpolyu nsat uratedfat(e.g. ,nu ts,oliveoil, canolaoil)and fish, part icu larly those highinomega-3fatty acids.Meat sh ig hinsatu rat edfat ,in clu dingbee f, por k,lamb,an dhigh-fatdairy product s,shouldbeconsu medonlyinsmallamoun ts.Similarly,foodsh igh in tran s-fatt yacidsshouldbe av oided. The abovedistributionofn utr ien tsforove rweightandobesepe oplewithty pe2diabe teswill Pr omot elong -termweightlossint hos ewith type 2diabet es.The combin ationofr estrictingcalories whilein creasin gthe int ake ofproteinandlow-glycemic-in dexfoodsmaydimin ish these nsat ionof hu nger . Improv ebloodglu cose con trolbe cause ofth erelat ive lylowe rcarb oh ydrat econ ten tan dthelower glycemicinde xofth ose carbohyd rate sthatare con sume d. Improv ethe body 'sresponse toinsu lin(insu linse nsitivit y),whet her orn otwe igh tlossisachieve d. Improv ebloodlipidprofile,particularlytr iglycer idesandh igh -densitylipopr ote in (HDL)ch olester ol, whe ther orn otwe igh tlossisachieve d.
P. 617
Red uceth estre sson theinsu lin-pr odu cin gcellsinth epan creasbyredu cin gthe nee dforasmu ch insulin.
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Itisalsoimport ant tor ecogn iz ethatamealplan prescriptionalon eisnotsufficie nttomaximize significantandsust ainedwe igh tloss.Physicalact ivity, behaviormod ification,andgoodsu pportsyste ms ar eextr eme lyimport ant adjun ctstothediet arypr escription d escribedab ove .
Glycemic Index
Allcomplexcarbohydratesandallsimplecarb ohy drat es(or sugar s)traditionallywereth ou ght t o gen eratedifferen tbloodglu cose responses b asedonmolecu larstru cture .Howe ver, aninconsisten t relat ionsh ipofglucoseresponse demonst rate dfromso-calle dsimple and c omple xcarbohy drate s sugg eststh iste rminologymay b emisleadingandre strictiveinme alplann in g.Thepositionofthe Ame ricanDiabete sAs sociationisthatprioritysh ou ldbe give ntothe tot alamou ntrathe rthanth esou rce ofcarbohydr ate. Controver syisongoingab ou twheth erth eingest ionofsimilar amou ntsofcarbohyd rate foodsprodu cesdiffe rent blood glu coseandinsu linre spon sesan dwhet hert hisin formationwillhave use fulclinicalapplication s. In1981, Je nkinset al.(36)sugge stedth att hebloodglucosean din sulin response toafoodcou ld b e expr essedasaglycemicinde x,whichqu an tifiesth epostprandialglu cose responset oaparticular foodin comparis ont oth eresp on setoastan dar damou ntofglu cose ,or anattempttoclassifyfoodsbyth e ext entt owhich t heyr aisethe bloodglu cose lev el. Glucosealonepr odu cesth elargest incr ease in blood glucoselevelan disassign edaglycemicin dexof100.Fib er-richfoods, acidicfoods,an dhigh-fatfoods oftenh ave lowglyce micin dexe s.Theglycemicin dexofsucrose,adisaccharide madeupofglucosean d fru ctose ,is lowerth ant hat ofsomest arch es,su chaspotatoe s,becausesu crose con tainslesspu re glucose. Thoseinfav orofreplacingfood shaving ahighglycemicin dexwithfoodsh avingalowgly cemicindex refe rtostudiesdemonstratingth evalue ofth eglycemicinde xin thediet aryman agemen tofdiabe tes (37,38,39, 40,41,42,43, 44,45,46).However ,other sfind thatthe st udyre sultsar enotcon sis tent or pre dictablean dnotclinicallyusefu l(47, 48,49,50).An oth ercontr ove rsyexistsoverth eimpactofmeals withah ig hglycemicindex versu smealswith alowglycemicinde xon we igh tlossandsat ie ty.Lu dwig (41)sugge ststh atth eingestionoflow-gly cemic-index foodstypically ind ucesh igh ersat ie tythandoes th ein gestionofh igh -glycemic-inde xfoodsan disfollowedbyth ein tak eoffewe rcalor ie satsub seque nt meals.Itisthe or ize dthatslowerr atesofdigestion and absorption oflow-glycemic-in dexfoodsst imulate nu trient recept orsint hegastroin testinalt ractforalongerp eriod, resultinginalonger periodof feed backtothe satiety cente rin the brain. Br and -Miller e tal.(42)sug gestth ath igh -gly cemic-index mealsdictate differ ence sin satietyandcaloricin take becau seoft hefasterdigestionan dabsorptionan d highinsu linr esponses,andth att heye xpan dfatstores. Pi-Sun yer(49)takesth epositionthatth edat a ar enotyet sufficien tan dthatmostofthe d atarelatingh igh -gly cemic-index mealst oincre asedfood intakewere colle ctedinsingle-mealexpe rimen taldesigns. Alth ou ghth eweight-lossbene fitofalowglycemic-inde xdie tcomparedwithahigh-glycemic-inde xdie tiss tillon lyahypothe sis, itmaybe helpful touset heglycemicind exasanadd itionalweight-losstool.Alow-glycemic-inde xdie tconsistin gof vege tables, fruits,andlegumes, amoder ateamoun tofpr ote in andu nsaturatedfats,andfewer refined car boh ydratefoodsalon gwith ove ralldecreasedcaloriein take and in crease dphysicalact ivity will assistpatientsint heirweight-losseffor ts(40).Asmorelong-te rmre sear chtrialsonglycemicre spon se tosin gle foodsan dcompletemealsar econ duct ed,th euse fulnessofthiscon ceptasate achingt oolis increasing(Table36.6).However, the g lyce micresponse tofoodd epend snoton lyont heamount and type ofcarboh ydratebu talsoonothe rvar iable s(Table36.7), whichcouldimpact t heglycemiceffectof th ecarbohy drat efoodeaten. Tofur ther deter minet heimpactofcarbohydr ate foodson blood g lu cose levels,re sear chersh ave comeupwithawaytodescribet heex tent towh ich theb loodglucoserises(GI) an dremainsh igh .Thisiscalledt heglycemicload(GL).The GLprovidesameasure ofth ele velof glucoseinthe blood,but also th ein sulin demand p rodu cedbyanormalse rvingoft hefood .TheGLconsidersafood'sGIaswellasthe amount ofcar boh ydrat eperse rvingan dgivesamor edetailedpictu re. TABLE 36.6. Glycemic Index of Common Carbohydrate Foods, Using Glucose as Standard P. 618
Greater than 70% Frenchbaguette,1oz Blackbread,1.7oz Cornflakes,1cup RiceChex,1
55%70% Pitabread,2oz Whitebread,1oz Cheerios,1cup Shreddedwheat,2/3cup
Less than 55% Pumpernickel,wholegrain,1oz Sourdoughbread,1.5oz(acid) All-branwithextrafiber,cup Frostedflakes,cup
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Ricecakes,3plain Vanillawafers,7 Dates,5 Watermelon,1cup Tofufrozendessert,cup Angelfoodcake,1oz Jellybeans,10large LifeSavers,6 Bakedpotatowithoutfat Rice,instant,1cup Millet,cup Bagel,1small
StonedWheatThins,3 Shortbreadcookies,4 Pineapple,2slices Raisins,cup Icecream,cup Blueberrymuffin,2oz Coca-Cola,1can Honey,1tbsp Whiteboiledpotato Basmatiwhiterice,1cup Couscous,cup Macaroniandcheese,1cup
SocialTeabiscuits,4 Twixchocolatecookie,2oz Cherries,10large Banana,1medium Icemilk,cup Poundcake,3oz Chocolatebar,1.5oz M&Mchocolatepeanuts,1.7oz Sweetpotato Brownrice,1cup Barley,cup Spaghetti,white,1cup
AdaptedfromBrand-MillerJ,WoleverTM,ColgiuriS,etal.The glucose revolution: the authoritative guide to the glycemic index.NewYork:Marlowe&Company,1999.
TABLE 36.7. Factors Affecting Glycemic Response
Food factors Structureofthefood Foodstorageprocedures Presenceoffat Protein/starchinterrelationships Cooking/processingmethod(particlesize, blending,grinding) Ripenessormaturity Presenceandtypeoffiber Resistantstarch Solublenonstarchpolysaccharides Resilienceofcellstructure
Human factors Variableratesofdigestionandabsorption Stimulationofgutpeptides Concomitantdiseases Bodymass/weight Preprandialbloodglucoselevel Compositionofpreviousmeal Exercise/activity Timeofday Genderandage Ethnicityandrace
TheGIdet ermin eshowrapidlyaparticularcarbohydratefoodmay r aisebloodglucose. TheGLdet ermin eshowmu chimpactacarbohydratefoodmay h ave on blood g lu coseleve ls, depe ndingonth enu mbe rofgramsofcarb oh ydrat ein aser vin g.
GIdividedb y100(glucoseis se ttoequal100)mu lt iplie dbyth ecarbohy drate grams/serv in g=GL(51) Fore xample ,itmaybere comme ndedt hat carrotsbee liminatede ntirelyowin gtot heirver yhighGI valu eof92.C ommonse nse, however, tellsu sthatcarr otsareaveget ablean dprovide fiber and h ealth y nu trient s.Fore xample : cup carr ots GI92/1004gcarb=GLof3. 7=Low GL 2 cup s carrots GI92/10016gcarb =GLof15=Medium GL Inge ner al,the GIishighe stifh igh GIfoodsareeaten in largequ ant ities. LowGIfoodsusu ally h ave a lowGL,bu tme diu mtohighGIfoodscanran gefromlowt oh igh GL. Th ere fore ,youcan redu cethe GLby limit in gfoodsthathavebothahighGIan dahighcarbohydrateconte nt.
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Most agree thatthe abilityofaper son toadher etoadietaryregimenisin verse lyre latedt oth e complexityofthe r egimen .Calcu latingth eglycemicinde xateachmealmaybebu rden someforsome individ uals.Because t hee xacte ffe ctoffood onaperson'sbloodglu cose lev elisan in div idu alresponse tospecificfoods andmeals,patient saree ncouragedtoide ntifyth eir ownglyce micin dexforcertain foodsbyu sin gself-manage me ntofblood glu cose. There fore ,wemayproposeth euseofthe glyce mic indexasan adjun cttot hedietarymanagement toolsalread yin usebyour p atient s. Informationabout g lyce micin dexmaybe reviewedwithpatient swh o(a)trackthe ircarbohydrateintake an dkeep bloodg lu coseandfoodr ecor ds;(b)monitorthe ir b loodglucoseleve lsatle asttwoorthre e time sperdayand arewillingtoevalu ate blood g lu coseleve lsfollowin gmeals ;(c )followupwitha reg iste reddietitian toe valuat eout-of-ran gebloodglucosevalue sthatmaybedu etocon sump tionof par ticulartyp esofcarbohydratefoods;(d) e xpressaninte restinmakingadditionalmod ificationsinthe ir eatingplant ofine-t une glyce miccon trol;and(e)e xpressaninte restinu sin gin formationab ou t glycemicinde xforh elpin gtoguidefoodchoicesfor weigh tcontrol. The p rimar ygoalisfor patien tstoachieve b oth gly cemican dweightcontr olwhile eating avar iet yof nu trition allybalance dfoods.Itisnotne cessar ytocomple telyavoid foodswith ah igh glyce micin dex, becauseman yare healt hy,n utritiousfoodsth atcanbeeaten in moderation .Howe ver,patient sshould bee ncouragedtoin clu demore unpr ocesse d,high -fiber foods,forwhichalowerglycemicre spon sehas bee ngen erated.E xample sofh igh -fibe rfoodsincludelent ils,be ans, leg umes,rawandu npee le dfruits an dvege tables,orfoodst hat have been minimallycooke d(52). Becausekn owledge offoodcomposition andph ysiology isnotsu fficient tope rmitacon siste ntpr ediction ofg lyce micresponse s,the principle t hat foodchoice scanbe refinedt oobtainmaximalcon trolofblood glucoseremainsapossibilityformotivatedindivid ualswhocloselymon itorth eirbloodglu cose le vels. Aware nessofdiffe rence sin gly cemicresponse tofoodhasplay edan importan trole ine xpan din gou r th in kin gabouth owtoimproved iet aryman agemen tan dou rund erstandingofwhat occu rsin thed aily management ofindivid ualswit hdiabet es.
Sucrose
The inclusionofsucroseinthe tot alcarbohy drate con tent ofth ediethasnotbee nfou ndtoimpairblood glucosecontrolinind ividualswith e it hert ype1orty pe2diabe tes(15).C on sumptionofmodest amou nts ofsu crosebyper son swith diabete sisacceptable aslong asbothmetaboliccont rolan dweightare maintain ed.For in stan ce,sev eralinvest igatorsfou ndnosignificantdiffere ncebet ween t hebloodglucose resp on sesofpe rson swit hdiabet eswhen they con sumedsucroseandwhe nth eyconsumedonlystar ch (53,54,55, 56). Inarecen tstu dy(57),nine childre nwithty pe1diabe teswere studiedinacon trolledset tin gtocompare glycemicre spon sesofisocalor icmix edme alsthatcon taine d2%sucrose(su crose -freediet )and17% sucr ose(su crose-contain in gdie t).Insu lininfu sionwasstart edth enightbe fore theb egin ningofthe stu dyperiodsoth atalloft hech ildren had fastingeu gly cemia. Dietswer ecare fullymat chedfornu trient an dene rgyconte nt,with onlysmalldiffere ncesn ote dforfiber .Theglycemicresponsewaslowerwith th e17%su crosedie tthanwitht he2%su crose die tove rthe 4-h ou rstudy p eriod. Th epeakblood glucoseresponse wasearlier andlowe rwit hth e17%su crosedie t.The resultssu ggestth atmoderate amount sofsucr oseisocalor icallyexch ang edfor starch lowere dtheglyce micresponseb etween breakfast an dlu nch in ch ildre nwhoweree uglycemicbe fore breakfast. Oth erinvest igatorshavestud ied t hebloodglucosere spon sein adu lt swith type1and t ype2diabetes an dfou ndn osignificantdiffere ncebe tween thebloodglucosere spon sestothe irconsu mpt ionofsucrose an dthe responsest oth eircon sumption ofonlystar ch(55,58). P. 619 The cr ossoverst udyofBant le etal.(55)with12patie ntswitht ype2diabetesinvolvedtwostudy die ts ah igh -sucrosediet(19%kilocalorie sfromsucrose)andah ig h-starchdiet(<3%kilocaloriesfrom sucr ose)for28day s.Thesu crosean dstarch die tsprovidedabout 55%kilocaloriesfromcar boh ydrate, 15%kilocaloriesfromp rot ein ,an d30%k ilocaloriesfromfat.The twodiet scont ainedalmostide ntical amount sofdietaryfib er,ch oleste rol,polyunsatur ate dfat,monounsatur ated fat,andsaturatedfat.No significantdiffere nceswer enotedbe tween thest udydietwith19%ofk ilocaloriesfromsu croserelative toadietde riv in gitse nerg yfromstarchonth eme anplasmaandu rin ary g lu cose, fastingse rum cholester ol,HDL c holest erol, low-densitylipopr ote in (LDL)ch oleste rol,andtr iglyceridesleve ls. Availablestu die shave allowedch ildren and adultswithdiabe testofeellesscon strain edbyallowing th emadie tmoreconsiste ntwithth esucr ose-cont ainingdietofthe irpe ers.R ealisticgu id eline sfor includingsu crose -con tainingfood sint hedietalsoimprovespatient adhe rence toover alldietary management .Howev er,su crosedoe sencourageth edeve lopmentofden talcaries, andsu crosecontain in gfoodsmaycontain asig nificantnu mbe rofcalories,e speciallywh encomb in edwit hfatin desse rtfoodssu chasbakedgood s,ice cream,andch ocolatebars.Thismaycontr ibu tetoelevat ed seru mlipidleve lsandweight g aininsomepe opleifthey aren ot carefu llymon itored .These find in gsare indicationsofh owglycemicin dexingismakin gusre con side rstronglyhe lddoctrine sandpe rmitting usto deve lopimproved d iet aryr ecommendation s.
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Fiber
The p opu lationwith d iabetesint heUn it edStat esconsumes,onaverage,only16goffiber p erday (59) , whichisbelowt here comme ndedint akeof20to35g/dayforthosewithorwit houtdiabe tes.Previous stu die son fiber ind iabetesh ave h adsome what in con siste ntre sults,pr obablyasaconsequ en ceof pre viouslyun recognizeddiffere ncesinth eamount s,type s,an dprop ertiesoffiber .Thebe nefitsoffiber inimprovingser umcholest erolleve lsandcolonicfunct ionarewelle stablished(60), andt heAmerican DiabetesAssociation curre ntlyrecommen dsthe con sumption of20to35g offiberdailyon the basisof th eseben efits.However, the e ffectsoffiber on glyce miah avebe enconsidere dtob eminimal(15). Seve ralstudiesh avede monst rate dthatdietspar ticu larlyhighinfiber(es peciallysolu blefibe r)are associate dwith lowerbloodglucoseandseru mlipidleve ls.Water -solublefibers, su chasthepe ctins, gums,st oragepolysaccharides,andafe wh emicellulose sfou ndinfruits, legu me s,lentils,root s,tube rs, oats, andoat b ran ,havelitt leinflue nceonfecalbu lk butmayre ducese rumle velsofglucosean din sulin (61,62,63, 64,65).Wole ver(66)re port edth atth eamountofsolu ble fiber inwh olefoodsisnotclose ly relat edtoglu cose responsebu tdiscern edaweak,bu tsignificant,corre lation b etwee nthe tot aldie tary fiberan dthe gly cemicresponse toafood.Hepostu latedth att hecellwallsoffoodsthatelicite dalow glycemicre spon sewere sturd yandh igh in cellu loseandhe micellu lose.Howeve r,th ediffe rence sin fibe r componen tsoffoodsdid n ot explainallthe v ariationinglycemicre spon se.Water-insolublefibers,su ch asce llulos e,lign in ,an dmosth emicellu losesfoun din whole-gr ainbre ads,ce reals,andwhe atbr an, affect gas troin testinaltr ansittimean dfecalbulkbut hav elittleimp actonplasmaglucose,insu lin, or cholester olle vels. Neweviden ceth athigh diet aryfiberint akeisben eficialintyp e2diabe tesconfirmspr eviou slypu blish ed rese arch (67,68,69).In are centcr ossoverst udy,C handaliaetal. (70)demon strat edthatintakeof dietaryfib er,particularlysolu ble fibe r,abovet heamoun tsrecommen dedbyth eAme ricanDiabete s Associationimprov esgly cemiccontrolandd ecreaseshyp erinsulinemiain patien tswit htype 2diabe tes, inadd itiontothe e xpecte ddecre aseinplasmalipidconcen trations. Thirtee npat ien tswithtyp e2 diabet esfollowed t wodiets, each for6weeks. Both die tscon sis tedofu nfortifie dfibe rfoods,15% protein, 55%carboh ydrate,and30%fat. Th ehighfiber studydiet p rovided 50goftotalfib erdaily,with solu ble andinsolublefib erprovidin g25geach .TheAmerican Diabe tesAssociationst udydietcontain ed 24goft otalfiberp erday ,wit hsolu blefiber cont rib uting8gand insolublefibercontribu tin g16g.Daily plasmaglucoselevelswere10%lower with theh ig h-fib erdietth anwith theAmerican Diabet es Associationdiet .Ren dell(71)statedth att hisstudyclearlypointe dou tth eimportan ceofd iet ary inter vent ioninpatie ntswithdiabetesandth att hede crease in thed egree ofhy perglycemiaach iev edin th estudy byChandaliae tal.byincre asingpatie nts'fibe rin tak eissimilart oth att ypicallyobtaine dby th eaddition ofanother oralh ypoglyce micdru gtot heth erapeut icre gimen. Asexpect ed,t hehigh -fiber dietre sultedinlower fastingplasmatotalch oleste rol,t riglycer ide ,an dvery-low-density lipopolysaccharid e(VLDL)conce ntration sthandidtheAmerican Diabe tesAssociationdiet . Although itisun cle arifimprovedglycemiccont rolassociated with highfiberintakeisduet oan in crease insolu ble fiber ,in solub lefiber, orb oth ,th etotalamou ntoffibe rfromun for tifiedwh olefoodsh asnow bee nbett erdefine d.Aprac ticalwayofpr ocee din gist odet ermin eth ecurre ntleve loffibe rin apat ie nt's dietandtoin creasethe amou ntoffiber gradu allyt oamaximumof50g/day.The gradu alin troductionof th efibe rminimize sgastr ointe stin alproble mssu chasosmoticdiarrh eaandflatu le nce. Increasedfiber intakeshouldbeaccompan ie dbyan in crease offluidin tak ean dcarefu latten tion tose lf-mon it oringof bloodglucosele vels.Int akeoflargequ an tit ie soffibercandelayorred ucepe akglucoseresponse sto car boh ydratean dperh apspre disposeanindivid ualrece iving antidiabe tesmedication toh ypogly cemiaif th edosageofthe medicat ionisnotadju stedtocompen sate forth ise ffect.
PROTEIN
The q uan tityofpr ote in requ ire dbydiabeticpatie ntsvarieswit hage ,weightand act ivityofthe caseaswellaswith t hecondition ofth ekidne ys.Itisasafe ruleat the beginn in goft reat men ttoin creasethe prot eingraduallyuptoth esamequantityas th atre quiredbyanormalind ividual. Thisisap prox imate ly1to1.5gramsperk ilogr am bodyweightforadu lt sbutforchildrenitmayre ach 3grams.(1) InatypicalWeste rndiet, t hee stimat edproteinintakeis1. 1to1.4g/kgofbody we igh tfor a70-kg per son ing esting2,000kcal/day,anamount consider ablygreatert han the minimu mre comme ndedby th eNation alAcademyofScien ces(72).Th e1989Recommende dDietaryAllowan ce(RDA)forprotein continu estostan dat0.8g/k gofbodyweightforadults.Thistranslate stoabou t10%to20%oft otal dailycalor ie sfr omproteinfromboth animalandve getable sou rces.Th ereisnoevidence tosu pporta highe r-or lower-th an -aver agepr ote in in take fort hosewit hdiabet es. Individualswh ose d iabetesisun dergood c ont rolap peart oh avet hesamepr ote in requ ire men tsas individ ualswit houtdiabe tes.Th us,wh eninsu linlevelsar enormal,proteiniscon serve din thebodyand th euseofamin oacid sforglucosesyn thes isislimite d(73).Howe ver,se vere insu lin d eficien cyin creases th elossofb odypr ote in ,an dthosewithpoorly cont rolleddiabet esmayhaveincre asedn eedsforprotein
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becauset heirlive rmayusep rot ein tos ynth esizeglucose.Astu dybyNairetal. (74) P. 620 demon stratedth atwith drawalofin sulin resulte din a97%incr ease in p rot ein lossinsubject swith type1 diabet es. Although t her eisn oe vide nceth atr estrictingprotein willpre ven torde laythe on setofneph rop ath y (75),sev eralsmallstu dieshavesugge stedth atp atient swith ove rtne phropat hywouldbene fitfr oma pre scribe dproteinres trictionof0. 6g/kgpe rday. Limitin gproteinconsumptionto0.6g/kgper day (alth ou ghstu dypar ticipan tsach ie vedarestriction ofonly0. 7g/kgp erday )suggest edamode st lower in gofth erateofd ecline in theglomer ularfilt rationrate.However ,the Modified DietinRe nal DiseaseStu dy(on ly3%ofpar tic ipantsh adtype 2diabe tesan dnoneh adty pe1diabe tes)didnot indicate anyclearben efit ofproteinr estriction (76).Thege neralconse nsu sistoprescr ibe aprotein intakeof0.8g/kgperdayinth osepatient swith ove rtne phropat hy,withapossiblelower in gto0.6g/kg per d ayonceth eglomeru larfiltr ation rat ebeginstodeclin ean dcare fulmonitorin gfor possibleprotein deficiencyandmuscleweakness(15). Becausepastdietaryrecommen dationsfor personswithdiabe tessome timesemphasiz edproteinand becauset heaverageAme ricaneatsmore prot einthanisnece ssaryt omaintain healt h(15%to20%of calorie s),cur rent recommend ation ssugge stthatpeoplewith diabete scon sumeamou ntssimilart oth ose consumedbype oplewithout diabetes .Eviden cesugge ststhatth isamoun tofprote in isnoth armful.
Protein and Glucose Concentration

Asearlyas1915,Jan ney r eportedt hat 3.5gofglucosecouldbeproduce dasth eresu ltofabe ef-protein mealfor e veryg ramofnitr ogen excre tedinth eurine .Ifbeefpr ote in is16%nitrogen ,56%ofbeef proteincanbeconve rtedt oglucose(77).However ,seve ralstudiescomp let edaft erJan ney 'scalculat ion th atfocusedont heeffe ctofprote in onglucoser espon sesug gestedt hat prot einin gestionbypatie nts withandwit houtdiabe tesdidnotelevatebloodglucoselevels.The seimportantfindingswer elost, an d Jan ney 'sth eor eticalcalculationpre vaile d.Inre cent year s,seve ralstudiescondu ctedbyNu ttalletal. (78,79,80)cont in uetosupport t hat glu cose con centr ation did not in creaseafte rproteiningest ionin peoplewit horwith ou tdiabet es.In 1999, Gannone tal.(81)rep ort edthatth ein gestionof50gofle an bee fp rot ein bypar ticipantswithty pe2diab etesre sultedinth eapp earanceofon ly about2.0gas glucoseinthe circ ulation moreth an 8hour slater. Th isre sultwascomparedwith t hat forpatient swh o consumedonlywate r.Although the ing estion ofbee fin crease dglu cose con cent rationby0.1mmol/Lat1 hour ,the con centr ationthe ndecr ease dsimilar lyt oth atofpart icipan tswhocon sumedonlywate r. Furth erqu estion sarosewhe nth eplasmainsulinle velremainedst eady in t hewatergroup b utth einsulin levelin creasedth reefoldandt heplasmaglucagon in creased50%int heprote in g rou p.If gluconeogen esisfr omproteinisfou nd,re sear cherscanonlythe or ize wh yglucosedoe snotappe arinth e gen eralcirculat ion. Se veralth eorie s,noted inareviewofavailablere sear chbyFran z(77),sugg estth e following: Theg lu coseconv erted fr omproteinismu chle ssthanth ethe orize d50%to60%, an dthesmaller amount ofglucosefromproteint hat actu allye nter stheg ener alcircu lation isoffsetbya correspondingincr ease in g lu coseu se,aslongasenough in sulin isavailable. Theconv ersion ofglucosefrompr ote in isinfact 50%to60%,butt hisglu cose d oesn ot actu ally en terth egen eralcirculat ion. Gluconeogen esisfromproteinmayoccurslowlyover24h ou rs,andth e glucoseisd isposedofove rthislon gperiod. Incr ease din sulin secretioncau sedbydiet aryprote in resultsinrapidst orageoftheg lu coseas glycog eninth elive rand sk eletalmuscles.Thisglycoge ncan bebroken down togluc osewh en ne eded;h owev er,t hebodydoesnotident ifyth eglucoseen teringth egen eralcirculat ionasa product fr omproteinorcarbohy drat e. Cu rren tstu diesofproteinanditseffectsonbloodglucoseconcen trationh ave possibleclinical implication sforboth type1and t ype2diabetes .Forth ose with type1diabete s,possibleincre asesin th eproteinconte ntofthediet ,whichsee mstohaveaminimalimpactonglucosecon cent rat ions,wh ile decr easingth ecar boh ydrateconten t,mayimprov ean dstabilize blood g lu cosee xcursions.Forthosewith type 2diabe tes,th eingest ionofmoreprote in alon gwith le sscarbohydr ate may in crease the concen trat ionofcir culatinginsu lin. Th esepossibilitie sdemonst rat ethe impor tan ceofe xamin in gthe ben eficialorpotent iallyharmfule ffectsofin gestingh igh eramount sofproteinforth osewith d iabetes.
FAT
The d iscovery ofinsulinhaslowere dthefatinthe diabetic'sdiet ,becauseh ecan t ake more carbohydr ate .Indirect ly, thismayret ardth edeve lopmentofharden in gofth e ar teries.Howmu chfat shouldadiabet icpatiente at?Thesafestanswerwouldbe:as litt le aspossiblyabove t hen ormalquantityinorder tomaint ainnormalbody we igh t. (1)
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Pe oplewitht ype1diabeteswh omaintain goodcontrolofbloodglucosewit hinsulinhaveplasmalip id levelssimilartothoseofthege neralp opu lationofthe sameage andge nder .Howe ver, t hepr evalen ceof hy perlipidemiaan dcor on aryh eart dise ase(C HD)amongpat ie ntswithty pe2diabe tesistwofoldto fourfoldh igh erth an int hege neralpopu lation. Fre quen tlipidabn or malitiesar ehype rtriglyceridemiaand decr eased high-den sit ylipoprot eincholesterol(HDL-C ),although con cent rationsoflow-density lipoproteinch oleste rol(LDL-C)ar eoft ennotsignificant lydiffere ntfromt hosein con trolpopulat ions. Howe ver, patien tswith type 2diabet esare twice aslike lyascon trolpopulat ionstoaccu mu latesmalle r, den serLDLpart icles, wh ich mayin creasethe riskofCHDeven ifLDL-Cleve lsarenotsignificantly increased(82,83). Accordin gtorecen trese arch ,diffe ren ttypesandsource soffat hav ebene ficialor detrimentale ffectson lipidlevels. Mon ou nsat urated fat sare liquidatr oomt empe ratu reandder ive dprimarilyfromoleicacid .Major dietarysou rcesareolive, canola,andpeanu toils;avocados;nu ts;an doliv es.The senones sential fat tyacids(NEFAs)helplower LDL-C lev elsandpossiblyr aiseHDL-C lev els.Ge ner ally, about10%to 15%oftotalcalorie smaycomefrommonounsatur atedfats.
Polyun satu rate d fatsareliqu idatroomtemperatur ean dderivedfromlinole ic, linole nic,an d ar achidonicacids.Major die tary s our cesar ecor n,safflower,se same,andsoybean oils.These esse ntialfatt yacids(EFAs)arek nown tolowerbothLDL-Candplasmach oleste rollevels.Omega-3 fat tyacids,atypeofpolyu nsat uratedfat ,lower p lasmatriglyce ridean dvery-low-density lipopolysaccaridech oleste rol(VLDL-C)levels.Majordie tar ysou rcesar efatt yfish ,flaxsee dand other veget ableoils,shorte nings,andliq uidorpartially hydrogen ate dmargarine s.
Sat urat ed fat saremos tly solidatroomtemperatur ean dsynth esizedinth ebod yfromace tate .Major dietarysou rcesareanimalproduct ssuchasbutt er,meat,lard, pou ltr yskin,wholemilk,che ese, sourcre am,creamch eese, and t rop icaloilssuch ascocon ut, cocoabu tter, palmoil,andpalmkern el oil.The seNEFAsinc rease tot alserumcholester oland LDL-C lev els. P. 621 Tran s-fatsaresemisolidatroomte mper atu re.Th echemicalproc essofh ydrogenation cause s un satu rat edfatt yacidstobecomemor esat uratedan dalter sthepositionofhydr oge nat omsaroun d th edou blebon d(on opp ositesides, ortr ans). Thisproce ssin creasesthe shelflifeoffoods.Major dietarysou rcesarepoly unsatur ated v egetableoilsin solidmar garines ,saladdr essin gs,sh ort ening, an dmanybakedgood s.Tran s-fatsincre aseLDL-Canddecr ease HDL-Candareassociate dwith an increasedriskofCHD.
Guidelines of the National Cholesterol Education Program: Adult Treatment Panel III
Res earch advancesint hepre vent ionandmanagement ofhighch olest erolinad ultsle dthe Nation al Ch oleste rolEdu cat ionProgr am(NC EP)E xper tPanelon Det ection ,Ev aluat ion,andTre atment ofHigh BloodCh olester olin Adults(AdultTreatmentPan elIII,ATPIII)toissu emajor n ewclin icalpr actice guidelinesin2001(84).In 1985, thisprogrambegantopromotegr eate rawarene ssbyphys ician sand pat ie ntsofCHDr iskstatus b ybloodcholest erolleve landtoprovide recommend ation sford iet ary tre atment and e ducationalpr ogr ams.Earliergu ideline swereissue din 1988and1993. The 2001ATPIII g uideline srecommen dane wse toft herapeu ticlifestylechange s( TLC s)thatinten sify th euseofnu trition, physicalact ivity, and we igh tcontrolint hetr eat men tofe lev ate dblood ch olest erol (Table36.8).The seguidelinesre flect chan gesinth eeatin ghabits ofAme ricans, in clu din gadecr ease in th econ sumption ofsaturatedfatsan dcholest erol. Th epre sentr ecommendation sallowupto35%of dailycalor ie sfr omtotalfat, prov ide dmostlyfromun satu rat edfat, whichdoesnotraisech olest erol levels.Abn ormalitie sin lipidandcarbohydratemetabolisminth ose with diabete smus tbecar efully asse ssedbecauseofthe pot entialriskofp romot in ghigher triglyce ridele velswith ah igh -carbohyd rate dietwhileat temptin gtodecreasetotalandsat uratedfat stolowe rLDL -C(85).Somepatient swith high triglycerideorlowHDLlev elsorbothmay n eedt oeatmore unsatur atedfatstokeept heirtriglycerideor HDL leve lsfromworse ning. TABLE 36.8. Therapeutic Lifestyle Changes: Nutrient Composition of Therapeutic Lifestyle Changes Diet
Nutrient Saturatedfata Polyunsaturatedfat
Recommended intake Lessthan7%oftotalcalories Upto10%oftotalcalories
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Monounsaturatedfat Totalfat Carbohydrateb Fiber Protein Cholesterol Totalcalories(energy)c
Upto20%oftotalcalories 25%35%oftotalcalories 5060%oftotalcalories 2039g/day Approximately15%oftotalcalories Lessthan200mg/day Balanceenergyintakeandexpenditureto maintaindesirableweightandpreventweightgain
aTrans-fattyacidsareanotherLDL-raisingfatthatshouldbelimitedinthediet.
bCarbohydrateshouldbederivedpredominantlyfromfoodsrichincomplexcarbohydrates,includinggrains, especiallywholegrains;fruits;andvegetables.
Dailyenergyexpenditureshouldincludeatleastmoderatephysicalactivity(contributing~200kcal/day).
FromtheNationalCholesterolEducationProgramExpertPanelonDetection,Evaluation,andTreatmentofHigh BloodCholesterolinAdults(AdultTreatmentPanelIII).JAMA2001;285:19,withpermission
ATPIIIalsoencour agesu seoffoodsthatcon tainplan tstanolsandster olsor arer ich in solublefiberto boost t heLDL-lower in gpower ofth ediet.Plantst anolsandst erolsareincluded ince rtain mar garine s an dsaladdr essin gs.Foodshigh in solublefiberincludece realgrain s,beans,pe as,legu me s,an dmany fru itsandve getables. Addit ionalgu ide line ss tressth eimportanceofweightcontr ol,whiche nhancest he lower in gofLDLle velsandincr ease sHDLlevels;an dphysicalact ivity, whichimprovesHDLvalue sand, forsome,LDLvalu es(86). The r ecommendation sfordietaryfat in take fort hose with diabete sdepen dson treatmentgoalsfor existingh yperlipide miaandriskofC HD,aswellasgoalsforbloodglucosean dweigh t.Ifth e recommen dat ionsfordie tar yproteinar eforabout15%oftotalcaloriesperday,th eremaining85%to 90%ofcalorie smaybedistribut edthr ou ghfat sandcarbohydrates. Th efirstlin eofde fenseistoget fewer than7%oft heallot tedcaloriesfromsaturatedfat,withdietarycholester ollimite dtolesst han 200mg/day .Upto10%oftotalcaloriesshouldbefrompolyun satu rate dfats, andu pto20%oft ot al calorie sshouldbefrommon ou nsaturatedfats.However, con sumption ofomega-3polyun satu rate dfats foundinse afooddoesnotn eedtobedecr ease din peoplewith diabetes. There main in gcaloriescanth en bede riv edfromcomplexcarbohydrates, in clu din gwhole g rains,fr uits,an dvege tables.
Fat Replacers
The medicalne edtodecreasefat in thediet softh osewith t ype2diabetesh asincre asedt hede man dfor palatable,lower-fat foodsand hasledtoth ecreationoffatr eplacers. Fatreplace rsare usedinman y fat -free, n on fat, redu ced-calorie ,an dlow-fatfoodsin anattempttolower fatan dcalorie in take .At pre sent, mostfat r eplacer sarecarbohydrate-based,b utsomearepr ote in -orfat-base d.One fat-based rep lacer,olestra,wasapprovedbyth eFoodan dDru gAdministration (FDA)in1996foruse in sn ack foodsandcrackers. St udiesoft hissynth eticoilin dicatedth atith asth epot entialtolowert otal cholester olan dLDL-C in p ersonsconsumingeithe rah igh -oralow-chole steroldie t(87). Although fatrep lacershaveth epotent ialt ore ducetotalandsat uratedfatin thediet ,pat ien tsmustbe edu cate dtou seth emwiselywit hinth econ text ofan ov erallfoodplan. Unfortu nat ely , manyp atient swith type2diabete sare n ot awar eofth epoten tialh igh -calorie con tent offat -freefoods madewithfatreplace rs.The sefoodsar ecreatedby u sin gmixtu resofcarbohy drate sorpr ote in sto simu lateth epropertiesoffatandcannotbee aten liber allywithout affecting caloricintake,glycemia, an dweight. P. 622
Plant Stanol Esters

Anewdiet aryapproacht ohe lping man age serumcholesterolle velsisnowbeingu sedinth eUnite d
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States.Plantst anole sters(PSEs)occurn atu rallyin plantprodu cts,espe ciallyoils,andar ethe satu rate d der ivativeofsitoster olknownas sitostanol.PSEsarestru ctur allysimilartocholester olan darev irt ually un absorbedb ythebody. PSEsarefoundinsoyan doliveoils,corn, rye,r ice ,wheat,andwood. More th an20pu blishe dstudiessu ppor tthe cholest erol-lowe ringeffect sofstanoles ters. Alan dmark15-mon th stu dybyMie ttinen etal.(88)inFin landfocusedatte ntion on thech oleste rol-lowe rin gben efit sofPSE in th efor mofmar garine with and with ou tsit ostanol. After1year ,totalchole sterolwasredu cedbyu pto 10%andLDL-Cby upto14%;HDL-Can dtriglycerideswer eun affecte d.AU.S. multicen terstu dy(89) conduct edin1999demon strat edth eefficacyan dsafet yofPSEspre ads.At2weeks, sign ifican t red uction sin tot alchole sterolandLDL-Cwer ereporte din allgroups .At12weeks, anaveragered uction inLDL-Cof12%ver susbase line wasach ie ved.Re sear chers h ave con clu dedth atPSEmaybeu sefulin th edie tar yapproach tocholest erollowe ringan dsugge staben efitbyadd in gPSEtoNCE PIIInu trition recommen dat ions.Th etradename sofcur rent plantPSEspreadsonthe marketinclud eBene coland Take Control.
Soluble Fiber and Cholesterol

Ch and aliaetal.(70)alsoreaffirmedth eresu lt sofpre viousr eportsoft hech oleste rol-red ucingeffect sof solu ble butn otinsolublefibe r.Thirte enpatientswith type2diabete sfollowedtwodie ts,eachfor6 week s.Thee ffe ctsoft heAmerican Diabet esAssociat iondiet(totalfiber, 24g:8gofsolublefiberan d 16gofinsolublefib er)were compare dwith ah igh -fibe rdie t(totalfibe r,50g:25gofs olublefiberan d 25gofinsolublefib er).Th ehigh-fiberdietr educe dtot alplasmachole sterolconce ntration sby6. 7%, red ucedtr iglycer ide conce ntr ation sby10.2%, andr educe dVL DL-Cb y12.5%.The LDL-C was6. 3%lower withth ehigh-fiberdiet .Ther eweren osignificant differ encesinHDL-C. Th isst udydemonstratedt he posit ive effectsofahigh-fiber d iet ,par ticu larlysolublefiber, on loweringplasmalipidconce ntration s.
Educating Patients about Fat Intake

Aprimarystrategy forpatie ntswithh yperch olest erole mia,be fore they usech oleste rol-lower in g medication s,isnut rit ioned ucat ion.K eyedu cationpoin tsforpatient swith diabete sshouldin clu dethe following: Un derstandingt hedifferen cebet weendiet aryandbloodlipidsan dhowtoch an gean ddecre aseth e dietaryfatst olowe rbloodlipidle vels. Red ucingtotalfat in take to25%to35%ofcaloriesbasedonnu trition assessmen t,withfewer than 7%ofcaloriesfromsatu rate dfatwhileme etingn eedsforessen tialfatty acids(seafood) . Shiftingth eemphasisfromanimalt ove getab lesour cesoffat. En cou ragingt heu seofliquid,un satu rat edoils,plant stan ols,andtu borliquidmargar in esan d red ucingth euseoffoodswithpartiallyh ydrogen atedoils. Emphasiz in ganincr easeinfiberb ytheinclusionofmorewholegrains, veget ables,andfru it s. Rec ogn izingt hat fatprovidesaconce ntratedsour ceofcaloriesinthe die tan din bodyst ore sfor th osewh owanttolosewe igh tlossorare obese . Red ucingorelimin ating alcoholin take fort hosewit hdyslipidemia,es peciallyth ose with elevat ed triglycerideleve ls.
ALTERNATIVE SWEETENERS Nutritive Sweeteners

Int hepast,th euse ofsucr oseandglucosealoneorinfoodsh igh in these sugars(cor nsyru p,fruit juice,h on ey,molasse s,dex trose,an dmalt ose )wasrestr ict edfor thosewit hdiabet es.Thisdietary app roachwasame ansoflimiting excur sionsofblood glu coseandlimitingcalorie sin theover we igh t per son with diabete s.Thisapproach gave rise tot hede velopment ofalte rnativ esweete ner sbothcaloric an dnoncaloric.Forye ars, these altern ativeswe eten ershaveplaye dadominantroleinprovidin gpersons withdiabe teswithswee tnessint heirdiet,much asth eydoforth ose with ou tdiabet es.Some p atient s withdiabe tesmayfee lth atswee ten ershe lpth emadh eretoth eir die t,contr ibu tetobet terdiabe tes control,an dare b eneficialforwe igh tredu ction .Unfortu nately,lit tle scie ntifice vide ncesu ppor tsthe se beliefs.The American Diabe tesAssociation n ot esthatth ereisnoeviden ceth atfoodsswee ten edwit h th eseswee tene rshavean ysig nificantadvan tageordisadv ant ageoverfoodssweete nedwithsu cros ein decr easingtotalcaloriesorcarbohy drate con tent ofth edietorin improvingoveralldiabete s control(15). Although fr uctosehaspreviouslybeen promotedasproducingasmallerincre aseinbloodglucoseth an equ alamou ntsofsucroseandmostst arch es,eviden cesugg estspoten tialn egative effectsoflarge amount soffru ctose (twice theamoun tusu allyconsu me d,or20%ofdaily calories)onser umcholest erol an dLDL- C(90).Howe ver, norecommendation shav ebeen madetoavoid foodswith naturallyoccurr in g
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fru ctose ,such asfruitsandve getab les, or e venmodestamount soffru ctose -sweete nedfoods. Sugaralcohols(poly ols)such assorbit ol,mann it ol,xylitol,isomalt, lactitol,maltitol,andh ydrogenated starchh ydrolysatearelesssweet t hansugarbut d oaddbulktofoods.The yare man ufacture dfrom mon osacchar ide s,disaccharides,orpolysaccharid esfor u seinfoods. Ofn ot e,sorbitoldoesnot contribut etothe sorbitolpathwaythathasbeen implicatedinn europat hyandret in alchan ges.On ce sorbitolhasbeen met abolizedint heliv er,itisnolonger availabletothe body (91) .Poly olsmayelicit lessofagly cemicresp on sebecau seth eyar eabsorbed moreslowlyan dprovid eon ly2.4to3.5kcal/gas comparedwith4calor ies/g fr omot hercarbohydrates. Th eincomplete absorption ofsu garalcohols, producingosmoticdiarrh eawh eninge stedinlarge amou nts(50g/dayfor sorbitol, 20g/dayfor mann it ol),constitu testh emain drawbacktothe iru se(21).Sorbit olan dmannitolmust have warn in g labelsaffixedt hat st ate ,Ex cesscon sumption mayhav ealaxativeeffect . The reisn oconcr etee vide nceth atsu gar alc oholsredu cetotalcalor ie sorth etotaldailycar boh ydrat e intakeoft hosewit hdiabet es.However, it isimportantt hat thosewit hdiabet eshaveagood un derst andingofth epot entialofnut rit ive swe eten erstoaffe ctbloodglu cose lev elsandt oaccoun tfor th eseeffect s.
Nonnutritive Sweeteners
Acesu lfameK, aspartame, saccharin,andsucr alose aret hecommon noncaloricin tense sweete nersu sed at presen tinthe Un it edStat es.Allh avebe enapprovedbyth eFDA.An accept abledailyin take (ADI)isdeter mined for th eseinte nseswee tene rs,asforallfoodadd itives. ADIisdefinedastheamoun tofafoodadditiveth at can besafe lyconsu me don adailybasisov erape rson 'slife timewithout hav in gany adver seeffects. The ADIalsoincludesa100-foldsafetyfactor . P. 623
ACESULFAME K
Acesu lfameK(acesu lfamepotassiu m)isawhite ,odorless,cr ystallin esweet ener .Ithasnocalor icvalu e an dis200timesswe eter t han sucrose. Itisde scrib edash avingaclean, fr eshtasteth atd oesn ot linger , but someper ceiv ethatithasabittert astewh enu sedinlarge amoun ts(92).Acesu lfame Kisa der ivativeofacetoace ticacid with astru ctur esomewhatsimilartothatofsaccharin.Approved foru seby th eFDAin 1988,it ismark etedinth eUn it edStat esun derth ebrandname Su net tewh enu sedasan ingre dien tinfoodsandasSwee tOne when soldasatable-t opswee ten er.Itsadvan tag esare its remar kablestabilitybothinliqu id sanddu ringbakin gorcookin g.Acesu lfame K isn otmetabolizedbyth e bodyan dise liminatedu nchange din t heu rin e.It ish eatst ablean dble ndswellwith oth erswee ten ers. The amoun tofp otassiu minth isswe eten erisminimal(only10mgofpotassiumperp acket ).Nosafety concern shavebee nraisedabou tace sulfameK,anditisr eportedt obesafefor allindividuals.Th eADI forbot hadu lt sandch ildre nis15mg/kgpe rday(onep acket con tainsabou t0. 4g)(93).
ASPARTAME
Aspar tameisaproteinswee ten er.Itisth eme thyleste rofL-p hen ylalanineandL-aspart icacid. Int estinalest erase shydrolyzeaspart ametoaspar ticacid ,me thanol, andph eny lalanine. Medicalnu trition th erap ycon trolsth euse ofaspartame prod uctsinper son swith phen ylketonu ria,ah omozygou s, rece ssiv ein bor nerr orofme tabolismthatmakesth emunable tometabolizeth eaminoacid phe nylalan in e. Aspar tameis160to220time ssweete rthansucr ose .Aspart amecon tains4kcal/gbut becau seofits inten seswee teningabilityprovidesne gligible calories. Itwasfirstap prov edfor usein1981an dis marke tedas Nu traSwe etboth in foodproductsandasatable-t opswee ten er.Aspartamedoesn otalt er glycemiccontr olin in div idu alswit hdiabet es(94).Itisme tabolized in t hegastroin testinalt ract andat recommen dedintakesdoesnotaccumulate .Aspart amemaydecomposewithlongexposur etohigh temper atu resan disn ot heatstable. Th eADIforad ultsan dchildre nis50mg/kgbodyweigh t(37mgin onepacket, 200mg ina12-ozd iet soda). The FDAh asaddressed man yconcern srelate dtoin gestion ofaspartame forindividualswithandwithout diabet es.Avarie tyofsafetyconce rnsh avebe enrais ed,i.e. ,thatmild,n on specificsymptomssu chas he adaches, d izzine ss,an dme nstru alir regu larit ies areassociat edwit hitsin gestionan dthatthe byproduct sofmetab olism(me thanoloritsby-product format e)are tox ic.Th ispr omptedth eCe nte rsfor DiseaseCont rolan dPre vent ion(C DC)t ofur ther evaluateaspart ame.The CDC reported t hat datadonot providefor thee xist ence ofseriouswidespread,adverse health con seque nces (95) .Aspart amehas rep eate dly b eende terminedtobesafefor both the gene ralpublicandpe oplewithdiabe tes.
SACCHARIN
Sacch arinisah eat-s table,sy nthe ticsweeten erth atis200t o700t imesswee terth an sucrose.Sacchar in iswith ou tcaloricvalu ebecauseitisnotmetabolize dan disex crete dunch ang ed.Conce rnabou tthe car cin oge nicpote ntialofsaccharin haslinger edforyear s,alth ou ghare viewofth elite ratu reh asnot
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yieldedeviden ceth atcanjustifygovern men talrest rict ion(96,97, 98).Alt houghsaccharinissy nth etic an dnotafood additive,th eJoin tExpe rtCommittee ofFoodAdditionsofthe WorldHealt hOrganization hassetanADIof5mg/kgbodyweightpe rday. TheFDAhasstat edth atsacchar in pose sn oh ealth hazar d.
SUCRALOSE
Sucraloseisth emostre centn on calor icswee tene rtobeappr ove dbythe FDA(in 1998), an ditsu sehas bee nconfir med bymanyre gulatoryagenciesth roughout theworld.Itis600timessweete rthansu gar an dmarket edun derth ename ofSplenda.Su cralose ismade fr omsucroseth roughachemicalproce ss th atalte rsthe sucrosemoleculeby r eplacingth reeh ydrogen/oxyge ngroupswith t hre echlor in eatoms. Sucraloseisnotre cogn ize dbythe body aseithe rasug aroracarboh ydrate.It doe snot affect car boh ydrateme tabolisman diseliminatedu nchange dbythe body(93, 99). Sucraloseishe atstable and may beuse din cookin gan dbaking. TheFDAstatesth atn oadverse or car cin oge niceffectsareassociate dwith con sumption ofsucr alose. TheADIforadultsan dchildr enis15 mg/kgbodyweightper day(93).
SODIUM
Saltisofgre atse rvic etot hediabe ticpatien t.Thep ercen tage ofsalt(sodiumch loride) inth eoce anandinth ehu manbloodisalike andt hebodyten dstokeepitconstant. The firste ssent ialforalowsodiumd iet istoomitalls alteither in thepr epar ation of foodorat t hetable.(1) The r ecommende dsodiumin tak efor peop lewith d iabetesisth esameast hat forpeoplewithout diabet es,witht hemaingoalbeingnottoexce ed3, 000mg/day. Somehealthprofession alsdo, however, recommen dnomoret han 2,400mg/d ay,wh ich iseq uivalent to1teaspoonofsalt.Because t he recommen dat ionsareth esameasth ose fort hege neralpopulat ion, guidelin esshouldbedirect edtoward th eent ire family.Sev eresodiumr estriction ,howeve r,maybeh armfulfor p ersonswhosediabe tesis poorlycontr olle dor wh oh ave p ostu ralhyp ote nsion orfluidimbalance. Pe rsonswit hdiabet eshavenotbee nfoundt obemoresen sit ive t osodiumt han personswithout diabete s ortob eatgr eat erriskofde velopingh ypert ensionassociated with highsodiu mintake. C on cern about sodiu mintakeisdir ected p rimar ilyatind ividualswith cong estivehe artfailur e,ne phropat hy, and hy perte nsion orwh oar eat r iskforth edeve lopme ntofthe secomplication s.Routine monitor in gofblood pre ssurewillhe lpiden tifythosewhomayben efit fromare ductioninsod iu mintake.Th erecommen ded intakeofsodiumislessth an2,400mg/dayfor t hosewit hmild-to-moderateh ypert ension an dlesst han 2, 000mg/dayforth ose with hyper tensionan dnep hropath y. Patient sshouldalwaysbecautionedabou tthe useofsaltsubst it utes, whichoft encontainpotassium rather thansodiu m.Wh enconsu me din excess, saltsubst itu tescanbeh armful,espe ciallyfor people withkidne yproble ms.Asanalter nat ive tosalt substitu tes,salt -fr eeseason in gblendsarere adily av ailable .
ALCOHOL
Adultswithdiabe tesdonothavetoabst ainfromalcohol. Indee d,th eguidelin esforalcoh oluse in individ ualswit hdiabet esmirr orth ose fort hegen eralpopulat ion. Howeve r,re strictionsonorab stin ence fromalcoholmay b enece ssaryforth ose with hypoglycemicun awarene ss,ne uropat hy,poorcon trolof blood glucoseorbloodlipids,pan creatit is, obe sity ,or ahistoryofalcoh olabu se,orfor t hosewhoare pre gnan t. Someissue sregar din gthe useofalcoh olrequ ir eatt ention.First,alcoholaddscalorie swith ou t nu trition albene fitandhasbeen showntosupplement rath erth an displace oth ercalories(100). Su tere t al.(101)and Flatt (102)demon stratedth at, where ascar boh ydratean dproteinoxid ation wasmostly un affect edbyth ein gestionan dme tabolismofalcohol, fatoxidation wasdecr ease dbyabout50%. The refor e,re striction ofcalorie sprovide dbyeth anolisadie tary st rat egyth atispositivelyrelat edto succe sswith weightloss. Secon d,ex cessivealcoholconsumptionbyape rsonwhoisfastingorskip pin g mealscan leadtohypoglycemiaviain hibit ionofglu con eogene sis.Th ismayposeaseriou srisk forth ose takin gin sulin or oralagent stocont rolhyp erglycemia.Eve nbloodalcohollevelsth atdonotexce edmild intoxication can resultinhy poglycemia(21).Third, in tox icationcanimpair aperson'sability tofollowa pre scribe dmanageme ntplan ort ore cogn ize sympt omsofh ypoglyce miaandobtaintr eat men tifn eede d. Fou rth, in gestion ofalcoholincr ease sthesy nth esisoflipoproteins,e speciallyVLDL.Because s ome per son swith diabete saresu sceptibletohyper trigly ceridemia,an dbecau sealcoholh asth epot entialto raiset rig lyce rid ele vels,alcoholingest ionsh ou ldbe discouraged. Recen tstud ies, however, in dicateth at moder ate amoun tsofalcoh olhavebeen associatedwith adecre aseinC HDat tribute dtoanincre asein lessden seHDL-C subfractions(15, 103,104,105,106). P. 624
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Alcohol Guidelines
Alcoh oluseandab usesh ou ldbe d iscu ssedaspartofthee ducationpr oces sforallpersonswith diabet essot hat they knowthefactsabout thee ffe ctsofalcoholon glyce mia. Exc essiv ealcoh olconsumption mayle adtoerr aticbehavior, lossofconsciousne ss,orseizure s, par ticularlyiffoodisnotconsu med with thealcohol.Alcoholshouldon lybe con sumedwit hfoodor aft erth eme al.
Fort hosewit htype 1diabet es,alcoholsh ou ldbe take ninadd itiontothe irre gularmealwithout omittinganyfood. Me tabolismofalcoholdoesn otr equireinsu lin. Fort hosewit htype 2diabet es,alcoholisbestsu bstitut edfor fatcalories:Onealcoholequivalen t equ alstwofatexch an ges(10offat).
Glu cagonisnoteffectiveint hetr eatmen tofalcohol-in ducedh ypoglyce miabe cause alcoh oldeplete s glycog enstores.
Alcoh olshouldbeuse don lywh endiabe tesisund ergoodcontr olan din moderateamount s.Alcohol shouldbest rict lyavoided wh endr iving. Gene ralrecommen dation sfor alcoh olin take are n omoreth ant woalcoholeq uivalent sperday for menandnomoret han on ealcoholequ iv alent p erday forwome n.Analcoholequivalen t,wh ich contain sabout1oz(15g)ofalcoh ol,isdefinedas12ozofbeer ,5ozofwine ,or 1.5oz of80-proof distilledspirits(15).
Apersonwh oinge stsalcoh olshouldalwaysbe encour agedt omon itorbloodglucoselevels. Wearingidentificationis e xtre melyimportantforindivid ualswhochoose todr in k,because intoxication an dsympt omsofh ypog lyce miacanoft enbe confu sed.Drinkingalone s hou ld alwaysbe discou rage d.
THE MICRONUTRIENTS: VITAMINS AND MINERALS

Int akeofvitamin san dminer alsshouldmee trecommen dedlevelsfor goodhe alth. Ifdiet aryintakeis balancedandad equate,t here isu suallynonee dforaddit ionalvitaminandmin eralsupp lemen tsfor t he majorityofpeoplewit hor with ou tdiabet es.Supp lemen tationofv itaminsandmin eralssh ou ldn otbe use din placeofavar ied ,balan ceddiettoens ureadequ aten utrien ts.However ,thosewh omaybeatrisk formicronut rie ntde ficienciesandarelike lyt ore spon dpositivelytomu ltivitaminsupp lemen tation include(a)thosewhoar eon aver y-low-calorie die tfor we igh tredu ction ;(b)thosewhoar etak in g medication sthatmayalter certain micronut rie nts;(c)th ose whohave docu me nted micron utr ie nt deficienciessuch asanemiaor oste oporosis;(d)t hosewhoarest rict veget arian s;(e)pregn an tor lactatingwomen ;(f)thosewhoare elderlyan dcon fin edor unable toe at;(g)ch ildren an dteen ager s whoseve relylimitfood sorwh olefoodgroups;and(h )thosewhohaveun con trolledh yperglyce miawith glycosu ria,wh ich canr esultinexce ssexcret ionofwate r-solublevitamins. Vitamin sand miner alsin volvedincarbohydrateandglucoseme tabolismthatar etopicsofcurr ent rese arch willb ediscu ssedbriefly.
Chromium
Fort unately,most people with diabete saren otch romiumdeficien t,andch romiumsu ppleme ntation isnot recommen dedu nlessade ficiency isclear lydocumen ted.Th istr acemin eralisnee dedtopotent iate insulinact ionbyt heproduct ionofglu cose toler ance factor.C hromiumdeficie ncyinbothanimaland hu manstu die sisassociate dwit helevatedbloodglucosean dlipidle vels.Populat ionsatriskfor chr omiu mde ficiency in clu dethe elderlyan dthoseonlon g-termtotalpar ente ralalimen tat ion.Astu dyin Ch in are port edin1997(107)sug gestedapossiblerole forch romiumsupplementation .Individualswith type 2diabe teswere give neithe ra1,000-gor200-gchromiu mpicolinatesupplemen tor aplacebo. Bothfast in gbloodglu cose andglycosylate dhemoglobin A 1 c leve lswe redecre asedinallth reegr oup s, but thosetakin gthe 1,000-g s uppleme nth admuchlar gerdecr ease sin fastingand2-h ou rinsulin concen trat ionsandintotalcholester ol.Although thest udyofAndersone tal.(108) inr atssh owedalack oft oxicityofc hromiumchlor ide andch romiumpicolin ateatconcen trat ionsatextr eme lyh igh limitsof whatise stimatedtobesafe ,other studieshavede monstr ated t hat verylar geamou ntsofchromiu m picolinat ecau sedseve rechr omosomald amageinanimals(109).Un tilne wr esearchcanclearly demon strateth eben efit sand safetyofchromiu msu pple men tat ion, t heAmerican Diabet esAssociat ion maintain sthatchromiumsupp lemen tationisofnokn ownbe nefitex ceptforthosewithch romium deficiency(15).
Magnesium
The mag nesiumlinkt odiabe tesinvolv esthe tran spor tofglucoseacrossmembranesandth eoxidationof glucose.Magn esiumdeficien cyhasbeen associatedwithinsu linre sist ance ,carb oh ydrat ein toler ance ,
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car diacarrh yth mias, c ong estivehe artfailur e,re tin opathy ,an dhype rten sion. Probablyth emostcommon cau seofmag nesiumdeficie ncyamongth osewith diabetesislossofmagnesiumthr ou ghchr on ic glycosu riaordiu ret icus e.Adeficie ncymayleadtoincr eased insu lin r esistan ceor may beare sultof insulinresistance(110).Seve ralsmallstu diesh ave fou ndth atsup ple men tat ionwithmagn esiumcan improvegluc osecont rolan din sulin sensitivity(111, 112).Th eAmer icanDiabetesAssociation doe snot recommen droutine e valuation ofmagne siu mstatusinh ealth yin div idu alswith diabete sbutre comme nds routine evaluation sforth ose people athigh risk formagn esiu mlosses,su chasth ose with poorglycemic control(diabeticketoacidosisandprolon gedglycosuria),t hoserece ivingdiur etics,th ose with intest in almalabsor ption, thosewithcalciumor potassiumd eficien cie s,an dpregn ant women. P. 625
Antioxidants
Antioxid ant shave received wideatten tion in t hepastdecadebecauseofthe ir abilitytone utralize reactivefree electronsandpre vent t oxiccellulardamage.Although the rear emanyantiox idants, includingvitamins,minerals, and e ven p lantsu bstan ces,th eemphasish asbee nonthe ir r olein red uction ofcancerandcardiovascularrisk. VitaminE isre ceiv in gcloseratten tion inp eoplewith diabet es.VitaminEh asbee nrelat edtoadecre ased r iskofcard iovascu lardisease .-Tocoph erolis considered t hemajorant ioxidan tforLDL-Candh asbee nreporte dtoincr ease theoxidativer esistan ceof LDLandimprovenonoxidativeglucosemetabolisminpeoplewit htype 2diabe tes(113, 114).R ecent rese arch byBurse lletal. (115)demon stratedth atvitaminE may redu cethe risk ofth edevelopme ntof ne phropat hyan deye d isease.An 8-mon thtr ialev aluat ed36pat ien tswithtyp e1diabe tesofshort dur ation.Patient swererandomlyassign edtoeithe r1,800IUvitaminEpe rdayorplaceb ofor4mon ths an dfollowedu pan d,aft ertre atment crossover ,were followedup foranother 4mont hs.Or alvit aminE tre atment appearedt oeffe ctiv ely nor malizere tinalhe modynamicabn or malitiesan dimprovere nal fun ction with ou tin ducingasign ifican tchangeinglycemiccon trol. Rec omme ndeddosage sofvitaminEforpeoplewit hcar diovasc ulardisease shouldbeinamou ntsn o gre ater than400IU /day. High erdosesmayincreaseth eriskofstr oke in peop lewith h ig hbloodpressu re an dofblee din gfort hos epatien tsrece ivinganticoagu lants.
DESIGNING THE MEAL PLAN

Treatmentre stsinthe han dsoft hepatient. Itisby die tand e xerciseaswellasby insulin,andth epat ien tswithth ewilltowinandth ose wh ok nowt hemost ,con ditions beinge qual,canliv ethe longest .Ther eisn odiseaseinwhichanun derstandingby the pat ie ntofthemeth od softre atment availsasmuch. Brainscoun t.(1) One ofth eprimaryreasonspeople with diabete shav esuch difficultyun derst and in gnut rit ionissue sis alack ofnu trition educationandcoun selin gbyqualifie dprofessionals(e .g., registere ddie titians). Inst ead, patien tsmaysimplybetoldtor estrictsu garorcu tdown on calor ies ormaybe give na samplemenu tofollowwit houtan ade quat eedu cation alfou ndation. TheDCCTprovidedimportant insightintoth eroleofnu trition int erve ntion in in tens ive d iabetest reat men tan dstatedth atre gist ered dietitiansarebe stqualifie dtomat chapp ropr iatemeal-plann in gappr oachestoth enee dsofth epatie nt (10). The t imere quiredbyth eedu catorandpers onwith diabetesd epend son multiplefactors,su chas emot ionalstatus, exte ndedsu pportsyste m,pr econ ceivedideasaboutth ediabe ticdiet ,an dthe per son 'ssocialandcultu ralatt itu des. Th econsiderat ionandinvolv eme ntofthe p ersonwithdiabe tesar e considered cr it icaltodevisingasu ccessfulmealplanth att hepe rson iswillingandabletofollowto promote p ositiveoutcome s. Aqualifiedregister eddietitianisan impor tan tme mbe rofth ediabet esteam, helpingpat ie ntsun derst and th erelationshipsamongn utrition ,exe rcise,an dme dication .Adie titiancangat heradetailedn utrition historyth atinclude sapers on'susu alin take ,th efrequ encywithwh ich heorshe eat sout side theh ome, eth nicin flu ence son foodchoice s,foodpre feren ces,weight histor y,dietsfollowe din the past, andfood allergies.C aloricne edsmayth enbe estimatedanddeve lopedint oaworkable mealplan.Mealplan salso ar ebase don anindividual'slifestyle, sociocu lt uralandeconomiccharact eristics,act ivityleve l,food pre fe ren ces,typ eofdiabe tes,medicat ions, andothe rdietar yrestr ictions.Th edietitiancaninstru ctan d counse lth epatie ntabou tallofthe aspect sofnu trition care asit relate stosick-dayfoodmanagement, rest aur ant eat in g,carb oh ydrat ecou ntingforinte nsiveinsulinthe rapy ,exer cise ,snacks,andhowto incorpor ate treatsintothe mealp lanwit hinth econ text ofoverallhealthyeating. Nutr itioninformation isusu ally presen tedinsmall, seque ntialstages.In itially,basicsu rvivalskillscan betaugh tan din div idu alize dwit hon ly gene ralguidelin esprovided,su chasconsiste ncywithtimin g, amount andt ypesoffoods,an dthe relation shipsamon gfood,activit y,an dme dication .Thisvisitsh ou ld layth egroun dwork inn utr itionbasicsan dserv etod evelop asou ndandtru stingre lationsh ipwith the pat ie nt. Inlat erstages,mor edetailedinformation can beprovid edtoexten dan dreinforceexistingk nowledge
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an dhelpth epat ien tsmakepositiveimprovemen tsin nut rit ionbe hav iorthr ou ghcontinu ou sreviewsof foodandbloodglucoserecords,lab oratoryvalue s,an dweightstatus. Inre centye ars, theimport ance of tailor in gnut rit ionpr ogramst oth eindividu al'scu lt uralframeworktoincludet radition alfoodshasbeen emphasize d.Ed ucat orsmustu seedu cationaltech nique sappropriate tot helit erac yofth eindividu al.The ne edfor toolsandt echn iqu essuitable forvariou sethn icgr ou psorlearningsty le sh asledtothe deve lopmentofawidevarie tyofteach in gtools,edu cat ionalmate rials, and meal-plan ningapproache s.
Meal-Planning Approaches
Ame al-plann in g approach simplyme anst heedu cationalres our ceuse dbythe die tit iantoteachth e pat ie nth owtoplanmeals(116). Severalmeal-plan ningalte rnativesar eavailableforpersonswith diabet es.
CARBOHYDRATE COUNTING
Basiccar boh ydrat e(car b)cou ntingmaybe usedforth oser eceivin gcon ven tionalt herapy,with or withoutinsu lin. Th isapproach assumesth atone carbohydr atech oiceisbase don theamoun toffood t hat contain s15g ofcar boh ydrat e(Table36.9).Patient smaysimplybegivenacar ballowan cetoaimfor at each meal, while e nab lingth emtospe ndth eirallowan cebase don healt hychoices,weight ,blood glucoselevels,orlipidabn ormalities.Advancedcarbohydratecoun tin gmaybeu sedfor thosewhowan t toach iev enear-normalglu cose le velswith mu ltipledailyin jection sofinsulinorcon tinuoussu bcutaneous insulininfusion.Thisapp roachcoor din ates foodin take (carbohyd rate )bymatchingt hepe akact ivityof insulinwithth epeakle velsofglucoseresu lt in gfromth edig estion andabsor ption offood. Th ismeth od allowsmor epreciseadju stme ntofpremealrapid -orsh ort -actinginsu linu sin ganinsu lin/carbohydr ate ratio.Th erat ioisbasedonth eassu mpt ionth atcarbohydrateintakeisthe main consider ation in det ermin in gmeal-r elated insu linr equiremen ts,togeth erwithv aluesfromse lf-mon it oring ofblood glucosean dpremealbloodglucosetargetsse tbythe physicianandth epat ien t.Agood u nde rstan dingof howcarb oh ydrat eaffect sblood g lu cose, what foodgroupscontain carbohyd rate ,an dwhichrefe rence bookspr ovidecarbohydrateconte ntofspecificfoods isne cessar yfort hisapproach tob eeffective. TABLE 36.9. Food Choices
Carbohydrate Starch15 gms carb, 3 gms pro Breads, Cereals, & Grains 1slice(1oz)bread (1oz)largebagel
Beans
Starchy Vegetables
Crackers/Snacks
Cbeans,peas (garbanzo,pinto, kidney,white, black-eyedpeas)
Ccorn/peas 1/3Cbakedbeans
3Cair-poppedpopcorn 20minipretzels
6inchtortillaorpita bread Englishmuffin
1Cwintersquash
6wholegraincrackers
3ozbaked,boiledpotato
3grahamcrackers, 2sq 2ricecakes,4across
Ccookedcereal Cdrycereal 2ricecakes 2sliceslow-calorie bread 1/3Ccookedrice/pasta Fruit
2ozbakedsweetpotato Cmashedpotato Csweetpotato
Milk
Non-Starchy Vegetables
Other Carbs
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15 gms carb
15 gms carb, 8 gms pro Fat-Free/Low-Fat (<3 gms fat)
15 gms carb
15 gms carb
1sm(4oz)freshfruit, banana
3Crawvegetables(lettuce, mushroomscauliflower,celery, cucumber,peppers,radishes)
1ozangelfoodcake
Ccndfruit,juice
1Cfatfree/skim/1%milk 6ozfat-free,low fat,liteyogurt Cevaporated skimmilk 1/3Cdryfat-free milk Reduced-Fat (35 gms fat)
2squnfrostedcake*
Cdriedfruit
2sqbrownie*
1Cwatermelon
2smcookies*
1Cstrawberries
Cicecream*
1Cmelon,raspberries
1Ccookedvegetables (asparagus,carrots,beets, broccoli,brusselssprouts, cabbage,greenbeans,spinach)
Csorbet
Cblack/blueberries grapefruit
1C2%-milkyogurt 1C2%soy/rice milk 6ozreducedfat yogurt
1Tblsp.jam/jelly 1Tblsp.honey/sugar
C(5oz)mango
17grapes 2Tblsp.raisins ProteinMeat and Meat Substitutes 0 gms carb, 7 gms pro Very Lean (01 gms fat) 1ozchicken/turkey (white,noskin)
1Cvegetablejuice
Lean (3 gms fat)
Medium-Fat (5 gms fat)
High-Fat (8 gms fat)
1ozchicken(dark, noskin) 1ozleanbeef/pork (ham) 1ozcheese(13 gmfat) 1ozturkey(dark meat,noskin) 1ozfish(salmon, swordfish)
1ozbeef(mostproducts)
1ozregcheese(Swiss, American,cheddar)
1ozchicken(dark,withskin)
1ozcheese(<1gm fat) Ceggsubstitute
1ozfeta/mozzarellacheese
1Tblsp.naturalpeanut butter 1ozpork
1egg
1ozfish(haddock, flounder,shellfish) Fat
4oztofu
1ozveal
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0 gms carb, 5 gms fat Monounsaturated (Heart Healthy) 1tsp. canola/olive/peanutoil Tblsp.peanutbutter
Saturated (NOT Heart Healthy) 1tsp.stick(2tsp. whipped)butter 2Tblsp.reg(3Tblsp. lite)sourcream 2Tblsp.half&half
Polyunsaturated (Heart Healthy)
1tsp.reg(1Tblsp.lite)margarine
1tsp.reg(1Tblsp.lite)mayonnaise
6almonds/cashews 10peanuts Free Food
1tsp.corn/safflower/soybeanoil 1Tblsp.sunflowerseeds 1Tblsp.regsaladdressing
A free food has no more than 5 gms carb and 20 calories/serving. Limit to 3 servings per day. 1Crawvegetables 1Tblsp.fat-freecreamcheese/nondairycreamer/mayonnaise/saladdressing/sour cream 4Tblsp.fat-free(1tsp.lite)margarine 1hard,sugar-free candy Sugar-freegelatin dessert Sugar-freegum Sugar-freesoftdrinks
cookedvegetables
Csalsa
2Tblsp.lite/fat-freewhippedtopping
Bouillonorbroth Coffee/tea
2tsp.litejam/jelly 1Tblsp.sugar-freesyrup
Fast Food/Combination Food Meatpizza,thincrust (of10inchpie) Cheesepizza,thincrust (of10inchpie) Casserole/hotdish(1c) *Starreditemsalsohaveadditionalfatthatisnothearthealthy. CenterforInnovationinDiabetesEducation.Winter2003.Copyright2003.JoslinDiabetesCenter.Allrights reserved. Reprintedwithpermission. 2carbs/1med-fatmeat/3fats
2carbs/2med-fatmeat/1fat
2carb,2meat/pro
THE EXCHANGE SYSTEM

Thisme al-plann in gapproach isbasedonth reemainfoodgr ou ps:the c arbohydr ateg rou p(star ch,fru it , milk,ve getable s,an doth ercarbohydrates), t hemeatand meat-subst it utegr ou p(prot ein), an dthe fatgroup(Table 36.10).Ex amples ofth especificamoun tsofcarbohydrate, prot ein ,fat ,or combinationofth esenu trient sin each foodgroupar efou ndinTable36. 9.Foodswithsimilarn utrien t valu esare listedt oge ther andmaybe exchange dort rade dforanyothe rfoodon the samelist(117). P. 626 P. 627
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Portionsizesforeach foodare listed andaremeasu redaftercook in g.Exch an gelistsareuse dtoachieve consisten ttimingandintakeofn utr ien tsan dtoprov ide s omevar ie tywhen plann in gmeals. Initially, exch an gelistsandamealplan can b eastartingpointforthosepatie ntsonconve ntion althe rapyor inten siv ein sulin manageme ntandcanhelpth emlearnt hecarboh ydrateconte ntoffoods. TABLE 36.10. Nutrient Content of Exchanges
Group/list Carbohydrate Starch Fruit Milk Skim Reduced-fat Whole Othercarbohydrates Vegetables Meatandmeatsubstitutes Verylean Lean Medium-fat High-fat Fat
Carbohydrate (g) 15 15 12 12 12 15 5
Protein (g) 3 8 8 8 Varies 2 7 7 7 7
Fat (g) 1orless 03 5 8 Varies 01 3 5 8 5
Calories 80 60 90 120 150 Varies 25 35 55 75 100 45
FromExchange lists for meal planning,withpermissionoftheAmericanDiabetesAssociationandtheAmerican DieteticAssociation,1995.
GUIDELINE APPROACHES
Anothe rsimplifiedgu ide line approach ,Health yFoodChoices,wassu ccessfu llyuse din t heDCCT(10). Thisappr oachprovidesan in troductiontodiabete smealplan ningandismostoftenu sedinth efir st stageofn utr itionedu cation.Itpr ovidesgu ide line sformakingh ealth yfoodchoiceswit han abbre viated, simplifiede xchangelist.
MENU APPROACHES
Thissimplifiedapproachisth ebasisofallme al-plann in gapproach esan dillustr atesh owmealscanbe designe dtoaccommodateth epat ie nt'sfoodprefer ence sandlifestylewhilemain tainingahealt hydietary intake.Men usmaybespe cificor offerse veralch oices.Th ismeth odinvolvesth epat ien tinth econ ceptof portion size .
COUNTING APPROACHES
Calorieorfat-gr amcoun tingmaybe appropriate forth eobesepatientwitht ype2d iabetes. Thesese lfmon itoringmeth odse ngage the p atient in recordingdailyfoodintakean dwillassistthe patient and t he dietitiant oindividualizenu trition goalsandachieveweight lossbyth epatien t.The semethodsalso providesomest ructu reinth efor mofanu mbe rofcaloriesorfatgramst ostr ive foronad ailybasis
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whileallowingflexibilityan dvariet yin mealplan ning. Insu mmary ,an yofth esemeth odscanbeappropriate foranygiven ind ividual, butde velopmen tofan individ ualme alplanre quiresth atth epatie ntbe e ducatedinbotht heprinciplesofg oodnut ritionand th eir effectiveimplemen tation.
MEDICAL NUTRITION THERAPY FOR THE ELDERLY

The h ealth care prov ide rwhotake sin toconsideration thech an gesth atcome with agecanvastly improve th enu tritionalst atu sofan dcar egiv entothe elderlypat ien t.In gene ral,th eelderlyhaveah ig her per centageofbodyfat,alowerlean bod ymass,an dalower caloricre quirement. Theex tent ofth e decr easeincaloricnee dsdepen dson healt hstatusandact ivityleve ls. Eatingpattern sin the e lde rlycanbe sign ifican tlyin flu ence dbymanyph ysical, me ntal,ande motional fact ors, suchasimpaire dvision,smell, hearin g,an d/ortast e;decre asedde xterityandmemory ; lon eline ssan ddepression;den talproblems;illn essan dmu ltipleme dication s;limite dfin ancialresour ces; an dproble msofmobilityan dtransportation. Poor teeth an dgumsorill-fittingde ntu resar ewide spread problemsint heelder lyandcommon ly leadtotheirconsu mptionofsofter foodshighinsu garandfat . Foodscon taining great eramount soffiber,su chasfr eshfru it s,vege tables, orwh ole-grain cerealsor bre ads,canbemor edifficulttoche w.De pression an dphysicallimitation scanlimitth eir accesst ofood orabilityt opre pare it. Allofthese factorscontribut etotheincr ease ddifficultiesth atth eelderlyper son h asincopingwit hth e manyd emandsimposedby diabetes. Theimportantfirstst epin nu tritionalman age men tfor thee lde rly pat ie ntisacomplete assessmen tofallfactorsth ataffectnu trition .Obtain in gnece ssaryinformation fromsome eld erlypersonsmaybe difficultbecauseofash ort atte ntion span ,poorsh or t-termmemory, orasev erede ficitin me ntalcapacity.Older p ersonsmaynotbe abletorecalltheirdietclearly enough toprovide the e ducator with the informationne cessar yformakingappropriate diet aryr ecommendation s. Ifpossible, familyorcaregiver sorboth shouldbeprese ntdu rin gedu cation session s. Inge ner al,it isprobablybe sttokeept hemeal-plann in gregimenofthe e lde rly simple .Nutr itionalgoals shouldaimatth eprovisionofsimple,balanced, con siste ntmealsth atfitlon g-stan din geat in ghab itsand th ephysicalan dpsych ologicalne edsoft heindividual. Tr yin gtoch an gelon g-stan din gfoodhabit sby imposingne w, rigid, and/orcomplicate dmealp lansmaynotbesu ccessful.On theoth erhand, many elderlyh aveth etime and int erest toge thighlyinvolv edin the irdiabetesman agemen tan dwille ager ly followinstr uctionswhen giv enth ene cessar ysupportandinformation . P. 628 Las t,finan cialdifficultie sand socialisolation ofth eelderlyandth edie tar yproblemsth eycreatecannot ben eglected. Thedietitian must besen sitivet oth esen eedsandbepr epar edwit huse fu lsu ggest ions. Many commu nitieshaveavarietyofsupportser vice sfore lde rly citizen s,an dallh ealth profe ssionals shouldbefamiliarwith the resourcesandse rvice savailable.
MEDICAL NUTRITION THERAPY AND PREGNANCY

Optimalmedicalan dnu tritionalcaremustbe gin beforeconcept iontoens ureahealt hypre gnan cyan da posit ive out come.In gene ral,th enu trition alrequire men tsofapregn an tpersonwithdiab etesare esse ntially thesame asthoseofapre gnantper son with ou tdiabet es.However, pregn ancy mag nifiest he importanceofadh eren cetonut ritionman agemen tprinciple sforth ose with diabete s,th erigidcont rolof glucoselevelsthr ou ghoutth ecourseofpregn an cy,an dthe avoid ance ofket on uria. Nutr itionmanagement d uringpre gnancyshouldbegin atth eear liestpossible time. Calor icintakesh ou ld bee valuatedassoonaspossible in t hefirsttr imeste rand atth estartofe acht rimeste rthe reafterto en sureadequ ate int ake .Du rin gthe first trimest erofpregn ancy ,dailycaloriclevelsmayvarybetwe en30 an d38kcal/kgofide alprepre gnan cyweight. Du rin gthe secon dan dthirdtr imester s,th islevelis increasedto36to38k cal/kgofidealpr epregn an cyweight(118).These addition alcaloriesdu ringth e secondandth ir dtrimest ersar enee dedforin creasesinmater nalbloodvolu meandincre asesinbre ast, ut erus, and adipose tissu e;placen talgrowth;fe talgrowth;andamniot icfluids(15).However, individ ualizedcalorict arge ts,bloodglucoselevels,andweightgoalsmayber ecommende d.Inaddit ion, pre gnan twomen nee dadequ ate prot ein(0. 75g/kgperdayplusan addition al10gperday)(15).For th osewith preexistingdiab etesinpre gnancy,t hree meals andth ree snacks sh ou ld b espace dnoless th an2hoursapart andn omor ethan4hoursap art. Distributionofc aloriesisasfollows: carbohydr ate, 40%to50%oft otalcalories;protein, 20%to25%oftotalcalorie s;and fat,30%to40%oftot al calorie s. Caloricrequ ire me ntsarebase don pregravidweig ht,h eight, age, activitylevel,andusu alin take .Weight gainmust alsobemeasure dduringpr egnancy.Both actu alwe igh tan dBMImay b eusedforweight asse ssme nt.Th eJoslinDiabetesC ent er'sr ecommendation sforweight gaindu rin gpregn an cyare listedin Table36.11. Pre gnan twomen shouldgainonly2to5poun dsdur in gthefirsttr imeste r.The reaft er,a steadygain ofabout 1pound perweek isre comme nded. Howeve r,u nderwe igh twomen shouldgain1.1 pound sp erweek ,an dove rweightwome nshouldgainonly0.7poun dperwee k(116). In addition ,special
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emphasissh ou ldbe placedonth efollowing: TABLE 36.11. Recommended Weight Gain During Pregnancy
Description Underweight Normal weight Overweight Obese
% of ideal body weight <90 90120
Body mass index (kg/m2) <19.8 19.826.0
Recommended weight gain during pregnancy (lb) 2540 2535
120135 >135
26.029.0 >29.0
1525 Atleast15
FromBeaserRC,andStaffofJoslinDiabetesCenter.Joslin's diabetes deskbooka guide for primary care providers. Copyright2001byJoslinDiabetesCenter.Reprintedwithpermission.
Mealplann in gtoin clu deappr opr iatecalcium,folicacid,an dot herv itamins Modification ofth emealplantoadd ressnausea,vomiting, heartbu rn,andconstipation Riskasse ssme ntan dprev entionoffastinghy poglycemia Adequ ate carbohydr ate ,protein,andfatin take atbe dtimetopre vent noc turn alhypoglycemiaor ket on es Cu rren tintakeofswe eten ersandcaffeine Adjustmen tofcaloriesfor gestat ionalage Weight -gaingoalsduringpr egnancybasedonpre gravidweight andclinicalassessmen t.
MEDICAL NUTRITION THERAPY FOR CHILDREN AND ADOLESCENTS

Foodan dfeedingissue sareve ryimportantinth ephy sicalandpsych olog icalgrowth ofchildren .Diet edu cationmu stbeapproache ddiffe rent lyandbe r esponsivetoeach child ,hisor h erde velopment al state,andfamilyd ynamics.Thech ildwithdiabe tesisaddingth ecomplexitiesofb alancing food,insulin, an dactivitytoth ealreadydemand in gneed sofphy sicalmatu rat ionandpsych olog ical, s ocial,an d cultu raldeve lopme nt. Adolescen tswit hdiabet esfaceu niquech alle nges. Atatimewhen they are at temptingtoseparate fr oman dbecomeinde pende ntofpare ntsandau thority, t heymust follow management r ou tin esfreq uen tly in conflictwit hth isne edaswe llaswithth eirnee dtoattain peer un iformit y.Specialatt entionmustbepaidtot hesen eedst oac hieveth eyoung p erson'smax imal coope rationwit hdietarymanagement. Itisnowpossibletoprov ide amore p ositiveapp roachtowhatcou ldbe apoten tiallyn egat ive t opicfor children andt eens:n utr itionmanagementanddiabe tes.He althcareprovidersonth ediabet esteammust notlose sigh toft heabilit yoffoodt oprovidemore thannu trient s,espe ciallyfor thisgroup.C hangesin eatingshouldnotbev iewe dasrest ric tionsandlosse sbutasahe althfu lway forth ewholefamilytoeat . Eve ryat temptshouldbemade tode sign amealplanth atr efle ctsthe child'sfoodpre fe ren cesan dthe family'ssocialan dcultur alattitu des.Fle xibilit yan dgradu ate dgoalse ttingar eimportantkey sto succe ss,increasin gthe chancesofthech ild'sachievingoptimald iabetesman agemen tan ddecreasingth e deve lopmentofcomplication s.Inth eat tempttomain tainth epleasuresofthe table, it isesse ntialthat th enu tritiongu id eline spromoten ormalhe althy e atingandpre ven tisolatinganddivid in gthech ildan d familyinth eirfoodchoices. Fort hech ildwit hdiabet es,fre quen tasses smen tofdiet andcarefu lmon itoringofgrowtharene cessary . Nutr itionalasse ssme ntsh ou ldinclude t here gularplottingofheight andweigh tme asur eme nton standardgrowthchartsinanefforttodete ctan y shiftingrowth. Me alplanswillnee dtobeadjust edonare gularbasist oaccou ntforchangesingrowth ratean dactivity. Th erecanbewidese asonalvariation sin caloricne edsasch ildren changeactiv ity pat tern sfromschooltohome ,onweeke ndsorvacation s,an dfromper iodsofsportsactivit ytolulls P. 629
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bet we ense asons.Gen eralguidelinestohe lpde velopapositiveworkingre lationsh ip with thech ildor adolescen tan dtheircaretakersareasfollows: Include childr enandtee nsinth ein terv ie wt oallowt hemtob epart ofth edecision-mak in gproce ss. Donotre fertoor lab elachildasadiab etic;the seare childr enwhohappen toh avediabetes. Int erviewprep ubert alchildr ensep aratelyan dtoge the rwit hfamilytostimu lateself-management. Pr ovider eassu ran cethatmostofthe child'susualfoodscanbe in clu dedinhisorher mealplan . De scribethe mealp lanasaroadmapforhe althyeating, r ath erth anarigiddiet. Stre sshealth yeatin gprac tice sforth een tirefamilyrathe rthanfocusingonjustt hechildwit h diabet es. Avoidn egat ive wordswh encoun selin g,such ascan not,donot,n ever ,bad, restrict, ande specially th ewor ddie t.Inachild'smind, die tcon notesde priv ation ,aswe llasashort-ter mprocessr ath er th ananongoin gon e.
Askabout favoritefoodsandav oidelimin ating t hese foods.Inst ead, stressbalance ,moderation ,an d varie ty. Rev ie wt here alit yofspecialtre atsforspecialoccasion sandr elatet reat foodstoextraexer ciseand act ive days. Advisecar egiversth atomitting foodsbecau seofasinglehighbloodglucosere adingisnot adv isable .
Cont in uedn utrition alfollow-u pande ducat ionarere quiredeve ry6month sto1yearasth echild g rows an ddeve lopsan dasth efamilyworkstogainex pertiseinth enu tritionalman age men tofdiabetes.
SUMMARY
Nutr itionmanagement forth epersonwith diabetesisoneofthe mostimportan tfact orsint he at tainment andmaint enanceofgoodmetaboliccont rol.Devisin gme alplansth atpr ovideflexibilitywhile conformingt ogu ide linesbasedoncur rent researchisaconstantch alle nget oth ereg iste reddietitian .To translate mealp lansintoanaction planforpatien tswit hdiabet es,aregistere ddie tit ianmusth avea th orough un derstandingofallth ecompone ntsofdiabete sman age men tan dhelpeachper son adap t diabet estohisorh erlife stylein steadofadaptinglifestyletohisor herdiab etes. Alth ou ghagr eat d eal ofinformationth atimpr ove sou rabilityt omanagediabe tescontinu estobegen erat ed,wed onotye t haveth efin alan swersab out what con stit utest heu lt imate die tar ymaneu vers. Th erefore, it is importantforthe cliniciant ostayabr eastofnewr esearchan dknowledgeandbewillingtotryn ew app roachest on utrition almanageme ntofdiabete s.
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88.Miettine nTA,Pu skaP,GyllingH,e tal.Red uction ofser umcholest erolwithsitostan ol-est er margarineinamildlyhy perch oleste rolemicpopulation. N E ngl J Me d1995;333:13081312. 89.Ngu yenTT,C rog han IT,Dale LC.MayoClinicandFoundation ,Rochest er,MN:Eu rope an Ath eroscle rosisSociet y,1998(abst ). 90.BantleJP,SwansonJR ,ThomasW,etal. Me taboliceffe ctsofdietaryfru ctose in diabeticsubject s. Diabetes C are1992;15:14681476. 91.GeilPM:Complexan dsimplecar boh ydratesindiabet esthe rapy. In:Power sMA,e d.Han dbook of diabe tes medical nut rit ion th erapy.Gaithe rsburg ,MD:Aspen ,1996:303319. 92.LipinskiGW V. Then ewin ten sesweete ner acesu lfame-K .Food Che mistry1985;16:259269. 93.American Dietet icAssociation .Use ofnu tritivean dnonnu tritiveswee tene rs(positionstatement). J Am D ie t Assoc1998;98:580587. 94.Neh rlin gJK,KobeP,McLane MP,et al. Aspart ameuseby personswithdiabe tes.D iabete s C are 1985;8:415417. 95.C ou ncilonScient ificAffair s.Aspar tame.Re viewofsafetyissues. JAMA1985;254:400402. 96.Morrison AS, BuringJE .Artificialsweet ener sandcance rofth elower u rinar ytract.N En gl J Med 1980;302:537541. 97.Morgan R,WongO.Are vie wofepidemiologicalstu die son artificialswee ten ersan dbladder cancer. Food Chem Tox icol1985;23:529533. 98.C ou ncilonScient ificAffair s.Sacch arin reviewofsafetyissue s.JAMA1985;254:2622. 99.MezitisN,KochP, MaggioC, etal.Glycemicre spon setosucralose, anovelsweet ener ,insubject s withdiabe tesmellitus. Diabet es Care1996;19:10041005. 100.De Cast roJM,OrozcoS.Moder ate alcoh olin take and sp on tan eou seat in gpatt ernsofhu mans: ev iden ceofunr egulate dsupplement ation .Am J C lin Nu tr1990;52:246253. 101.Sute rPM,Schu tzY,Jequ ierE. Th eeffect ofeth an olon fatstorageinhe althysu bje cts.N En gl J Med1992;326:983987. 102.Flat tJP. Bodyweigh t,fat stor age, andalcoholmet abolism.Nutr R ev1992;50:267270. 103.BurrML, Feh ilyAM,Butlan dBK,e tal.Alc oholand h ig hden sity lipop rot ein chole sterol:a randomizedcont rolledtrial.Br J Nu tr1986;56:8186. 104.Steinber gD, Pearson TA, KullerLH.Alcoh olan dath eroscle ros is.An n Int ern Med1991;114:967 976. 105.SuhI, Shat enBJ,C utlerJA, e tal.Alcoh oluse andmor talit yfromcoron ary heartdisease :the roleofh igh -densitylipopr ote in cholest erol. Ann In tern Me d1992;116:881887. 106.GazianoJm,BuringJE ,BreslowJL,etal. Moderatealcoholint ake, in creasedlevelsofh igh den sit ylipoproteinan dit ssubfractions ,an ddecreasedriskofmyocard ialinfar ction .N Engl J Med 1993;329:18291834. 107.Ander son RA,Ch engN,Br ydenNA,e tal.Elevatedint akesofsupplement alchromiumimprove glucosean din sulinvar iable sin ind ividualswith type2diabete s.Diabe tes1997;46:17861791. 108.Ander son RA,Bryde nNA,Polansk yMM.Lackoft oxicityofch romiumchlorideandch romiu m P. 631
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picolinat e.J Am Coll Nutr1997;16:273279. 109.StearnsDM, WiseJP,Patiern oSR, etal.C hromium(III)picolinat eproducesch romosome damagein Ch in esehamst erovary ce lls.FASEB J1995;17:16431648. 110.Alzaid A, Dinn eenS, MoyerT,e tal.Effe ctsofinsu linonplasmamagn esiuminn on -in sulin dep ende ntdiabe tesmellitus:ev ide nceforin sulinresistance. J C lin E ndocrinol Metab1995;80:1376 1381. 111.LimaJDL,C ruzT,Pou sadaJC,e tal.The e ffectofmagnesiumsupplement ation in in creasin g dosesonth econ troloftype 2diabet es.Diab etes C are1998;21:682686. 112.PaolissoG,Sgambat oS,C ambarde llaA,e tal.Dailymagn esiumsupplementsimprov eglucose handlinginelderlysub je cts.Am J C lin Nu tr1992;55:11611167. 113.Cer ielloA,GiuglianoD,Qu atr aroA,etal. VitaminE redu ctionofproteinglycosylation in diabe tes:ne wprosp ectforpreve ntion ofdiabe ticcomplicat ions?Diabe tes Care1991;14:6872. 114.ReavenPD, HeroldDA,Barn ett J ,etal. E ffectsofvit amin Eon suscep tibilit yoflow-de nsity lipoproteinandlowde nsitylipoproteinsu bfractionstooxidationandonproteinglycation inNIDDM. Diabetes C are1995;18:807816. 115.Burse llSE,C ler montAC ,Aie lloL P,et al.Hig h-dosevitamin Esup ple men tat ionnormalizesret in al bloodflowandcreatinineclearan cein patien tswit htype 1diabet es.D iabetes C are 1999;22:1245 1251. 116.Diabe tesCareandEdu cat ionDiet eticPracticeGrou pofth eADAMeal plan ning app roaches for diabe tes management ,2n ded.Alexandria, VA:American Dietet icAssociation ,1994. 117.Amer icanDiabetesAssociation an dtheAmerican Dietet icAssociation .Exch an ge lists for meal plan ning.NewYork:Ame ricanDiabete sAssociation,1995. 118.Bease rRS,et al.Joslin's diabete s d eskbooka guide for primary car e provid ers.Boston:Joslin DiabetesC ent er,2001.
Chapter37 Behavioral Research and Psychological Issues in Diabetes: Progress and Prospects
Barbara J. Anders on Ann E. Goe bel-Fabb ri Alan M. Jacob son Over thepasthalf-ce ntu ry,th ere h asbe enanexplosionofresearchandclin icalworkfocused ont he cen tralrole ofbeh avioralan dpsychologicalissu esinth elivesandcareofpersonsliving with chronic illne ss,part icu larlydiabete s.Clin ician san dresearche rsalik eackn owledge thatbehavior(i.e .,selfmanagement b ehavior)isthe mostfun damentalsour ceofboth thet reat men tan dprev entionofdiabetes. More ove r,be havioralscientistsplayanimportantr oleinrese arch focu sedon the preven tion and cu reof type 1an dtype 2diabet es.Asdescr ibe dbyGlasg owan dcolleagu es(1),Themostcompelling evidence oft hecomp lemen tarityofbeh avior alscien cean dbiology isth eobservationt hat clinicaladvance s,such asint ensiveth erapy,isle ttransplan tation,orgen etictesting and'eng in eering, 'raise r ath erth an eliminat ebeh avior alandpsy chologicalquest ionsan dne eds.In thep astdecade, b ehavioralscient ist s an dme ntalh ealthclinicianshaveformedthe CouncilofPsy chologyan dBehavioralMedicinewithint he Ame ricanDiabete sAs sociation.Beh avioral-sciencer esearchhasaddr essedbroad -ran gin gissu esabout livingwith diabetessu chastheimpactoftig htbloodsug arcontrolon thecognitivefu nction in gan d qualityoflifeofthe personwithdiabe tes,h owfamily memberscanhe lpt hepe rson with diabete slivea he althylifestyle,andwhatconstitut esthe mosteffect ive treatmentforth epersonwithdiab eteswh o alsohasmajordepre ssion. Researchstu dieson behavioralandpsych ologicalaspectsofdiabet esare now
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pub lished inmedicaljou rnalsaswellaspsy chologicaljourn als.Most impor tan t,th isatten tion t o beh avior aland p sychologicalissu esinthe treatmentofdiabete shas r efocu sedth efie ldonh ealth promotion in livingwithdiabe tesandonprev entionoft hediseaseit self.Thebe haviorspecialistisnow ar ecogn izedme mbe rofth emultid isciplin arydiabe tescareteam. Wearewritingth isch apte rforclinicianswhowor kwit hpersonslivin gwit hdiabet es.Weh ave atte mpte d toprovide anu p-to-date reviewofr esearchprogre ssfocus edon behavioralandpsych ologicalaspectsof diabet esthatar erelevantt oth eprofession alswh ocareforpersonswith diabetes. Wehavedividedth is rev iewint ofoursect ions. Firstwediscussps ychosocialissuesth ataresalient ateachstageof deve lopmentacrossthelifecycle.Second, wediscu ssrese arch onfactorsthataffec tadaptationto chr on icillne ss:stress, coping, socialan dfamilyen vir on men ts,adher ence, an ddiabete sburn ou t.In th ethirdmajorsection ,wefocusonne wp aradigmsoft hepatient-pr ovider relation ship.In theformatof an inter vent iontable ,wepr ovideanoverviewofresearchoninte rven tionst rate gie sandt echn iqu es relevantt opracticin gclinicians. Inourfinalsect ion, we addre ssspecialpsychologicalproble msth at ar iseint hecareofp ersonswithdiabe tes,su chase atingdisorders, sexualfu nctioning,anddep ression . Toconclud e,were vie wprogr essinan dsugges tprospectsforfutu rere search on behavioralissue sin diabet es.
DIABETES AND THE LIFE CYCLE

Ateachstageinth elifecycle,t heindividualiscon fron tedwith aseriesofdeve lopme ntaltasksor goalsin physical,psych ological, and socialdomains. Wit hinthiscontex t,diabe tespre sents peoplewit hun iqu eadd itionaldeman dsatparticularde velopmen talstag es.Personswithdiabe tesface th echalleng eofadapting t oe achn ormat ive developmen talstagewhilebalan cin gthe influe nceofeach ne wstageont hecomplext asksofdiabete sself-careandmanagement . The d emandsofdiabete sself-caremaye xacer bate thepr essure sofn ormaldeve lopme nt. At each stage ofd evelop men t,family membersofpersonswithdiabetesareconfronte dwit hthe taskofbeingsen sitive tothe impor tan ceofe stablishingade velopmen tally appropriate balan cebetwe enth epat ie nt'sneedfor indepe nden cean dhisor hern eedforfamilysu pport and inv olvement in self-caretasks.Th isdile mma raises u nique issu esatdiffere ntstagesofchildandadultdevelopme ntforfamiliesofpatient swith diabet es.The strug gle t obalanceinde pende nceanddep ende nceinth erelat ionsh ipsbe tween thepe rson withdiabe tesan dfamilymemb ersprese ntsmajorcoping t asksforallmembersofthe family. P. 634
Childhood
Itiswelldocument edth atth ecomplexdailyregimenofdiabete scare canaffecteve ryaspe ctoffamily lifeandch ildan dadole scent d evelop men t(2, 3,4). Although d iabetesisrelat ive lyr areamonginfantsandtoddlers, wh enitisdiagnosedinth isagegroup, th epare ntsorcar egiversareth erealpatient s(5).Par entsarefac edin it iallywithth echallen geposed byth eirgriefov erth elossofahe althy, perfe ctchild.Whilestillinthe midstofthisacu te adju stme ntph ase, pare ntsmustalsole arn thefu ndamen talsofd iabetescareandaccommodat ethe ir familyliv estoin clu deth edaily tasksofdiseaseman age men t.Man ypare nts, duringth isfirstph ase of th edis ease, reportincre asedmar italconflictan dfe elin gsofde pression ;however, ove rtimeandwith gre ater opportu nitiesfor d iabetese ducat ion, pare ntsre port great erconfidence andmoreflexibilityin the diabet esregimen(6). Diabetesintoddlersandchildren ofpre schoolage p resen tspar entsandh ealthcarepr oviderswith the challen geofadapt in gdiabete scaret oth etoddler'sn or maldev elopment alstrugg leforindepe nden ce. Ch ildren 'sn atu raldrivetoward autonomyisoften reflectedinr efusalstocooper ate wh enr eceiving injection sor bloodg lu cosemonitor in gandinconflictsaboutfood .Inth isway,diabe tescan fuelpar entchildcon flictsth atty pifyt hisd evelop men talstage.Pare ntscanhelpfostert heirchild'ssen seof indepe nden cewithoutcomp romisin gdiabete scareby allowin gchildr entochoosebetwe entwosnacks, bet we eninject ionsites, andwh ich fin gerstouseforbloodglucosemonitoring.In addition ,forchildr en whoare fin icky e ate rs,administering Hu maloginjection safte rme alsmayhelpeliminat epar ent-ch ild powerstru gglesatmealtimes.Tempert ant rumsare commoninchildren atth isage,bu tth eymayalso beindicat ive ofhy poglycemia.Man ypar entsiden tify difficultiesin diffe rent iatingdiabet es-relat edmood change sfr omage-appropriate behavior(6).Once hypoglycemiah asbe enru le dou t,parent sneed t ose t asfirmlimitsasthey wouldforthe irch ildifheorshe didn oth ave diabetes. The t ran sit iontoschoolisapar ticu larlydifficulttimefor p aren tsofy ou ngchildren with diabete s. Paren tsstru ggle with an xie tyabout theirch ild'ssafetyandsup ervision. Parent sshouldbeencour agedt o takean activer oleinedu catingdaycar ework ers,n an nies,babysit ters, andt each ersab ou tsign san d symptomsofhighan dlowbloodglucosele vels,app ropr iatetre atmen tofh ypog lyce mia,andth e mechanicsofbloodglucosemonitoringandinsulinadministrat ion. The reisagrowin gbody ofeviden ceth atmildcognitivedeficit smayresu ltfromrecur rent ,seve re episodesofh ypoglyce miainyoun gchildr en. Researche rsusingn europsych olog icalassessme ntsh ave foundsignificant differ ence sinv erbalinte llig ence, visu al-motorcoord in ation ,an dvisuospatialabilit iesin
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comparin gyouth swith diabete stoage-match edcontrols(7,8,9,10).Rovet andcolleague sfoun dthat children d iagnosedwithdiabe tesbeforeth eag eof4year shadmorefrequ ent hypoglycemicseizu res th andidchildren diagnosedlate rin childh ood,su ggestingt hat severe hypoglycemiad uringth eperiodof brain developme ntmayimpair latercognitivefun ction in g(10).Inlig htofthese fin din gs,clin ician sand car egiversofveryyoun gchild renwith d iabetesmust activelyavoidthe t ren dtowardinten siv egly cemic controladvocate dbyth eDiabe tesCont rolan dComplication sTrial(11, 12).Age-spe cificbloodglu cose ranges, aimed atpre vent in gsevere hypoglycemia,shouldbeth estandar dofcareforthe seyoung pat ie nts(13). Becausepe errelat ionsh ipsaresoimportan toncech ildren start school,itisimpor tan ttob eawareoft he impactofdiab etesonsocialfu nctioning.Diabete sduringth eschool-ageyearscan affect t hech ild'sse lfeste em.Infact,manyst udieslin klowself-estee minch ildren topoorly con trolleddiabe tes(14,15). For th isre ason,ch ildren wit hdiabet esshouldbeen cou rage dtop articipate fu llyinsch ool-basedactiv ities, sports,andclubsth atcanser veassour cesofsu ppor tfor t hede velopmen tofposit ive self-estee m.For th istobeaccomplish ed,ch ildren mayrequ ire in dividu alize dcare plansinschool(16)withchange sin lunch schedu le sand extratimeforsnackstopreve nth ypoglycemia.Pare ntsmayn eedtoadv ocatefor th eir childsothatth esesafe typre caut ionscanbepu tin placetoallowforfullinte grat ionofchildre n withdiabe tesintothe regular schoolroutine. Parent sshouldbeen cou raged toworkwithsch ool per son neltoe nsu reth atth eirchildmissesaslit tle classroomtimeaspossible.The ove rallg oalof diabet estre atment duringth eschoolye arssh ou ldinclude themin imaldisrupt ionofsuccessfu l expe riencesinsch ool.
Adolescence
Res earch hasconsiste ntlyshownadeclin ein met aboliccontrolofdiabe tesdur in gadole scence influen cedpar tly byphysiologich or monalch ange sduringpu berty andpartlybyadeclin ein diabete s self-care duringt histime(17,18, 19).Theroleoft hepe ergrouph asbee nimplicatedinth edecr ease in self-care exhibitedby adolesce ntswithdiabetes. Jacobson and c olle ague s(20)reportth atmor ethan one-h alfofad olescen tswit hne wlydiagn ose ddiabete sdon otdisclose theirdiabe testothe ir close friendsandth at35%oft hese teen sreportth atth eybe lievet heirfriends wouldlike themmore ifth ey didnothavediabet es.Oth erre sear chhasin dicatedth atadolesce ntswillskipnee dedinsulininjection sin an att empt tofitinwithth eirpeer soroutoffear thatdiabete sself-carewilldrawnegativeat ten tionto th emse lve s(21,22).On t hepositiv eside ,howeve r,rese arch on bene fitsofpeer supportforadole scent s withdiabe tesshowsthatpee ran dfamilysupportincomb in ation isdire ctly assoc iatedwithth e integ rationofdiabetesse lf-carebeh avior in todailyadolescen troutine s(23,24). Afin alare aofd iabetesman agemen tthatposesaparticularch alle ngeacrosschildde velopment isth e gradualtr ansition ofdiabe tesre spon sibilitiesfromparen ttochild .Theconsen susisgrowin gacross rese arch studiesth atch ildre nan dadole scent sgive ngreater responsibilityfor diabete sman age men t makeagreatern umberofmistake sin self-care, are lessconsisten tinadh eringt oth eirtreatmentplan , an dhavepoore rme taboliccontr olthanth ose ch ildre nwhoseparent sremaininvolv edin diabete s management (25, 26,27,28,29, 30).Resu lt softh esestu die shav ele dmanyclin ician stoadvocate a diabet estre atment approach where bypar entsandte enssh are r esponsibilityfor thet asksofdiabete s car e.Thisinvolve sope ncommunicationbe tween pare nt P. 635 an dchild t ore ducediab etes-r elatedconflictsaboutout -of-rangebloodsu garsandtoen cou rage amore matte r-of-fact,pr oblem-solvingapproachtobloodsugarcontrol.Eachfamilyn eedstobeen cou rage dto deve lopitsown patt ernofpar ent-adolesce ntte amwork soth atth echildwith diabete scancont in ueto feelsupp ort forth edailyburd enofdiabete scareandbe lessatriskfor t hede velopmen tofdiabe tes adh ere nceproblems.
Early to Middle Adult Years

Incont rastt oth eext ensiveempiricliteratur eon childandadolescen tdeve lopmentwith in t hecont extof diabet es,re lativelylittlere searc hhasbeen c arriedoutonadaptation tod iabetesdu ringearly adulth ood. One areaofint eresth asfocusedone xamin in gthe proce ssoftr ansition in gfrompediatricman age men tof diabet estomanage me ntinth eadu lt health care system.Inasurv eyofpatient smak in gthistransition, Pacau dan dcolle agu es(31)reportth atu pto50%ofthepatients su rvey edreporte ddelaysorlossof reg ularmedicalfollow-updu ringth istr ansitionperiod.One wayofu nde rstan din gthe barr ier to transition sin health care provide rsisimplicat edbyfindingsre port edbyWysockiandcolle ague s(32)that difficu ltiesinadju stingtodiabet esduringadolesce ncepe rsist in toadulth ood.Stu dies ofth istr ansition per iod,whilerar e,argueforth eimportanceofin terve ntionsaimedatsmooth in gthe tran sit ionofcare fromadolesce ncetoadu lt hood. Th isisespe ciallyimportantforhigh-r isk patien tswhohav ealready bee nstru gglin gwith theirdiabe tesman agement duringch ildhoodand adolesce nce. The d evelop men taltasksofmiddleadulthoodarecomple xand t ake t imetomaster. These t asksinclude house holdandlife stylemanag eme nt, childre aring, andcaree rmanag eme nt. Dur in gthemiddle adult years,e achofthe setask sin volvesacceptanceofthe in evitableprocesse sofagin g,aswellasan invest men tinext ernalsocialsystems.AccordingtoNewmanan dNewman, Th etasksofmiddle
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adu lt hoodde mandan expandedconce ptualanalysisofsocialsystemsan dacap acitytobalan ce individ ualne edswit hsyste mgoals.The adultn otonlylear nshowtofu nctioneffect ive lywith in lar ger groups, s/hecome stoinv esten ergyinth ose grou pswit hwhichs/h ecan mostreadilyiden tify (33). Diabetesimp osesconflictsbetwe enanadu lt 'sresp on sibilitiesformain taining h is orh erown healt han d bloodsugarlevelsan dresponsibilitiesfor mee tin gthe nee dsofothe rfamilyme mbe rs(34).Fewstudies havebee ndoneonth eimpactofdiab etesinapare ntonth efamilyen vir on men tofch ildre n(35). Int erest h asce nter edprimarilyonu nderst an din gtheinflue nceofspou sesupp ort .Ahlfie ldet al.(36) stu die dtheimpactofdiabete son marriageandqu ality ofdailylife. Th eyre port thatadu ltswith diabetes per ceiv edthatth ediseaseint erfer edwit hfamilyactiv itiesandfinan cesmore thandidthe irspouse s,who didnothavediabet es.Significantlymore men thanwome nwit hdiabet esfeltthatth edise asewasa sourceoffrictionint heirmarriage . She nkelan dcolleagu es(37)reporte dthatthe impor tan ceoft hediabe testre atmen tregime ntothe spousewh odidnothavediabe teswasdire ctly r elated t oleve lofadhe ren cetothet reat men tplanint he spousewh oh addiabet es.Pie peretal. (38)reported t hat ,inasampleofpatien ts40year sorolderwho hadtype 2diabet es,th ehighe rthe ratingt hat nondiabet icspouse sg avet oth eben efit sofdietth elower th eyperce iv edthe irabilitytohelpth epar tner with diabete s.Diet arych ange sweremost freque ntly ratedast hemost difficultpar toft hediabe tict reat me ntreg imen. Pieper e tal.(38)concluded ,Fort he marriedpe rson diagnosedashav in gdiabetes inmiddle ageorlate rlife,lifestylechange s,especiallyin reg ardtodietan dme dication s,mayimpacton maritaladjust men t.Alackofund erstandingoftheimpact ofd iabetesont hemaritalre lationsh ipmay allowacoupletousediabe testone gativelyinfluen cethe ir marriage and d iseasecontr ol.
Pregnancy
The e xperien ceofpr egnancyforawomanwithdiabe tesisshapedbyan umberofforce s:the deve lopmentofhe rself-con cept,se xuality,andbodyimagedur in gchildh oodan dadolescence ; information sh ehasrece ive daboutdiabe tesasitre latestohe rabilityt obe comepreg nan tan dhav ea n ormal,h ealthy baby;t hequ alit yofhe rdiabet escon trolbe fore pregn ancy ;thepr esen ceofany diabet escomplication sbefor epreg nan cy;her accesstohighlyspe cializedh igh -riskpren atalcare;he r resour cesfor copingwitht heph ysicald emandsofdiabete sself-man age men tdur in gpregn ancy andwith th eemotionalstre ssrelate dtou ncer tainh ealthout comesforher selfandth ebab y;and, fin ally, the av ailabilityofinv olvement andsu ppor tfromap artn erandfromh erext ende dfamilyan dfrie ndsbefore, dur in g,an dimmediatelyaft erth epregn an cy. Rec entr esear chdocuments t heabilityofwome nwithdiabe testogivebirtht on ormal,h ealth yin fan ts ifthey h ave tig htbloodglucosecontrolatconcept ionandcan main tainitth rou ghoutp regnancy. More information isnowavailable ont heimpactofpregn ancyont heh ealthofwomen with diabete s.Women withmore advancedocular ,vascu lar,andre nalcomplication sare fr eque ntlyadv ised n ot tobe come pre gnan tbecauseofthe pote ntialfor pregn ancy toaccelerat ethe sephy sicalcomplicationsan dcau se seve reph ysicaldisab ilit yor e vend eath ofth emoth er. Forthe sereason s,th edecisionabou twhe ther an dwhen tob ecomepre gnantisacomplexone forth ewoman wit hdiabet es.Inv olvement and su pport fromth epartne rare crit icaldu rin gthisstre ssfuldecision-makingp eriod, especially ifth ereare contrain dication sforpr egnancy. Medicalmanage me ntofdiabete sisespe ciallyinte nsedu rin gpregn an cyin termsoft hefre quen cyof contactwit hspecialistsan dthedailydiabe tesself-car ethatisrecommende d.Insu linn eedsoften decr eased uringth efir sttrime sterofpregn an cybutincr ease d uringth esecondandth ird t rimest ers. Throug hou tth epregn an cy,mostwome nmustincre aseth efreq uen cyofbloodsug armon itoringt oat least four timesad aybecause t hestabilizat ionofblood-sugarle velsismor edifficultdu rin gpregn an cy an dbecauseh ypoglyce miaan dhype rglycemiapresen triskstothe d evelop in gfe tus. Give nth ehealt hrisksofp oorlycon trolleddiabe tesdu rin gpregn an cy,itissu rprisin gthatth emajorityof women with diabete sdon oth ave accesstopre -pregn ancy coun selin g.Infact,asfewas34%ofwomen withdiabe tesrece ive con ception guidan cebeforeth eyge tpregn ant (39),an dfewerth an halfof pre gnan cie sin womenwithdiab etesareplan ned(40). Holin gand colle ague s(40)foun dthatwomen who hadun planne dpregn an ciesr eportedth att heirdoctorshad d iscouragedth emfr omgett in gpregn ant , whe reaswome nwithplan nedpr egnanciesrep ort edthatth eir doct orsh adre assur edthe mofthe irability tohaveah ealth ybabyde spit ethe irdiab etes. Su chre sear chun derscoresth eimportanceofpositive pre pregn ancye ducationandsu ppor tiv epatien t-doctor in teractionst hat allowwomenwith diabeteswh o ar eofch ildbearingage tofe elt hat they cane ngag ein familyplann in gan dwork with theirh ealthcare teamt osu pport ahe althypr egnancy. De spit ethe researchadvan cesan dthe in creasedlikelihoodofthe delive ryofahe althy, normal b aby,a gre atdealofappr ehe nsion accompaniesapre gnancyinth econ text ofdiabe tes.In addition tot he normalcon cern sthatallpr egnant P. 636 women exper ie nce,t hepre gnantwomanwithdiabe tesmustcopewithconcer nsabout theimpactofher diabet eson the health ofh erbabyan dther ecip rocalimpactofpregn ancy on h erownhe alth. Research
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byLanger andLange r(41)fou ndth atpre gnantwomen wit hdiabet esweresignificant lymorean xious th rou ghoutt heirpre gnan cie sthanwere womenwithout diabetes. Thisin crease dan xie tymaybefu ele d byth emultipleph ysiologictes tsthatwomen with diabete smust unde rgoin orde rtoassessth ehe alth an dcon ditionofthe developin gfetust hrough ou tthe irpr egnancy. Th eincre asedworkinvolv edin managin gapr egnancyinconjun ctionwitht heinte nsee motion alexperien ceoft hepre gnancymake supp ort fr omthe husbandorpar tner ane xtremelyimportantfactor in t heoutcomeofpr egnancyin diabet es.Sup port fromexte nded familyan dfr ie ndsalsoiscriticalin helpingth epreg nan twoman maintain thediscipline ande motion alstability need edfor thedu rat ionofthepr egnancy.
Late Adulthood
Int helate radu lty ears, the primar ydevelopme ntaltaskscon cern the r edirectionofe nerg yton ewrole s an dactivities,th eacce ptan ceofone 'slife andt heph ysicalandcognitivech ange sassociatedwithagin g, an dthe developmen tofapoin tofviewabou tdeat h.R etirement r equiresman ypersonst ofindne w outletsforth eir in telle ctualcapacitiesan dsocialsupports. Lit tle hasbe enwritte nab ou tdiabete sin the late radu ltye ars. Emp iricdat aoncopin gissu esfacingt heelder lypatientwith diabetesaren otavailable. Ret ir eme ntcanplacefinancialcon straint son patien tswith diabete s,whomaynolong erhaveth esame acce sstoh ealth care reimbu rsement st hrough private employee-basedh ealthinsu ran ce. Comp ared with theirfun ction in gin middleadu lt hood, lateradulthood isape riodwhe nth enormal phy sicalde terior ationoft heagin gprocessin combinat ionwithth eonset andpr ogre ssionofdiabete s complication srealistically limitth efun ctioningofmanye lde rly p atient s.More ove r,elder lypatientswith diabet esfrequ ent lycopewithmultiple med icalcondition sand multiplecomplexmedication schedu le s simu ltaneously. Th us,itmaybe difficultfor familyme mbe rsan deld erlypatien tstodist in guishth e det erioration relate dtot hen ormalagingpr oce ssfr omthe prog ression ofdiabet escomplication s.Worry, fru strat ion,andalien ation mayresu ltfr omthed ecline in lev eloffun ctioning .More ove r,depr essionisa seriousan dun derre cogn ize dproble mamongth eelderly.In thep atient with diabete s,depre ssioncan decr easet heirmotivationanden ergy fordiabe tes-re latedself-car e. Health care profe ssionalscaringforelderlypat ien tswithdiabe tesmustbeale rttothe need t oassess issuesoffunct ionalstatus .Assuch, the yaree ncouragedtoassess t hepatient'sle velofman ual dext erity,qu alityofvision and h earin g,an dability tobe physically active. Th efun ctionalst atu sofeach pat ie ntinfluen ceshisorherabilitytocarr you tthe complextasksofdiabe tesmanagement ;in clu din g administeringmedicat iondosesaccu rat ely,mon itoringbloodglucosereg ularly,inspe ctin gthe irfe et, rememberingmedicalrecommen dationsan dappointment s,prep aringmeals,anden gagingine xercise.If self-care abilitiesdecline, flex iblearran gementsn eedt obemade forgr eate rfamilyorprofession al involv eme ntindiabe testre atment and d ecision-making. Youn gerfamily membersfindt hat t heymust becomeeducatedindiab etesandmakede cisionsconcern in glivingarran gement sforanelderlyparent withdiabe teswhoisn olongerabletoin jec tin sulin in depen dent ly, tot akemedicat ionsatappropriat e time s,ortoe atre liably. Insu mmary ,acrossth elifespanfr omin fan cytot helate radu lt y ears the strug gle t obalance indepe nden cean ddepen den cein the relation shipsbetwe enth eper son with diabete sandfamily membe rs,esp eciallywithre specttoself-car e,pre sentsu niquecopingch allen gesforpat ien tswith diabet esan dthe irfamilies.
ADAPTATION TO CHRONIC ILLNESS

One ofth emostsignific ant out comesofthegr owth ofth efields ofhe althpsych ologyan dbehavioral medicin ehasb eenpu blicationofscientificevidence ofth econ tribut ionofpsychologicaland social fact orst ohu manh ealth, part icu larly toadapt ation toch ronichealth proble ms, su chascance r,he art disease ,stroke, anddiabetes(42). Th ish asledtoawideacce ptan ceoft heinte rplaybet ween psych osocialfactorsan dbiologicou tcomesinboth type1and t ype2diabetes. Three broadpsych osocial fact orst hat impactaperson'sadaptationtochronicillnessarestr ess,copingabilit y,an dthe socialan d familye nviron me nt. Alth ou ghth esefact orsint erac t,eachwillbeconsidered se paratelyforpurposesof rev iew.
Stress
Numerousre port shav eexamined t heinfluen ceofemotion ally stressfu lex perience son health stat us.For example, Rah eetal. (43), usingscale dmeasure soflife e vent s,foundt hat acute me dicalillne ssesten d tooccu rat t imesofchan ge.Ot herst udiessugge stthatstre ssfulexper ien cescanbeimportante tiologic fact orsinth epathophysiologyofd isablingch roniccon ditions,su chascoronaryvesse ldisease(44).The courseofach ron icilln esssuch asdiabet escan alsobe affecte dbystressfu le xperien ces(45).Stu dies oftene mph asizeth eadditiveeffe ctsofmultiple stressfu llife even ts.In additiont oth enu mbe ran d inten sit yofth eselifeeven ts,th eirpar ticu larmean in gtot heindividualalsocon tribute stot heirultimate influen ceon healt hstatus(45,46, 47).
STRESS AND DIABETES ONSET

Int erest ine xamin in gthe roleofpsychologicalorenvironment alstressorsindiabe teshasalon ghistory.
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Earlyreports(48)sug gestedt hat theonse toft ype1diab etesmaybe triggere dbypsychologicalstre ss inaph ysiologicallysusce ptib leindividual. St einan dCharles(48),us in gretrospect ive docu men tat ion, foundahigher prevale nceofdist urbancesininfantfee din gpatt ernsinasmallgroupofdiabeticchild ren th aninth eirsiblings. Since psychologicalstre sscanalt eract ivityinth esympath eticne rvou san d adr enome dullarysyst ems, elevat eplasmacor tisolle vels,possiblyen han ceth esecre tionofglu cagonand growthh or mone(49), andaffectimmun efunct ions(50), athe ore ticallyr ele van tsetofbiologicpat hways ar eprese ntth atcouldmediatearelationshipbet weenpsy chosocialstre ssorsanddiabe tesonset .Indee d, someanimalst udiesusingt heBBratasamodeloftype 2diabe teshaveindicate dthatan in creasein en vir on men talstre ssshorten sthet imetoon setofove rtdiabe tesmellitus(51). Although s tress, b oth psychologicalan dphysical,h asbee nshowntohavemajor e ffectsonmetab olic act ivityandh aslon gbeen su specte dofplaying arole int heonset oftyp e1diabe tes(52),t here isn o solideviden cebase forth isconn ectionbetwe enstr essan ddiabete son set.However ,rece ntre search in gen etics,immun olog y,an dendocrinologyh asident ifiedamulticomponen tmodeloft hepathogen esis of type 1diabe testh atlin ksau toimmu nede struct ionofin sulin -prod ucingpancreatic-cellswithge netic an denv ironmen talfactors.E xistin gstud iesofthe roleofstressint hedev elopment oftype 1diabe tes havebee nlimit edbymeth odologicproble ms,includ in gsmallsubjectsamplesandar elianceon ret rosp ectiveaccoun tsofmajorlifest ressors(52,53).Despitemeth odologiclimitation s,existing stu die ssuggest thatin div idu alswith type1diabete sare morelike lyt ore por tamajor lifestre ssoror P. 637
familyloss p riortothe on setofsympt omsofdiabe tes(48).Aprovocativer ecent paper byThern lu ndand associate s(54)r eportedth atst ressfullifee vent sduringt hefirsttwoyearsoflife dist in guishedch ildre n whodeve lopeddiabe tesfrommat chedh ealthy con trols. Th ehyp oth esisisth atmajorstressors, in clu din g illne sses,occurring e arlyinth elifeofagen eticallysuscept ibleindividualcouldimpairimmun efun ction dur in gthiscriticaldevelop men talper iod,whichover t imetr igge rsthe onse toft ype1d iabetes. Anothe rrece ntlin eofr esearchhasexamine dther oleofst ressasatriggerfortyp e2diabe tes.Su rwit an dcolleagu es(56)notedt hemount in gexperiment alevidence ofalter edsympath eticner vou ssystem act ivityint ype2diab etesiden tifiedfr omsever alanimalmodels.They h ave demon strat edthatob/ob micedifferfr omtheirleanlitt ermatesinh avinge xagge rate dbloodglu cose responsestoen vir on men tal stre ssor sandt oth eexogen ou sadmin istr ation ofe pin ephr in e(55,56).Oth erre sear chsugge ststhat ob/obmicemayhaveen han cedad rene rgicr esponsestoen vir on men talstre ss(57). Res earch on obe sebutoth erwisehealthymen(58)sh owsth att heye xhibit analt erat ioninautonomic ne rvoussyste mfun ction in gspecificallyadecre aseinsympat hetican dpar asympath eticactivity associate dwith anincr ease in b odyfat.Thisfindingindicate sthatadisor dered h omeostaticmech anism mayexistth atcouldpromote excessivestorageofe ner gybydecre asingsympat heticact ivitybu tat the sametimedefen dagain stweightgain bydecre asingparasympat het icactiv ity . Itisnotclearwh eth erth esean dot herch an gesin neu roendocrineactivit yare causative,arere latedto th eon setofhype rgly cemiaand/orhy perinsu linemia,orar esimplychancefindingswithout sign ifican ce forthe p roblemoft ype2diab etes. Howeve r,th isisan areain whichfur ther researchmaye laboratet he role ofstr essan dcentr alnerv ou ssystemcon trolinth eonsetandcourse ofty pe2diabe tes.Th ereis consen susth atty pe2diabe tesisstronglygen etically d eter minedandmost likelyisp olygen icand he terogen eou s.Gene sin volvedinsomesubty pesoft ype2d iabetesh ave r ecen tly been iden tified ( 59): The rehasbeen cle arde monstration thatob esit y,phy sicalinactivit y,an dot herlifestylefact orsare importanten viron me ntalriskfac tor sforth edeve lopmentoftype 2diabet esin the gene ticallysusce ptible in dividual. Furth erre search isn eede dtoclar ifyth einte rplaybet we enge neticfact ors, lifest yle factors,obesity, andst ressinth eon setoftype2diabete s.
STRESS AND THE COURSE OF DIABETES

Stre sshasboth dire ctan din dir ecteffect son out comesinchr on icillne ss(60).Ithasbeen post ulate d th atstr essmayaffect thecour seofdiab eteseith erdirectlyth rought hestr esshormon esaffect in gblood glucoselevelsan din sulin met abolism,or in dire ctly,th rou ghstr essproducingch ange sin self-care beh avior (61).Stress, bot hpsych ologicalandphy sical, h asbe ensh ownt oh avedirect effectson metab olicactivit y(62).Ph ysicalstressors,su chasilln essortrau ma,havebe ensh ownt ocause hy perglycemiaan deven tualke toacid osisin personsdiagn ose dwith type1diabete s(63).Amongch ildre n withtyp e1diabe tes,e pin ephr in ein fusion producedmoreelevatedbloodglucoselevelsan dmorerapid ket on ereleasethanamongchildren with ou tdiabet es(64).Rec entworkex amin in gnegativelifee vent s amongindivid ualswit htype 1diabe teshassugge stedth atth eset ypesofst ressorshavean adve rse effect on g lu cosecont rol(63,65).In con trast,stu die softh eeffect soflaborat ory-ind ucedstr esson glycemicfu nction in gofindividualswitht ype1d iabetesh ave b eenmoreequ ivocal(66).Possibly, differen cesacr ossstu die sin thet ypesoflaboratorystre ssorsinv estigate d(e.g. ,noise,mental ar ith me tic) may have con tribute dtot hecontr adictoryfin dings,asnotallsu bjectsmayfindth ese expe riencest obe st ressfu l.In deed, studiese xamin in gthe e ffectsofstressh ormonesonglucosecontrol haveproduce dmoreconsisten tfindings(62).Some researchh assugg estedt hat t her emaybestr essreactivesu bgroupsofind ividualswith diabetesforwhomstressmainlyaffect smet aboliccontrolthrough directph ysiologicalmechanisms(67, 68).
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Inadditiont oadire cteffectofstres sonmetabolicactivity,st resshasan in dire cteffect onmetabolism byinfluen cin gthe self-carebe hav iorsoft hepe rson with diabete s,whichintu rnh ave animpacton metab oliccont rol.Str essfuleven tsdistract thep ersonwit hdiabet esfromu sualpat tern sofself-car e. Stre sscause sdisru ption sin rou tinesanddecr ease sin resourcesandsu ppor tsthatar elikelytoresu lt in lessstab lepatte rnsofself-carebe hav iorfor patien tswit hdiabet esan dtheirfamilies. Th us,t oth e ext entt hat thepe rson'sse lf-carebeh aviorsare influe ncingmetaboliccont rol,by d isru ptingself-car e beh avior ,stre ssin dir ectlyin flu ence smet aboliccon trol. Insu mmary ,the reareintriguing su ggestionsfrominitialstudiesofan imalmodelsofdiabe testh at psych olog icalandphy sicalstr essmayplayaroleinth eon setofdiabete s,espe ciallytype 1diabe tes. De fin it ive con clu sionslin kingstre sswith the onse tofe ith erty pe1ortype 2diabe tesawait fu rth er multidisciplinaryre sear ch.The evidence isstr on gerth atstr essaffect sthecour seofdiab etes, both th rou ghadire ctneu roendocrinee ffectan dan in dire ctbeh avior aleffectonth eme taboliccontr olofth e per son with diabete s.
STRESS AS A CONSEQUENCE OF DIABETES OR DIABETES-SPECIFIC DISTRESS

Health psychologistsh avere cogn iz edthatinadd itiontothe p ossibleeffectsofstres sont heonset or courseofvar iousch ron icph ysicalilln esses, the chronicillnessitselfan dit srequired treatme ntalso constitut estre ssorst hat theindividualmustconfront (60).Polon skyan dcolleagu esat theJoslin DiabetesC ente r(69)le don eoft hefirstscient ificeffortstoide ntifythe sediabet es-specificst ressors. More ove r,th isgr ou phasde velope dan dvalidatedame asur eofdiabe tes-spe cificdist ress PAID(P roble mAre asin Diabet es).Because ofth ein novat ive andimp ort ant perspect ive thatun derstanding diabet es-specificd istr esscan hav eforh ealth care prov ide rs,inth issect ionwelistthe 20sour cesof diabet es-specificd istr essthataffe ctpatien tsth atwere ide ntifie dbyPolon skyan dassociatesand measu redinth ePAIDmeasur e(69,70,71). 1. Not hav in gclearan dcon crete goalsfordiabe tescar e 2. Feelin gdis cou raged with thediab etestr eat men tplan 3. Feelin gscare dwhen thinkingabou tliving with diabetes 4. Un comfor tablesocialsitu ation srelat edtodiabete scare(e .g., peop len aggingabou twhattoeat ) 5. Feelin gsofde privationregardingfoodandmeals 6. Feelin gdepre ssedwhe nthink in gaboutlivin gwith diabete s 7. Not knowin gifmoodsorfeelin gsare relate dtodiabetes 8. Feelin gov erwhe lmedbydiabe tes 9. Worryingabou tlowbloodsugarreaction s 10. Feelin gan grywhe nthink in gaboutlivin gwith diabete s 11. Feelin gcon stan tlycon cern edabout foodand e ating 12. Worryingabou tthe futu rean dthe possibilityofseriou scomplications 13. Feelin gsofgu iltoran xie tywhe nofft rackwithr espectt odiabe tesmanagement 14. Not accep tin gdiabet es 15. Feelin gun satisfie dwith the diabete sp hysician 16. Feelin gthatdiabet esist akingu ptoomuchment aland p hysicalene rgyeve ryday 17. Feelin galon ewithdiabe tes 18. Feelin gthatfriendsandfamily aren otsu pportiveofd iabetesman agemen tefforts 19. Copingwithcomplicationsofdiab etes 20. Feelin gbur nedout bythe con stan teffor tnee dedtomanagediabet es Weinge ran dJacobson (72)hav edemon strat edth ath igh erlevelsofdiab etes-spe cificdistressinadults withtyp e1diabe tesrelatetopoorer met aboliccontrolaswellastolowerself-reporte dqualityoflife. Futu rerese arch isn eeded toiden tify s trat egiesforpr even tingdiabet es-relat eddistressandfor inter vening with patien tsove rwhe lmedbyth estre ssesoflivin gwit hdiabet es.Wen owaddressth ewide variation seeninh owpe rson shan dlethe sediabet es-specificst ressorsaswellasth estressofchronic illne ss.
P. 638
Coping Ability
Copingisabroadconst ructth atg ener allyr eferstoth estrategiesth atpe opleu setoman age and
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master stressfu lcircumstancesandtominimize then egat ive impact oflifest ressorson psychological well-b ein g(73).The con ceptofcopingint rodu cesth econceptofper son or in dividu aldiffer ence fact orst hat in flue nceanindividual'sadapt ation tothest ressesofchronicillness. Fr omabiopsy chosocial model,t heseind ividualfactors(such asself-estee m, health belie fs,personalmod els, egostren gth, and per son ality )affectandar eaffect edbyothe rfactorsinth emodel(soc ialen viron me nt,diseaseitself, he althcaresyste m). Differe ncesincopingstylesandper son ality typesinfluen ceth eappr aisalofstr ess(74)and t her efor e can affect t heindividual'sexper ien ceofwhat const it utesastressfu llife sit uat ion.Su chindividual differen cesmayaffe ctnoton ly thee motion alandbe havioralconsequ ence sofstr ess,asn ot edearlier , but alsoth ehormon alcomponen tsofth estre ssresponse incardiovascular illn ess(75)an dperh apsin diabet es(76).Similarly,Wolffet al.(77)fou ndth atvariation sin personalcopingstylesareassociate d withvariation sin cort icoster oidle velsofindividualsun derst ress. Clearly ,in dividu aldiffe rence scolorthe meaningandexpe rie nceofbeingillaswe llasth especific problemsposedby thatillness. Th esediffere ncesinfluen ceth emanag eme ntofacomplexch ron icilln ess such asdiabe tes.U nder stan din gsuchind ividualdiffere ncescancontribu tetothe t hough tfuldesignof tre atment plans. Stud iesofapatter nofind ividualdiffere ncesinre spon setothe diagnosisofdiabete sfaile dtoiden tify a diabe ticpe rsonalityan dprovedu nproduct ive ove rall(78). Th isledtostu dyoft hecognitiveand beh avior alstrategiespatie ntsu setomanage diabete sandt heiremot ionalre spon ses(79).Fir st,we ne edtocon side rthe majorset ofcopin gtaskst hat faceth epers ond iagnosedwit hach ronicphysical illne sssu chasdiabete s.MoosandTsu (80)ide ntifie dseven fundame ntaladapt ive tasks with wh ic hthe per son with any ch ronicilln essmustcope: 1. De alin gwit hpainandincapacitat ion 2. De alin gwit hth ehospit alenvironment andspe cialt reat men tprocedu res 3. De veloping adequ ate relation shipswit hprofession alstaff 4. Pr eserv in gareason ableemotionalbalance 5. Pr eserv in gasat isfactor yself-image 6. Pr eserv in grelation shipswit hfamilyandfrien ds 7. Pr epar in gforanun certainfutu re Coping skillsist hete rmu sedtodescribet hosein div idu aldiffer ence sin thewaysin whichper son sface an dhandlestre ssfult askssu chast hoseabove. Laz aru sandFolkman (81)suggest edth atth ecopin gprocessbeginswhe nap ersonappr aisesor evalu ate sthe st ressfu lsituation andt hat t hepe rson evalu atesboth thest ressfulasp ectsoft hesitu ation aswe llash isorher abilitytodeale ffe ctivelywit hthe sestre ssors. Wit hinthisth eory,individualscope withstr essin on eoft womajor ways:byattemptingtochanget hen atu reoft hestr essfulsit uat ion (problem-focuse dcoping)orbyman agingth eiremotionalreaction stot hestr essfulsituation(e motion focusedcoping)(74).E motion -focu sed cop in gisdescr ibe dasdirectinge ner gyaway fr omthe sou rceof stre ss,byavoidan ce,de nial,ordist raction.Proble m-focused copingre fe rstoeffor tstoresolve the problem, tofocuse nergy andr esou rcesonsolv in gthepr oblemor r educingst ress.St udieswit h adolescen tswit htype 1diabet esgiveconflictingr esultsab out the r elation shipbetwe enth esetwotype s ofcopingskillsandlevelofmetaboliccon trol(82, 83). Howev er,instu dieswit hadolescen ts,consisten t associationshavebee nreporte dbetwe enself-car ebeh aviorandty peofcopingskill,with e motion focusedcopingassociate dwith poorer lev elsofself-care behavior(84,85).
COPING AND THE COURSE OF DIABETES

Anincre asingn umb erofsy stematicstud iespointtoth ein flu ence ofindividualcharact eristicson t he courseofdiabet es,withre specttomanagement(adhe rence ),me taboliccontr ol,andoveralladjust men t (86,87). Se lf-est eemisone ofth easpe ctsofpe rson alit yimportan tinadaptat iontodiabet es.Highor robustse lf-e steemmayserve asapr ot ectivefact orinapatien t'sadju stmentt oth evicissitu desoft his complicatedilln essan dtot hepoten tiallyconfu sin g,an dat t imesinadverte ntlyhu rtful,r espon sesof significantothe rssuch asfamilymembers,closefriends, schoolmates, andcolle ague s.Alongt hese lines, Jacobsonet al.(88)hav efou ndth atpr eadolescen tsand adolesc entswithlowself-e steemhadlower levelsofadher ence atth etime ofdiagn osisan dove rtimet han didt hosewit hhighe rself-estee m. Seve ralstudiesh avefoun dthatot her aspects ofpat ie ntad ju stme ntandcopin gability arelinkedt o adh ere nceandglycemiccontr ol(88,89).Forexample,anumberofinvest igator shav econ side redh ow th epat ien t'sleve lofsocioemotion al(ego)developme ntmaybe arup on h isorh erexpe rienceofan d resp on setotype1diabetes .Egodevelopme ntre flect stheind ividual'smatur ation alon gthe linesof impu lse c ont rol,moraldevelopme nt,cognitivecomp lex ity ,an din terpe rson alrelat ionsh ips(90).Barglow an dcolleagu es(91)fou ndth ate gode velopmen twasth ebestpr edictor ofan adole scent 's
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resp on sive nesstoabr iefint erven tion designedt oen han cead here nceandglycemiccont rol.In con trast , psych opathologywasnotassociatedwith t here spon setothe educativeinter vent ion.Th esefindingsand th eor eticalcon side rat ionssug gestth atth elevelofe gode velopmen tapatie nth asach ie vedcan affect th eben efit sofedu cationalan dme dicalint erven tion sdesignedtoimprovemetaboliccon trol, adh eren ce, orcoping st rat egie s.Re search ersh avesu ggeste dthatah igh erlevelofe gode velopmen tmayprovide an individ ualwit hth ecog nitiv eand emotion almatur ityn eede dtod ealeffectivelywithth edeman dsof havingach ronicilln ess(92).Furt herr esearchisnee dedtodevelopin terve ntionsthatar eeithe rtailore d toin div idu aldiffe rence sin psychosocialfun ction in gorde sign edtoalle viatepr oblemsin psychosoc ial fun ction in gthatimpede adhe ren ceamon gpatien tswit hdiabet es.
COPING WITH THE DIABETES REGIMEN: REALISTIC EXPECTATIONS AND READINESS TO CHANGE
Itiswelldocument edth atmostp eoplelivin gwith diabete sfin dit d ifficulttoadhe retothe daily deman dsofth ediabet esme dicalr egimen .Accordin gtoRubin(93), copingpr oblemsare P. 639 common amon gpeople with type1and t ype2diabetes largelybecauseth edeman dsofdiabe tes management aresosubst ant ialandun remit tin g.Specifically, the r egimen isde mandingandun ple asant, fact orsout side t hepatient'scon troloften affect g lyce miccon trol, and t heavoidanceofdiabete s-relate d complication scan notbeguaran tee d.Itisparadoxicalt hat although itiswid ely recognizedth atth e tre atment demandsplacedon the personwithdiabe tesar ecomplexan dbur densome ,manyclinicians, familymembers,andpatientst hemselvesexp ectpe rfectadher encet oth isr egimen .Thisexpe ctationof per fection ismhasbeen docu me nted ason eofthepr imary cause sofn on complian ce(94)and diabe tesbu rnout(95). Clearly, h avingr ealistice xpectation sforth epat ie nt'sself-man age men t beh avior isanimportantaspectofthecopingprocess. Ith asrece ntlybee nrecognized t hat thep atient 'sre adinesst och ange in flu ence sthepr oce ssofcopin g withth edeman dsofdiabe tes(96).Proc haskaan dDiClemente (97)suggest thatpatien tscan be ident ifiedasbe in gin on eofsixstagesofchan gefr omprecont emp lation, in whichindivid ualsar enot cur rent lye ngag edin beh avioralch an gean ddon ot in tendt och ange ,allthewaytothemaint enance stageat wh ich in div idu alshavemadeah ealth ybeh avior alchan gean dhavemaintain edit for6month s orlonge r.Futu restu die softh elin kbetwee ncopin gstylean ddiabete sself-c aremustinclud ethe se dime nsion sofrealisticexpe ctat ionsforself-manage me ntbeh avioran dofpatie nts'readin essto change .
The Social and Family Environments

The social/familyen vir on men tisthet hirdmajorpsych osocialme diator ofad aptation t och ron icilln ess an dmain ten ance ofh ealth. Inrece ntye ars, in crease datt entionhasbeen give ntothe roleof inter personalorsocialsu ppor tvariab lesint heprocessofadaptat iontochronicillne ss(73). Social supp ort isth ou ghtt ohaveabufferin g,mediating, or moderatingeffe cton the stressoflivingwith ach ronicilln ess.Wh ilemost ofth isatten tionh asfocusedonsu ppor tfromwithinfamilies, t her ehas bee nsomeinve stigation oft heben efitsofsocialsupportoutsideth efamilyforth echronicdisease sof can cer, acquired immu nodeficien cysynd rome(AIDS), Alzh eimer 'sdisease ,an dcardiovascu lardisease (73).However ,very fe wempiricstud iesh ave examinedth esociale nviron me ntoutsidet hefamilyfor adu lt swith diabete s(98).Socialsupp ort suchaswor ksit e,ne igh bor hood, andcommun it yfactorsin adu lt swith diabete shav erece ive dalmostnoexamination (1). LaGre caan dcolleagu es(99,100)hav econ ducte dresearchonsocialsupportsoutsideth efamilyfor adolescen tswit hdiabet esan dreported t hat peersandfrien dsserve su pportfun ction sforth eadolescen t withdiabe tesspecificallydiffere ntfromt hoseprovid edbyth eadolescent s'family. Wher easfamilies providedmore supportfordailymanage me nttasks(in sulin ,bloodglucosemon itoring), fr ie ndsprovided more supportforthe lifesty le aspect sofdiabet esmanagement(i.e .,providin gcompanion shipduring exe rcis eor wh ene atingmealsawayfromh ome).Moreover,pe ersre presen tedasign ifican tsourceof emot ionalsu ppor tforadolesce ntsliv in gwith diabete s.Insu mmary ,asidefromt heempiricresearchwith adolescen ts(23,101), the rehasbeen littleinve stig ation ofsocialsu pportoutsideth efamilyfor individ ualswit hdiabet es.
THE FAMILY AS THE PRIMARY SOCIAL ENVIRONMENT FOR LIVING WITH DIABETES
Diabetes, likesev eralothe rchronicphysicaldisease s,placesde mandsonth epat ien tfor self-careand forclinicaldecision -makin gresponsibilitiesthatre quiremajoradjustment sin lifestyle(102).More ove r, th eselife styleadjust men tsaffec tmanycompone ntsoffamilylife food,activ ity ,fin an ces,andtime (34).Thissect ionfocusesonh owcharact eristicsofth efamilyen viron me ntinfluen ceself-manageme nt beh avior and h ealth ou tcomesinth eper son with diabete s.First, it iscriticaltop ointout t hat the relat ionsh ipbe tween familycharact eristicsandt hepatie nt'sbehaviorandh ealthisabidirectional relat ionsh ip. Inother words, ju stasfamily stressh asbee nreporte dtop rodu cepoor d iabetescont rol, similarly,poor c ont rolmaytr igge rstressamongfamilymember s.
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CHILDREN AND ADOLESCENTS WITH DIABETES

Empiricr esearchhasdocume nte dthatsuccessfu lman agemen tofachild'sdiabet esmakesitnec essary forfamilie stor edistribute responsibilitie s,reorganizeth eirdaily rou tines, andre negotiat efamilyrole s (17).Wh enaveryyoun gchild isdiagn ose dwith diabete s,the pare ntsare,inre alit y,th epatien t(4). Golden andcolleague s(103)reporte dthatth epare ntsofchildr enwh oar ediagnosedwith d iabetes beforeth eag eof5year swhor eceivetr ainingininten siv ediabet esmanageme ntandar eprovid ed multidisciplinarysu ppor tsreportlessfamilyst ress,fewe rhospitaliz ation s,an dfewere pisodesofsever e hy poglycemiainthe irv eryyoun gchildr enwithdiabe tesascompare dwith familiesrece ivingst andard diabet escar e.Withre specttoschool-agedchildren with diabete s,the reiscon sensu sfromempir ic stu die sthatthe followin gfamilych aracteristicsare linke dtoboth goodme taboliccontr olan dadhe ren ce tothe treatme ntre gimen :paren talwar mth and caring;positive pare ntalinvolvementwith d iabetesrelat edtasks;lowle velsoffamily conflict;familyru le sthatare followedbyallfamilymembers;an d agr eement betwee nbothparent saboutdiabe tesgoals(13). Longitudinalr esearchbyJacobsonandcolleagues(88, 104)rev ealedth att hech ild'spe rceptionoffamily conflictatdiagn osiswasth estronge stpredictorofp ooradh eren ceovera4-yearfollow-u pperiod .Ina stu dybyMille r-Johnsonandcolleagues(105),parent -childconflict wasrelat edtobot hadh eren cean d glycemiccontr ol.Multivariat ean alysesindicate dthatfamilyconflict mightint erfere with gly cemiccontrol bydisrup tin gadh eren cetotreatment(105).The mostsignificantfamilych aracteristicofsch ool-aged children wh oh ave t hebe stglycemiccontroland wh oareth emostadher entt oth ediabet estre atment reg imenisthe shar in gofre spon sibilit yfort hetasksoft hetr eatmen tregimenbet weenp aren tan dchild (25,106,107). Ce rtainde mographicchar acte rist icsoffamilie shav ealsobe enlinkedt ometabolicout comesinchildren withdiabe tes.C hildr enwithdiabe tesfromsingle-paren tfamiliesor frometh nicminorityorlower socioeconomicback grou ndsh avebe enre por tedtobeatin creasedriskfor p roblemswit hadh ere nceand diabet escontrol(108,109). Foradolesce ntswithdiabe tes, familysupporth asconsisten tly b eenlinkedt ooptimalse lf-carebeh avior . Howe ver, familysupportdoesn otconsiste ntlyrelat edir ectlytomet abolicoutcome s(61). Ithasbeen sugg estedt hat familycon flicthasbothad ire ctan danindirec teffectonadhere nceby itsimpacton familyinte ract ions.In acompr ehen sivereviewofthe literatur eon adole scent swith diabete s,Skinne r an dcolleagu es(61)reporte dthatade velopmen tally appropriate lev elofpar entinv olvement in thet asks ofd iabetesman agemen tist hesinglemost impor tan tpredictorofpositiveadolescen thealt han dselfcar ebeh avior out comes.
ADULTS WITH DIABETES

Incont rastt oth ebroadrange ofstu die soffamilyfactor sanddiabetesoutcomesin child renand adolescen ts,lit erat ure ont hefamiliesofadu ltswithd iabetesisquitelimited. Thefewearlystudiesof adu lt swith diabete sfocu sedexclusivelyonth erelat ionsh ipofspou sesupp ort t oadher enceand metab oliccont rol inth eadu ltwith d iabetes. Schafe ran dcolle agu es(110)dev eloped anobjectivequ estion naire for asse ssin gthe freque ncywithwh ich familyme mbe rsengageinbeh aviorsdefinedassupportive. For adu lt swith type1diabet es,gre ater perceived n egativ espou seinte ractionswere associatedwithpoorer adh ere nce. Howeve r,foradu ltswith type2diabetes ,norelationshipwasfoun dbetwee nne gativespouse inter actionsan dadh eren ce. Rec entworkbyFisherandcolleagues(111)hasprov ide dboth ath eoreticalframeworkan dempir icdata onfamilych aracteristicsofadultswit htype 2diabe tesfromHispan icandEu ropean -Amer icaneth nic bac kgrounds(98, 111).Fishere tal.(98)identifiedfou rar easoffamilylifet hat relate dtoh ealth outcome sforadultswithtype 2diabe tes(98):1)familystruct ureandorganization;2)family valuesand beliefsaboutt heworld;3)familye xpression an dmanage me ntofemotion s;4)family p roblemsolving. Usingobjectivescale swith excellentpsy chomet ricp rope rtiestomeasure the firstt hree are asoffamily fun ction in g,Fish eretal. (111)rep ort edsig nificantdifferen cesbet we ench aracteristicsoft hefamilyand disease manage me ntoutcome sforHispan icascompar edwit hEu ropean -Amer icanfamilies.Th efamily's worldv iewandman agement ofemotionswaslinke dtod iseasemanagement among European-American pat ie nts, wh ereasfamilystr uctu re/organ ization waslin kedtodise aseman agemen tamon gHispanic pat ie nts. In gen eral,optimaldiseasemanagementisrep ort edin familiesthatar ewellorgan iz ed,h ave clearandtr adition algende rroles, havean optimist icbeliefabout life,andinwhichspouse sareable to resolvedifferen cesofopinion aboutdiab etescare. Insu mmary ,the reisaclose con nectionbetwe enth edisease -relate dcoping andst resslevelsoft he per son with diabete sandh isorhe rsocialen vir on men t.E speciallyforsocialinfluen ceswithinth efamily, levelsofsu pportan dcon flicthaveasign ifican timpact on adhe ren cean dhealth ou tcomesindiab etes. P. 640
Adherence and Burnout

The Diabet esControland C omplication sTr ial(DCCT)proved thatin ten sive in sulin man age men tof
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diabet es,aimedat achieving near-normalglycemia,sig nificantlyredu cesth eriskofmedical complication softh edisease (11,12).Formostpeople with diabete s,ach ie vin gnear-normalblood glucoselevelsme anst reat men twithmultipled ailyinjectionsofin sulin ,frequ ent b loodglucose mon itoring, orth euse ofasu bcut ane ou sin sulin in fu sionpu mp .While adh eren cetothediab etesse lfcar eregimenisbelie vedtobeth emostesse ntialingred ien tindiabet esmanageme nt, patien tscommonly havedifficu lt ywith sustain in gthe burde nofse lf-careovertime.Thiswast rueinth eer abefore dissemin ation ofth eDCCTfindings,bu twithth ehopefu lne wsformedicalou tcomesfr omthe DCC T,the nu mbe rofdailydiabe tesself-care tasks (andth ere fore thedailybu rden ofth edise ase)h asincre asedfor mostpe opleliv in gwith diabete s. Tocomplicat ethe matter, evidence showsthatadh eren ceisn ot aun ivariate phen omenon. Onepatient's adh ere ncetoamealplan ,for example,maybe u nre latedtoadh ere ncetoapr escribedreg imenofblood glucosemonitoring.In gene ral,fewsignificant corr elation shav ebeen fou ndbet weent hedifferen t componen tsofadhe renc etot hese lf-careregimen(112,113, 114,115).The refore,h ealth carepr ovider s shouldnotassumethatapatient'sdifficultywith adhe rence toone compon en tofth eregimenindicat esa globaldisav owalofther egimen .Initialasse ssmen tmustincludeacare fulexaminat ionofpatien ts' adh ere ncetoeachaspe ctoft here gimen . Whe npeoplebecome ove rwhelmedbyth ecomplexityoft heirdiabe tesreg imen, they mayfeelthat noth in gthey doorhowhardthe ytrywillhaveap ositiveimpacton the irdiseasecourse. Thisiswhat diabet estre atment teamsar enowreferr in gtoasthe prob lemof diabete sburn ou t,whichPolonsky(95) hasdefinedsu ccin ctly:Burn ou tiswh ath appe nswhe nyoufeeloverwhe lmedbydiab etesandbyth e fru strat in gburde nofdiabetesse lf-care.People wh oh ave burn edou trealize t hat gooddiabet escare is importantforthe ir health ,but the yju stdon't have the motiv ation todoit.Atafundame ntalleve l,t hey ar eatwarwit hth eir diabete san dthe yare losin g.Wh enbu rnoutisaffe ctin gthe patien t(or t he diabet olog ist), it canbe helpfultoremembe rthe wordsofJoanHoov er,anearly diabetesadvocate wh o wasappoint edtothe first C on gressionalAdvisor yCommitt eeonDiabetesint hel970s:Diabete sisn ota doity ou rselfdisease(94). Diabet esmanageme ntisbur densome andsu pportoft hepatientis ne cessar y.Thissupportcanincludefamilymember s,friends, co-worker s,an damultidisciplinary diabet estre atment team.Su chasu ppor tsystemcan helpth epatien tsetsmall,realistically attain able goalstoh elpmovegr aduallyoutofthe strugg lewith b urnout andt owardimproveddiab etes management (116).
THE PATIENT-PROVIDER RELATIONSHIP

Over thelast decade ,empir icre sear chhasin creasin glydocumen tedth eimportanceofthe p atient providerre lationsh ip t oth ead here nceofpatien tswit hchr on icdiseas etoapar ticu lartre atment regime n an dtohealth ou tcomes. Themulticente rnationalMedicalOut comesStu dydemon strat edth ata collab orativerelat ionsh ipbe tween patien tan dprov ide ran daparticipatorydecision -makin gstyleof phy sician s(117)impr ove dadh eren cean dhealt hou tcome sinp atient swith chronicillnesse ssuchas can cer, arth ritis, and d iabetes(118).DiMatt eoandcolleague s(119)reporte dthatpat ien tsat isfaction withth einter personalcommun icationwith t heirproviderisrelat edtoadhe ren cetothediabe tes tre atment regime n.Morerece ntly,C iec han owskian dcolleagu es(120)de monstr ate dthatadh eren ceto th ediabete sregime nisassociatedwithth etyp eofattach me ntth ead ultpatien tdisplaysin the c ont ext oft hepatient'sperce ption ofth equalityofcommu nicationwithth ediabet esprovid er.C learly,th e beh avior ofth eprovideran dthe qualityofthepatient -prov ide rrelationshipar enowrecognizedas criticalvariab lesaffectingadher enceofpat ien tswithdiabe testothe comple xtreatment r egimen .Over th elastdecadean ewpar adigmofthe patien t-provid errelat ionsh iph asbee ndescr ibe din d iabetes: patie nte mpowerment (121).
Patient Empowerment
AsframedbyR .Ande rson ,M.Funn ell,andcolleaguesatth eUn ive rsit yofMic higan(122),th e empowe rme ntapproachisbase don thre ekeyp rin ciples:(a)Moret han 98%ofdiabete scareisprovided byth epat ie nt;th erefore, the p atient isth elocu sofcontrolandd ecision-makinginth edailytreatment ofd iabetes;(b) t hepr imarygoaloftheh ealth care t eamist oprovideongoin gdiabete sexper tise , edu cation,andpsych osocialsupportsothatpatien tscan makeinforme ddecisionsabou tthe irdaily diabet esself-care ;and(c)adultpatie ntsaremuchmor elike lytomakeandmaintain behaviorch an gesif th osech an gesar epersonallymean in gfulandfr eelychosen. Per hapst hemost defin in gcharact eristicof th eempower me ntap proachisthe philosop hyth att hepatie ntandth ehe althcareprovidersare equ als(123). Diabet eshe althcarehasbene fite dbecauseth edeve lopersofthe emp ower men tmodel havetr anslat edthe ir philosop hyintopract icalint erven tion sandh ave p rov ided e mpiriceviden cefor its effect ive ness. Inarandomize dcon trolled trial,An dersonan dcolleagu es(124)d emonst rate dthata6-weeke mpowerment in terve ntion program, deve lopedby Fest e(125), sign ifican tly improveddiabe tesself-efficacy,diabetesattitude s,an dgly cemic control.Thee mpowerment modelhasbe ende scribedbyAnde rson an dcolle agu es(122)asfollows: Wh enappropriatech ang esin rolesaremade, bot hth ehealt h-car eprovid eran dthe patien tcan find P. 641 P. 642
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th emse lve spart ofasatisfyin gpart ner shipthatresu ltsinimprov edglycemiccontrolfort hepatie ntand an enh an cedsens eofself-efficacyandlevelofsatisfactionwit hcar efor both part ie s.Fin ally, the empowe rme ntmode lisdirecte dtowardphy sician s,nu trition ists, diabete seducators,an dbeh avioral clin ician s,allthemembersofthe multidisciplinar yteamth ath asbecomethe recommende dstan dard for th ecare ofpatie ntswithdiab etes.
The Multidisciplinary Team in Diabetes Care

Ith aslon gbeen r ecognizedth atbe cause diabete sissuch acomplexdisease,patient sn eeda multidisciplinaryte amofhe althpr ofessionalsforopt imalcare (126).The curre ntStandardsofMedical CareforPatientswith Diabet esMe llitusoftheAmerican Diabe tesAssociation(127)recommen dthat peoplewithdiabe tesshouldrece iv ethe irt reat men tan dcare fromaph ysic ian-coordinatedt eam.Such teamsinclud e,but are n ot limited to, physicians, nurse s,dietitians, an dmen talhe althprofession alswit h expe rtisean daspe cialinte restindiabe tes. Inreality, however, mostpat ie ntswithdiabe tesdonot haveaccesstoamu lt idisciplinaryte amandr eceiveth eirdiabete scareint heofficeofan in tern ist or familypr acticephy sician (128).Appr opriat ely,beh avior alscie ntistshavere centlyfocusedont ran slatin g inter vent ionstoimprovediabetesse lf-carebeh avior andq ualityoflife(129)forofficepracticesth atdo noth aveamu ltidisciplinaryteamasaresour cefor p atient swith diabete s.Table37.1prese ntsan overviewofthemostrecen tan dempir icallytest edoft hese int erve ntion s,withinformation abouth owto acce ssmorecomplet ein for mationforth eclinicianwh owouldliket olear nmore aboutth eseinte rven tion strategies. TABLE 37.1. Office-based Interventions
Intervention BloodGlucose Awareness Training (BGAT)
Description BGATisapsychoeducationalintervention designedforpatientswithtype1diabetes.Its currentversion,BGAT-III,isastructured8-week program,conductedingroupsorprevention, awareness,andresponsetoextremefluctuations inbloodglucoselevels.Thepatientsmostlikelyto benefitfromBGATarethosewithpoorabilityto recognize/predictbloodglucoseextremes,on intensiveinsulintherapy,withreduced hypoglycemiaawareness,withahistoryof recurrentseverehypoglycemia,withfearof hypoglycemia,withrecurrentdiabetic ketoacidosis,and/orwithpoormetaboliccontrol. MIisacounselingstrategyfocusedonpersons reluctantorambivalentaboutchangingtheir behavior.Initiallyformulatedforchanging addictivebehaviors,MIhasrecentlybeenapplied tobehaviorchangeinpatientswithdiabetesand otherhealthissues.Itdiffersfromatraditional, nondirectivetherapeuticapproachinthatthe counseloroffersadviceandhelpsthepatient exploreandresolveambivalencetoenhance motivationforchange. Appropriateforusebyhealthcareprovidersnot justbycounselors,thismodelofworkingwith patientsintegratestheempowermentmodeland MItechniqueswiththetranstheoreticalmodel (StagesofChangeTheory).Itisapatientcenteredapproachthathelpsidentifyaperson's readinesstochangebehaviorandtothenidentify andprioritizeself-managementgoalsindiabetes. Assuch,itprovidesthehealthcareproviderwitha frameworkthatbreaksdowntheprocessof changeintoaseriesofstages. Severalpediatricoffice-basedinterventionshave recentlyreportedencouraging,although preliminary,results.Theimpactofacareambassadorintervention,atrainedassistantto supportparentsofpediatricpatientsinmaking appointmentsregularly,resolvinginsuranceand billingquestions,andhelpingschedulespecialty appointmentshasbeenshowntoimprove medical-visitfollow-upandreducecostlyadverse
Primary source Coxetal.(130)Gonder-Fredericketal. (131,132)
Motivational Interviewing (MI)
Milleretal.(133)Smithetal.(134)
Stageof Change Counseling
Dohertyetal.(96)Prochaskaetal. (97,135)
Pediatricofficebased interventions
Laffeletal.(136)
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outcomessuchasdiabetes-related hospitalizationsandemergencydepartmentvisits. Alow-cost,family-basedpsychoeducational interventionaimedatsustainingparental involvementindiabetes-managementtasksand reducingdiabetes-relatedfamilyconflictthathas beenusedwithadolescentsandrecently diagnosedpediatricpatients.Thiseight-module interventionisimplementedbyatrainedassistant atthetimeofthemedicalofficevisit.Preliminary resultsindicatethatthisinterventionhelps improveadherence,parent-childteamworkin diabetesmanagement,andglycemiccontrol. CBTaimsatchangingpatients'thoughtsabout diabetesanddiabetesself-caretasksthat interferewithdiabetesmanagementaswellas actualdiabetesself-carebehaviors.CBTinvolves consciouslyidentifyingandchallenging maladaptivebeliefs.Behaviorchangeinthis modelisachievedbyworkinggraduallytoward small,achievablegoals.CBTcanbeimplemented inindividualizedtreatmentorinagroupformat. Thisgroup-basedtreatmenttechniqueisaimedat helpingadolescentsand/oradultscopebetter withdiabetes-relatedstressorsandimproving theirtreatmentadherence.Ithasbeenshownto beeffectivewhentaughtbyahealthcare professionaloracounselorwithdiabetes expertise.CopingSkillsTrainingteachespositive copingskillstopatientswithdiabetesthroughthe useofroleplayingandactiveproblemsolving. Heterogeneoussupportgroupsforpatientsor lovedonesofpatientswithdiabetescaninclude peoplewitheithertype1ortype2diabetes. Anothersupportgroupmodelinvolvesa homogeneousgroupinwhichpeoplewiththe sametypeofdiabetesaregroupmembers. Internet-baseddiscussiongroupsarebeingused toprovidediabetessupportandeducationfor personsunabletoaccesssupportgroupsinperson. Telephonecareisthemostwidelyused technologyasasupplementtooffice-based diabeteseducation.Telephonecarehasrecently beenextendedtoincludeautomatedtelephone diseasemanagement(ATDM).ATDMinvolves assessmentofbothhealthandself-careproblems thatarosebetweenoutpatientvisits,aswellas educationintheformofhealthtipsor interactivedietaryeducationmodules.Two randomizedstudiesshowedthatforpatientswith type2diabetes,ATDMasanadjuncttousualcare improvedglycemicoutcomes,frequencyofblood glucosemonitoring,satisfactionwithcare,and self-efficacytoperformself-careactivities.ATDM enhanceddiabetescareforpatientslivingata remotedistancefromtheirdiabetesproviderand fornon-English-speakingandilliteratepatients. Oneofthefirstcomputer-basedinterventionsin diabeteswaspioneeredbyGlasgowand colleagues.Thisearlyinterventioninvolveda15mintouch-screencomputerassessmenttohelp patientsidentifypersonaldietarygoalsand barrierstoachievingthesegoals. Responseswereimmediatelyscoredandprovided topatientandphysician.Thepatientthenmet withahealtheducatortocollaborativelydevelop Andersonetal.(137)
Cognitive Behavioral Therapy(CBT)
Weingeretal.(72)VanDerVenetal. (138)
CopingSkills Training
Greyetal.(139)Rubinetal.(140)
Supportgroups
Tattersalletal.(141)
Zrebiecetal.(142)
Telephonebased telemedicine technologies
Pietteetal.(143,144)
Computer-and Internet-based telemedicine technologies
Feiletal.(145)Glasgowetal.(146, 147)
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anactionplanthattookintoaccountthe individual'sbarrierstoadherence.This interventionwasdocumentedtobecost-effective andpatientsmaintainedimprovementsindietand serumcholesterolovera12-mofollow-upperiod. Thisworkalsodemonstratedthatolderpatients withoutpreviousInternetexperienceseffectively participatedinInternet-basedself-management supportprograms. Acomputerizedsystemtoassesspatients,code andanalyzedata,andprovidefeedbacktoboth thepatientandhealthcareteamhasalsobeen designed.TheDiabetesPsychosocialManagement Aid(DPMA)hasbeenusedsuccessfullyinan inner-cityhospitalwithpatientswithlowliteracy andcomputerskills. Diabetesinformationhasrecentlybecome availableforeducationandsupportoverthe InternetfromseveralWeb-basedsites. Welchetal.(148)
http://www.jdrf.org; http://www.diabetes.org; http://www.childrenwithdiabetes.com; http://www.diabetes123.com; andhttp://www.joslin.harvard.edu
SPECIAL PROBLEMS IN DIABETES Psychiatric Disorders in Diabetes

The literatur eexaminingth erelat ionsh ipofdiabete stop sychiatr icdisor derscontinu estogrow.These stu die sfocusp rimarilyon the relation shipofdiabetest odepr ession ,an xie tydisord ers,andeating disor ders. Withre gardt oth eincidence andpr evalen ceoft hese d isorder s,it nowappearsthatpat ie ntswithty pe1 diabet esare atparticularr iskforth edeve lopme ntofdepre ssive disorder s.Thede velopmen tof depr essivedisorde rs,wh ileincreasin gwit hth eduration ofdiabe tesan dthe developmen tof complication salsooccur sr elativelyearly in t hecourse ofillne ssbeforethe on setofcomplications (149, 150,151).Wh ileth ereisle ssresearchonanxietydisorders, asimilartre ndisemergingfromt hese stu die s,especiallyamon gpat ien tswithtyp e1diabe tes(152, 153).Th ecau sallinksbe tween psychiat ric disor dersan ddiabete sare notwellun derst ood,bu tgrowin gevidence fr omrese arch su ggest st he conne ctionde scribedinFig. 37. 1.
Figure 37.1.Hypothesizedmodeloftherelationshipofdiabetesandpsychiatricdisorders.
Most st udieslookingat ther elation shipofdiabe testopsychiatricdisorder sarecr oss-sect ionalinde sign . Dire ctionalityandcausalityinth eserelat ionsh ipsh asye ttob efullyde termined. Afe wlongitudinal stu die sdosu ggestth atpatient swith depressive d isorder sandoreatingdisord ersapp eart odev elop
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worseglycemiccontr olan dgreaterriskforretinopathyovert ime(154, 155).Th us,asshowninFig. 37.1,at leastinpat ie ntswithty pe1diabe tes,itisreason abletoassu met hat diabetesitse lfmay increaseth eriskofde velopingsomespecificpsy chiatricdisord ersan d,whe npre sent, thatdiabete s outcome sareinflue ncedn egat ive lyby theirpre sence . Stud iesoftype 2diabet esare le ssclearwithre gardtoth edeve lopme ntofpsychiat ricdisorders, ashas bee npoin tedoutbyTalbotandNou wen(156).The incr ease drate sofdep ression in patien tswith type 2 diabet esappe artooccurbe fore t heonse tofillne ss,th erebyr aisin gane ntirelydifferen thyp oth esis about thee tiologicrelat ionsh ip(i.e .,th atde pressivedisor dersth emselvesmayplacepatientsatriskfor deve lopingdiabe tes).Su ppor t forthishypoth esisderivesfromth efact thatpatien tswit hdepr ession h ave alteration sin t he hy poth alamic-p itu it aryaxis ,whichleadt oincre asedratesofcor tisolproduction (157, 158,159). De presse dpatien tsalsode creasephysicalact ivityandincre asecardiovascularr iskfactorsbysmoking an deat in ghighcaloricandfattyfoods, sugge stin gthatindivid ualswhoare depress edmay,be cause of th eir chan gesinlifes tyle ,deve loptype 2diabe tes(160, 161,162,163, 164). Someinve stigatorsalsohav esugge stedth atth emetab olicpr oblemsofdiabe tes(incre asedr atesof hy poglycemiaan d/or hyper glyce mia)couldth emse lve splayarolein the develop men tofde pression. The reisinc reasinge vid encet hat diabetes leadstochan gesinth ewhitematt eroft hebrain(162)and th atth eseabnormalitiesinth ewhitematt er,ifprese ntinth efrontallobe,mayplayaroleint he deve lopmentofdepr ession(165).Ch an gesin frontalwhite mat terh avebe enfoun din studiesof depr ession inpatient swith ou tme dicalilln essan dcou ldleadtoch an gesinthe fron tal-striat altrac ksthat reg ulateaffect,t here byincreasin griskforaffectre gulatoryproblemsandconse quen tlyofde pression (161, 166,167,168,169, 170,171,172, 173,174).Whateve rthe dir ection ofcausalityoft here lations hip,it doesappe arth at su ccessfultre atmen tofde pression and anxiet ycanleadtoimprov edglycemiccontr ol inpat ie ntswithdiabe tes(155). Insu mmary ,the frequ encyofcommonps ychiatricproblems su chasdepressionan dan xie tydisord ers app earst obeincr ease damon gpatien tswit htype 1diabet esan dther eis n owe vide ncet hat improved tre atment canleadtob ette rou tcomesinte rmsofglycemiccontr ol.The combin ationofh igh prevalence ofcommonpsych iatricillnesse ssuchasdepre ssionandan xietydisor dersinpatie ntswithdiab etesand other medicalcondition sandt hetr eatabilityofsomeofthese con dit ionsmean sthatit iscriticalto ident ifypatientswith t hese con ditionsearlyin theironset andt oimplement treatmentst rate gie sthat ar ewide lyr ecog nizedtobesucce ssfulwith the sepat ien ts.Basedonasmalln umberofstudies, the efficacyoftreatmentofdepr ession, in clu din gcog nitiv ebehaviort herapyan dan tid epressantt herapy,in pat ie ntswithdiabe tesappear stobe equivalen ttothe e fficacyin patien tswit houtco-occu rringch ron ic disease (175,176).Thu s,at tent iontoasse ssmen tofd epressionshouldbemaintain edwhe ntre ating pat ie ntswhoar ehavin gproble msadaptingt odiabe tes,sh owingdifficultie smain tainingmetabolic control,an d/or oth erproblems with adap tationan dstress. These p atient smaywellhaveanun derlying tre atable psychiat riccondition .Scree ningmeasu ressu chasth eSymptomCh ecklist 90R(177)maybe use fulin iden tifyin gpatien tswit hdiabet esan daffect ive disorder s.More ove r,diabet es-specificmeasure s ofq ualityoflife,such asth ePr oblemAreas inDiabete sScale(PAID)(71,178)andth eDiab etesQu alit y ofL ifeMeasure (DQOL)(179, 180), may alsobeu sefulinscree ningpatie ntswh oar eatr iskforth ese condition s. P. 643
Eating Disorders
The rehasbeen con side rableinte restinex amin in gtheimpactoftype1diabete son thede velopmen tof eatingdisord ers.Although researchr esultsinth isareaaresome what con tradictory, t hemost recen t controlle dstudiessug gestan in creasedriskofe atingdisordersamongfe malepatients with type1 diabet es.For example,Jonesandcolleagues(181)reportth at t heriskofdevelopin gan e atingdisorder was2.4t imeshigh erinyoung womenwithty pe1diabe testh an in age-match edwomen wit hout diabet es.Some r esearcher shav eargu edth atdiabe tes-spe cifictreatmentissue s,like then eedt o car efully monitordie t,exe rcise,andbloodglucosemaycon tribut etothede velopmen tofeatingdisor der symptomsamongwomen wit hdiabet es(182). R esearche rsand cliniciansh aveargue dthatthe atte ntion tofoodportion s,bloodsugars,andweightt hat ispartofr ou tinediabe tesmanagement p arallelsther igid th in kin gaboutfoodandbodyimagech aracteristicofwome nwit heatin gdisorde rs.Addition ally, in ten sive insulinmanagementofdiabet eshasbeen s hown tob eassociatedwith we igh tgain(183). Res earch erswh odonotreporth igh erratesofeat in gdisorder sin fe male patien tswith type 1diabet es oftendonotincludeu nder dosingoromission ofinsulinasapurging sy mptom.Fairburn an dcolle agu es (184)compare d56womenwithty pe1diabe testo67age -matchedwomenwithoutdiabetesu sin ga stru ctur eddiagnosticinter vie wforeatingdisor ders,t heE atingDisorder Examination(E DE) .Theyfoun d th atth edifferen cein the rate sofeatingdisor dersbet weent hese g rou pswasnotstatisticallysignificant ; howeve r,th eyalsohighligh tedth eimportanceofthorough assessmen tsofdisordered eatingandinsu lin misu sein thispopulatione speciallyasapoten tialcauseofpoorglycemiccon trol. Th eseauth orsfoun d widespreadinsulinmisuse amon gwomenwithd iabetesandemphasiz ethatth isbe haviorisn ot limited t o women whomee tfor maldiagn osticcriter iaforeatingdisor ders.In an 8-yearfollow-u pofth issame
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cohortofp atient swith diabete s,the aut horsnoteth ath adth eyincluded in sulin misuseinth eireatin g disor dergroup, 39%ofthewomenwouldhav ebeen in clu dedinth eeatin gdisorde rgroup(185). Another stu dyexaminingdisordere deating amongadolesce ntswithdiab etesalsoreporte dnosign ifican ce bet we en-gr ou pdiffe rence sin rate sofeatingdisor ders(186). Howev er,th ete ensinth isstu dywere quite young ,an don lyone halfoft hemadmin ist eredinsu linwithout pare ntalsu pervision. Itmaybeth at insulinmanipulat ionoromissionbe comesamoresignificantproblemin olderadolescen ts,aspare ntal supe rvisionofin sulin admin ist rationdecr ease s. Whe nsymptomsofdisorder edeatin gdonot mee tthe le velofseve ritytowarrantaformaldiagnosisof an eat in gdisorde r,inter mitten tinsulinomissionanddosere duction for we igh tlosspu rpose shasb een foundt obeacommonpr acticeamongwomen wit htype 1diabet es.For example,Polon skyan d colleagues(187)fou ndth at31%ofag rou pof341womenwitht ype1diabetesbe tween theagesof13 an d60yearsreported int ent ionalinsu linomission .Rat esofomission peak edinlateadolesce nceand early adulth ood,with40%ofwome nbet weenagesof15and30ye arsre port in gin ten tionalomission . Insu linu sean dtighte rbloodsugarmanage me ntcausedsignificant p sychologicaldist ressforthe se women ;with 42.5%re port in gfears t hat keepingt heirbloodglucosein goodcontr olwou ldcauseweigh t gain, 44.3%re port in gbeliefst hat takinginsu linwouldcau seweightgain ,and35.9%be lievingth atg ood controlwouldcauseth emtobe comefat (187).In addition ,studiessh owth att hisbehaviorplace s women ath eighten edriskforme dicalcomplicationsofd iabetes. Womenr eportinginten tion alin sulin misu sehadhigher lev elsofglycosylatedhe moglobinA 1 c (HbA 1 c ),high erratesofh osp italandemerg ency roomvisit s,an dhigher r ate sofne uropat hyan dretinopathyth an didwome nwhodidnotreportinsu lin omission(187).Areportby Rydallandcolle ague s(154)lendsfu rthe rsupportt oth elin kbetwee ninsulin misu sean dmed icalcomplicationsofdiab etes. Th eyfound t hat disorder edeatin gat b aselin ewas associate dwith microvascu larcomplication sofdiabe tes4ye arslat er,with86%ofy ou ngwomen with seriouseatingdisord erspres entingwith r etinopath ycomparedwith43%ofwome nwit hmode rate eating disor dersan d24%ofwomen with noreportede atingdistu rban ce. Women wit htype 1diabet esmayuse in sulin man ip ulation (i. e., admin iste rin gredu cedinsulindosesor omittingn ecessarydosesaltogeth er)asame ansofcalor icpu rging.In ten tionallyindu cedglycosu riaisa powerfulweight-lossbehavioru niquet opatie ntswitht ype1d iabetes. Asmen tione dabove, itisalso ver y P. 644 dan gerous, and p laceswomen atgre ater risk forde velopinginfe ctions, pot entiallyfataldiabe tic ket oacidosis(DKA),andlon g-ter mmedicalcomplicationsofdiabet es.Once establishe dasalongstandingbeh aviorpatt ern ,the prob lemoffr eque ntinsulinomissionmay b epart icu larlydifficulttotreat. Fort hisreason, ear lyde tectionan din terve ntionappe arstobecr ucial.Open -ende dquest ionssuch as, Doyoue verchange you rin sulin dose orsk ipinsu lindosestoin flu ence you rweight?canbeh elpfulin scree ningforin sulin omission, e specially wh enpatient shave elevat edHbA 1 c value soru nexplaine dDKA. Disordere deat in gbehaviorsareoften we llhidden ,but patient sshouldbeen cou rage dtobr in gupan d discussissuessu chas t heircur rent le velofsat isfactionwith theirweight ,the ir we igh tgoals,an dif willin gth eirexpe rie nceswithb in geeat in g.
Neuropsychological Aspects of Diabetes

The n umberofstudiesofthe pote ntialfor patien tswit htype 1an dtype2diabete stode veloppr oblems incognitionandothe rsig nsofalt eredbr ainfun ction h asbe engrowing.Th esestu die shave focu sedon th reemeasu resofthe brain:cognitiveabilit y;cor ticale vok edpotent ials;andmagn eticresonan ce imagin g(MR I)-based assessment sofbrain stru cture .Thisresearchsu ggestst hat patien tswith eithe r type 1ortype2diabet esmaybeatin creasedriskfor ch an gesinbrain struct ure, in clu din gwhitematt er lesions andatrophy(162).De crement sin c ogn itivefu nction,esp eciallyinareasofme moryand psych omot orspe ed,h aveb eenfoun d.Ch ang esin cor ticale vok edpotent ialsindicat ethe possibilityofthe riskfor developmen tofacen tralne uropath y.Olderpatients with type2diabete sappeartodevelop cognitivedeclin esatear lieragesan dhigher rate sthanage -matche dcon trolswithout medicalillnes s. Ch ildren wit honsetoftype 1diabet esbeforeth eage of6y earswh ower estud ied d uringadolescen ce an dyoungadulthoodalsoappeartode monst rate subtlecognitiveperforman ceproble ms(188,189, 190). Itisnotclearwh eth erth esecognitivediffe ren cesrepr esent developmen taldelay sorpr oblemsthat per sistint oadulthood. Inchildren especially ,seve rehyp oglycemiacau sin gseizure ,coma, and un con sciousn esshasbeen con side redasanimp ort ant c ausativefact orinth edeve lopmentofcog nitiv e problems(188,189, 191,192,193,194, 195,196,197). Asmallbody ofre search alsosu ggestst hat per siste nth yperglycemiaalsomayplayarolein declin esincog nitiv efunct ioning(190,198). Finally,in olde rin div idu als,th edevelopme ntofcerebr alvascu larillnessh asbee nsugge stedtoplayanimportant role in cogn itive d ecline (190). Twolar geclin icaltr ialscarefullyevalu atedt heimpactofin tensived iabetest reat men tan dsever e hy poglycemiaon the developmen tofc ogn itivepr oblemsin patien tswit htype 1diabet esdiagnosedwh en th eywere eit heradolesce ntsoradu lt s.These studies, theDCCTandth eStockholmDiab etes Int erven tion Study(SDIS),didnotshowane ffe ctofint ensivetr eat men torsever ehypoglycemiaon the deve lopmentofcognitiv eproble ms(199,200). Howeve r,bothst udieshadrelativelysh ort follow-up per iods.Mor eov er,be cause ofth enatur eofth esetr ials, then umberofsever ehypoglycemice pisodes
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waslimited. Th us,t hese studiesmayun derst ate t hepr oblem(201,202).Afewother studiesofadultsdo sugg estth eposs ibilityt hat severe hypoglycemiain t ype1diabetescouldplayaroleinth edeve lopment ofcogn itivepr oblems(201,202,203,203). Th erole ofsev ereh ypoglyce miainth edeve lopme ntof cognitiveproble msre main shighlycon troversial.R ecen tly ,the rehavebee nsug gestion sthatthe demon stratedproblemsin cogn ition,br ainstru ctur e,an dfun ctionmayalsobeassociat edwit hth e increasedinciden ceofde pression in patien tswit htype 1diabet es(204). Todat e,n ostu die shav e explicit lye xamin edth ish ypot hesis.
Sexual Functioning
Itiswellest ablish edth atmencommonlydeve lopere ctiledysfu nction(ED)secondarytodiabete s.The pre valence ofEDin me nwithdiabe teshasbeen estimatedat35%t o70%(205).E Dhasbeen ide ntified ascont ribu tingsignificantlytodecre asedq ualityoflifein men wit hdiabet es(206). Longer durationofdiabet es,poor g lyce miccon trol, and p resen ceofdiab etescomplicationssuch as diabet icn europathy, vascu lardise ase, retinopat hy,andn ephropathyarestr ong lycorre latedwithth e pre senceofEDin men wit hdiabet es(207,208).In addition ,the reportedr iskofEDisgre ate ramon g menwhosmoke cigarett esan dself-r eportsymptomsofdepression,anxiety ,an dtreatme ntfor hy perte nsion (208).Sinceth emedicaltreatme ntsfordepr ession, an xie ty,andhyp erte nsion canalso havesideeffect son sexualfu nctioning,medicalin terv entionsformen wit hlon ger-te rmdiabe tessh ou ld bere comme nded after t hese risk saretaken in toaccou nt. Although t heorganiccompon ent in EDh asbee nwidelyrecognized, psychosocialfact orsalsomay contribut etothe d evelop men tofE Dinasign ifican tsubset ofmenwithdiab etes. Indee d,somere sear ch sugg eststh atinasman yas20%ofdiab eticmen wit hreporte dimpotence ,th edysfun ction may have a primarilyps ychogenicorigin(209,210).Anyev aluat ionofEDmust ther efor ebesen sit ive both toprimar y psych olog icalfactor sandt osecondaryfac tor st hat mayin flu ence sexualfu nction in g.For example, an xietyabou tperformance mayfurth erex acerb ateapart iallydysfu nction alepisode in organically impaire din div idu als.Ign orancealsomaycontribut etosuchpr oblems.Man ycou ple sdon otre aliz ean d ar enotinfor med thatdiabete scanpr omot eEDandmay misin terpr etth esou rceofthe problem, believingth atitisduetolossofloveortoan e xtramarit alin tere st.Most fr eque ntly,organicand psych olog icalfactor scoex ist, soth atbe hav ioralan dpsych ologicalinte rvent ionsmaybe valuable in facilitatingadju stmentt oth elimit ation spose dbythe org anicimpairmen t. Littlerese arch hasfocuse don theimpactofdiabete son these xualfun ction in gofwomen .In fact,since 1971,only16suchst udieshavebee npub lished ( 211).The sestu diesp resen tcon flictingev ide nceonth e existe nceofdiabete s-associatedsex ualproblemsinwome n.In theircompr ehe nsiverev iewofthe lite rat ure, Enz linan dcolleag ues(211)atte mpte dtod rawconsen susbet weenconflictin geviden cefrom th esestu die s.Thu sfar,itap pear st hat womenwithd iabetesmaye xperien cediminishedlibidoan dmore paind uringinte rcou rseascompare dwit hwomen with ou tdiabete s.Howe ver, womenwithdiab etes app eart obeatespe ciallyhighr iskfordecr ease dorslowe dsexu alarousal.R esearcher spost ulatet hat th ismayre latetoinade quatevagin allu brication ,whichoccursin30%ofwomenwithdiabe tes(twice th atofthep opu lationwith ou tdiabete s).Ther eisalackofconsisten teviden ceth atdiabe tescau ses problemswith achievingorgasminwomen . Whe reasther eisgr owingconsen susth atse xualproblemsin men with diabete sareinflue ncedby au tonomicneu ropath icdamage,th eet iologyofsexualarousalproblemsinwome nwithdiabe tesremains un cle aratthistime .Fu rth erstu dyoft heimpactofd iabetesandth ecomplexinte rplaybet ween psych olog icalandphy sicalfactor son fe male s exualityiscle arlyne eded.
CONCLUSION
Insu mmary ,wehaveprovidedanupdateofthe sign ifican tprogressmade b ybehavioralscien tist sand clin ician sfocu sedon personslivin gwit hdiabet es,th eirfamilie s,an dthe irh ealth care teams. Du rin gthe lastdecade,th erole ofpsych ologyin diabete scareh asmove dfromat radition ally psych iatricormedicalmodeltoabiop sychosocialmodel,inwh ich behavioralinte rven tionsint heformof telemedicinete chnologyorbeh avioralstrategiesforopt imiz in gself-man age men thavebee nshownto improvebiologic,psych ological,andbe havioralou tcome sforper son swith diabete s. Nowatthe beginning ofth e21stcen tury, behavioralscien tistsfocu sedondiabet esare preparedto app lyt heirskillstoane venbr oaderspe ctrumoffactor shav in ganimpactonth equalityoflifefor per son slivingwit hdiabet es(1). Incre asingly,beh avioralissu esar eseen ascriticalin basicresearch towardfindingacure forandpre vent in gtype1diabete sandiden tifyin ggene ticande nvironme ntalrisk fact orst hat couldbemodifiedtoprev entt ype2d iabetes. Wit hthe adve ntofnewefficacioustre atment s an din novat ive techn ologie s,basicscientistsanddiabe tesclin ician sare se ekingth econtribut ionsof beh avior alscie ntistsast heycollaborateonth ecomplexbiopsychosocialdile mmasincur in g,pre vent in g, an dtreatingdiabe tes. P. 645
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withanxiety, affective, an dsubstanceu sedisorde rs.Am J Psych iatry1989;146:14401446. 153.WellsKB, BoldingJM,Burn amMA. Affe ctiv e,su bstan ceuse, an danxiet ydisorde rsin persons witharthr itis,diab etes, heartdisease ,highbloodpre ssure ,or chroniclu ngcondition s.Gen Hosp Psychiatr y1989;11:320327. 154.RydallAC,R odinGM,Olmsted MP,etal. Disor derede atingbe hav ioran dmicrovascu lar complication sin youngwome nwithinsulin-dep ende ntdiabe tesmellitus. N E ngl J Me d 1997;336:18491854. 155.Lustman PJ, An dersonR J,Fr eedlan dKE, e tal.Depressionan dpoorglycemiccon trol:amet aanalyticreviewofthe literatur e.D iabetes C are 2000;23:934942. 156.Talbot F,Nouwen A.Areviewofther elation shipbetwee ndepr ession anddiab etesinadults:is th erealink?D iabetes C are 2000;23:15561562. 157.Ge rin gerE D. Affec tiv edisorde rsan ddiabetesmellitu s.Neur opsych ol Beh av Aspect s Diabete s 1990;239272. 158.Camer on O, KronfolZ,Gred enJ,e tal.Hypothalamic-pituitary-ad renocorticalactivityinpat ien ts withdiabe tesmellitus. Arch Gen Psychiat ry1984;41:10901095. 159.HudsonJ,Hu dson M, Rot hschildA,etal. Ab normalre sultsofde xameth asonesu ppressiontest in non-d epresse dpatien tswit hdiabet esme llitus.Arch Ge n Psychiatry 1984;41:10861089. 160.ArakiY,Nomur aM,Tan akaH, etal.MRIofthe brainindiabe tesmellitus. Ne urorad iology 1994;36:101103. 161.LyooIK, LeeHK, JungJH, etal.Wh ite matter h yper in tensitiesonbrain MR Iin c hildre nwith psych iatricdisorde rs.2001.U npublishedworkcitedwith p ermission . 162.De jgaardA, GadeA,Larsson H,etal. Evidence fordiabe ticencep halopath y.Diab etic Me d 1991;8:162167. 163.Schur hoffF,Be lliv ier F, Jouv entR ,etal. Ear lyandlate on setbipolar disorder s:twodiffere nt formsofmanic-depre ssiv eillness. J Affe ct Disor d2000;58:215221. 164.WoodsBT,Yur gelun-ToddD, MikulisD,e tal.Age-r elatedMRIabnormalitiesinbipolarillness:a clin icalst udy. Biol Psychiatr y1995;38:846847. 165.JacobsonAM, Weinger K ,Jimer son D,et al.Factorsrelat edtothe develop men tofMRI abnormalitiesintype 1diabe ticpatient s.2001.Un publish edworkcitedwithpe rmission . 166.CoffeyCE ,FigielGS, Djang W T, etal.Su bcor ticalh yperint ensityonmagn eticresonance imagin g:acomparison ofnormalan ddepre ssedelderlysubject s.Am J Psychiat ry1990;147:187189. 167.Krishn anKR ,McDonaldWM,E scalon aPR ,etal. Magnet icre son ance imagingofthe caud ate nu cleiinde pression :preliminaryobs ervations. Ar ch Gen Psychiat ry1992;49:553557. 168.Brown FW, LewineRJ, HudginsPA,etal. W hitematte rhype rin ten sit ysign alsin psychiat ricand nonp sychiatr icsu bje cts.Am J Psychiatry1992;149:620625. 169.Buch sbaumMS, WuJ,DeLisiL E,et al.Fr on talcor texandbasalgangliametabolicr ates assessed bypositronemissiontomographywith[18F]2-de oxy glu cose in affectiveillne ss.J Affect D isord 1986;10:137152. 170.CoffeyCE ,FigielGS, Djang W T, etal.Le ukoence phalopat hyinelderlydep ressedpatients re ferred forEC T.Biol Psych iatry1988;24:143161. 171.CoffeyCE ,FigielGS, Djang W T, etal.Su bcor ticalwh it ematter hyper in tensityonmagn etic re son ance imaging:C linicalan dneu roanatomiccorr elatesint hede pressed. J Ne uropsych iatry
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1989;1:135144. 172.CoffeyCE ,WilkinsonWE ,Weiner RD, etal.Qu ant it ativecer ebralanat omyin depre ssion:a contr olle dmagnet icre son ance imagingst udy.Arch Ge n Psychiatr y1993;50:716. 173.DolanRJ, CallowaySP,Th acker PF,etal. Thecer ebralcorticalappe aranceinde pressed su bje cts.Psychol Med1986;16:775779. 174.FigielGS,K rish nanKR, DoraiswamyPM,e tal.Subcorticalhy perinte nsitie son brainmagn etic re son ance imaging:acompar isonofnormalandbipolarsubjects. J Ne uropsychiatry Clin Neur osci 1991;3:1822. 175.JacobsonAM, Weinger K .Treatin gdepre ssionindiabe ticpatient s:isth ere analt ernativeto medications?An n In tern Me d1998;129:656657. 176.Lustman PJ, GriffithLS,Free dlandKE ,etal. Cognitiv ebeh avior t her apyfordepre ssioninty pe2 diabe tesmellitus:aran domiz ed,contr olle dtrial.Ann Inte rn Med1998;129:613621. 177.De rogatisLR.SCL -90-R admin ist ration,scoring,andpr ocedu resman ual,II. Towson,MD:C linical Psychome tricResearch, 1983. 178.Polonsk yW,Ande rson BJ,WelchG,et al.Assessmentofdiabet esspecificdistre ss.Diabe tes C are 1995;18:754760. 179.JacobsonAM, Samson J A. Theev aluat ionoftwomeasuresofqualityoflifeinpatie ntswitht ype Ian dtype IIdiabetesmellitu s.Diabe tes Care1994;17:267274. 180.JacobsonAM. Psych ologicalcareofpatien tswith in sulin -depe nden tdiabete smellit usN Engl J Med1996;334:12491253. 181.Jon esJM,LawsonML,Dan emanD,etal. Eat in gdisorde rsin adole scentfe maleswith andwith out typ e1diabe tes:crosssectionalstu dy.BMJ2000;20: 15631566. 182.Levine MD,Marcu sMD.Women ,diabe tes,anddisor derede ating. Diabet es Spectru m 1997;10:191195. 183.CarlsonMG,Campbe llPJ. Inten siv ein sulin the rapyandweight gaininIDDM.Diabe tes 1993;42:17001707. 184.Fair burn CG,Pe velerRC ,DaviesB,etal. Eat in gdisorde rsin you ngadultswit hinsulindepe nden t diabe tesmellitus:acon trolledstu dy.BMJ1991;303:1720. 185.Bryden KS,NeilA, Mayou RA,etal. Eat in ghabits, body weigh t,andinsu linmisu se.A lon git udinalstu dyoft eenagersandyoun gadu ltswith type1diabetes .Diabet es Care1999;22:1956 1960. 186.Striegel-MooreRH, Nicholson TJ,etal. Prev alence ofeatin gdisorde rsymptomsinpreadolesce nt andadolescen tgir lswithIDDM.D iabetes C are 1992;15:13611368. 187.Polonsk yWH,Ande rson BJ,Lohrer PA.Disorder edeatin gan dregime nmanipulat ioninwome n withdiabe tes:re lationsh ip stoglycemiccon trol.D iabete s1992;40[Su ppl1]:540A(abst). 188.RyanCM.E ffe ctsofdiab etesmellitu sonn eur opsych ologicalfu nctioning:alifespan perspec tive . Sem Clin Neuropsych iatry1997;2:414. 189.RyanC, Ve gaA,Drash A.Cognitivedeficitsin adole scent swh ode velope ddiabete searlyinlife . Pediatrics1985;75:921927. 190.RyanCM,GreckleM.Wh yislearningandmemorydys fu nctionintype 2diabet eslimit edtoolder P. 648
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adults.Diab etes Metab Res R ev2000;16:308315. 191.BjorgaasM,GimseR, VikT,e tal.Cognitivefu nction in type1diabeticchildren with andwith ou t episodesofh ypogly caemia.Acta Pae diatr1997;86:148153. 192.Hersh eyT,Bhargav aN,Sadler M,e tal.Conv entionalvs.int ensivediabe testh erapyin childr en withty pe1diabe tes:effe ctson me moryan dmotorspee d.Diabe tes Care1999;22:13181324. 193.RovetJF,Eh rlich RM.Theeffe ctofh ypog lyce micseizure son cogn itivefu nctioninchild renwith diabe tes:a7-yearprospectivest udy.J Pediatr 1999;134:503506. 194.RovetJ, Alver ezM.Atten tion alfunct ioninginch ildren andadolesce ntswithIDDM.D iabete s C are 1997;20:803810. 195.Holme sCS,Richman LC.C ogn it ive profilesofch ildre nwit hinsulin-depe nden tdiabet es.J D ev Beh av Pediatr1985;6:323326. 196.RovetJF,Eh rlich RM,Czu chtaD.In telle ctualch aracteristicsofdiab eticchildr enatdiagnosisand oneye arlat er.J Pediatr Psychol1990;15:775788. 197.RovetJF,Eh rlich RM,Czu chtaD,AklerM.Psychoedu cationalcharact eristicsofchildren and adolescen tswithinsulin-dep enden tdiabet esme llitus. J L earn Disabil1993;26:722. 198.Leibson CL,R occaWA,Han son VA, etal.R iskofdementiaamongp ersonswit hdiabet esme llitus: ap opu lation-b asedcohortstu dy.Am J Epidemiol1997;145:301308. 199.Effects ofinten siv ediabete sthe rapyonn europsych ologicalfu nction in adu ltsinth eDiabetes Cont rolan dComplicationsTrial.Ann In tern Me d1996;124:379388. 200.ReichardP, PihlM, Rose nqvistU, etal. C omplication sinIDDMar ecau sedbyelevatedblood glucoselevel:th eStock holmDiabe tesInt erven tion Study(SDIS)at10-ye arfollowu p.Diab etologia 1996;39:14831488. 201.De aryI, C rawfordJ,He pburn DA,e tal.Seve rehyp oglycemiaan din telligen ceinadu lt patien ts withinsu lin-tr eat eddiabet es.Diab etes1993;42:341344. 202.De aryIJ, FrierBM.Sev ereh ypoglycaemiaandcognitiveimpairme ntindiabet es:lin knotproven. BMJ1996;313:767768. 203.Pe rros P,Dear yIJ,SellarRJ,e tal.Brain abnormalitie sdemonst rat edbymagne tic r esonan ce imagin gin adu ltIDDMpatie ntswithandwithoutahistoryofr ecurr entse vere h ypogly cemia. Diabet es Care1997;20:10131018. 204.JacobsonAM, Weinger K ,HillTC ,et al.Brainfu nction in g,cognition ,an dpsychiat ricdisordersin patie ntswitht ype1d iabetes. Diabet es2000;50[Suppl1]:A132(abst). 205.Me islerAW, Care yMP,LantingaLJ,et al.Ere ctiledy sfunct ionindiabet esme llitus:a biop sychosocialappr oachtoetiologyan dassessmen t.Ann Behav Me d1989;11:1827. 206.NIHC on sensu sConfer ence. Impoten ce:NIHConsen susDevelop men tPanelonImpote nce. JAMA 1993;270:8390. 207.Klein R,KleinBE ,LeeK E,et al.Pr evalen ceofse lf-re por tedere ctiled ysfunct ioninpeoplewith lon g-termIDDM.Diabe tes Care1996;9:135141. 208.Fe deleD, Bort olot tiA, Cosce lliC,et al.,onbeh alfofGrupp oItalian oStu dioDeficitE rettilene i Diabetici. Ere ctiledysfu nctionintype 1an dtype2diabeticsinItaly. Int J E pide miol2000;29:524 531. 209.Kar acan I,SalisPJ,WareJC, etal.Noctur nalpen iletu me scence anddiag nos isindiabet ic
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impoten ce.Am J Psych iatry1978;35:191197. 210.Lehman TP,Jacob sJ A. Etiologyofdiab eticimpot ence .J Urol1983;129:291294. 211.En zlinP,Math ie uC,Vander schue ren D,et al.Diab etesmellitu sandfemalese xuality:ar eview of25y ears 'rese arch .Diabe t Me d1998;15:809815.
Chapter38 Exercise in Patients with Diabetes Mellitus

Jeanne H. Ste ppe l Edwar d S. Horton Exe rcisehaslongbe enre cogn ize dasan importan tfact orint hetr eatmen tofdiabe tesmellitus. Befor e th edis cove ryofinsu lin, patien tswit hdiabet es,particularth ose with type1diabete s,were v erylimited inth eir abilitytoexe rcis e,becauseitwasalmostimpossibleforth emt oav oidket osisan ddehydr ation. Afterinsu lint herapywase stablishedasamainstaytreatment, exer cisewasnolonge ran e lu sive act ivity. Wit hthe ir abilitytoexe rcise ,itbecamee vide ntth ath ypoglyce miafre quen tlydevelopedbothin th eimmediateposte xerciseper iodan dduringth e24hoursaftere xercise.It alsowasrecognizedth at ket osiscou ld b ein duced byexer ciseinpatient swith poorglucosecontrolandt hat e ven p atient swith exce llen tcon trolwouldsomet imesdeve lophyp erglycemiaafter vigorousex ercise.Asouru nders tan din g ofe xerciseinth epat ie ntwithty pe1diabe tesh asin creased,t hegoalhasbeen t oman ageglucose homeost asisand fu elmet abolismsoth atpatientscanparticipatefu llyinallformsofex ercise. Exe rcisealsoplaysacriticalroleinpatientswith t ype2diabetes. Itcan helpimproveinsu linse nsitiv ity an dassistwithre ductionan dmain ten ance ofbodyweightinobesepatient s.Exe rcise ,togeth erwithdiet an dpharmacologict herapies,isimportan taspartoftheover allapproacht oimpr ovingglycemiccon trol an dredu cin gcardiovascu larriskfactors.In deed ,exer cise often is prescribed asath erapyfor type2 diabet es.The manyben efitsofe xerciseinth esepatie ntsinclude improvedlon g-termglycemiccontr olas ar esultoft hede creas ein in sulin resistan cean dofth ecumulat ive bloodglu cose -loweringeffe ctsof individ ualboutsofexerc ise. Inadd ition,re gulare xercisehasbeen showntoimprovelip idabnormalities an dlowerbloodpr essure (1,2,3).Fin ally, exerc isealsomaybeanimportantcomp one ntofweight-loss reg imensforth esepatie nts. When usedincombination with die tary chan ges(espe ciallycalorie rest ric tion), exercisepr omot eslossofadipose t issu ewithpre servationofle an b odymass(4,5).In add ition,e xercisemaypromote aben eficialred istr ibu tion ofbodyfat. Abdomin aladiposity appearsto haveag reat erimpactonin sulin resistanceth an d oesfatdepositionatot her site s,an dexer ciseh as rece ntlybee nshowntodecr easeabdominalfat in post men opausalwome n(6). Unfortu nat ely,th ereare somesignificant risk sofexe rcisein the patient with type2diabete s,includingsymptomatic hy poglycemia,which canoccuru pto24h ou rsafte rexe rcise ;exace rbat ionofknownorpreviously un knowncardiacdisease ;worsen in gofsy mptomssecon dary tode gene rative join tdisease ;andpossible damag etojoin tsinth esetting ofne uropath y.Itisparticularlyimportanttoscree npat ie ntswithty pe2 diabet esfor existin gcard iovascu lardisease befor eprescr ibinganexe rciseregimen. The rear esever aluniver salrisk sofexe rcise in patien tswit htype 1ortype2diabete s.Mostimport ant , vigor ou sexercisecancau sere tin alhemorrhageorvitreousbleeding inpatient swith proliferativ e ret in opathy .Maneu verssu chastheValsalvamaneu vert hat in crease in traabdominalpre ssure shouldbe av oided, asshouldjarringh ead motionst hat mightindu cere tin aldetachment .Inaddit ion,patient swith sen sory neu ropathy shouldrefrain fr omhigh-imp actex ercisetoreduc ethe riskofsoft tiss uean djoint injury. Thepre sence ofau tonomicneu ropath yoft enmakesp erformanceofhigh-inte nsityexe rcise difficu ltbe cau seofde crease daer obiccapacit yan dpost uralhy pote nsion .Pr ote in uriat endstoincrease withex ercisein patien tswit hne phropat hy.Howeve r,th isisthough ttomer elybeare sultofatransient change inr enalbloodflow, asop pose dtoworsen in gofre naldisease .Angiotensin-conv ertingen zyme inhibitorshav ebeen showntodecre aseth ise ffect(7, 8, 9).
PHYSIOLOGY OF EXERCISE IN HEALTHY INDIVIDUALS

Tou nde rstan dme tabolicre gulation in patien tswit hdiabet es,itishelpfulfir sttod iscu sstheph ysiolog y ofe xerciseinh ealthy in dividuals with ou tdiabete s.Sever alhormonal, cardiovascu lar,an dne urologic resp on sesthatoccurdu rin gexer cise e nablet hebodytorespondt oth eincreaseden ergyde mand. Int here stin gfaste dstat e,beforee xercise,bloodglucoseleve lsaremaintain edbyabalance ofth e product ionofglu cose bythe liverandth eupt akeofglucosebybodytissues(50%byth ebrain;15%to 20%byskeletalmuscle;an dthe remainder bykidney, splanch nicbed,bloodcells,an dot hert issu es). Glu cose p rodu ction bythe livere arlyinfasting occu rspredominantlyviaglycogenolysis,wit hon ly about
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25%con tribute dbyglu con eogene sis(Fig.38.1).Inpatie ntswitht ype1d iabetes, upto45%ofglucose product iondu rin gthe nonexe rcising s tate derivesfromglucone oge nesis,ev enearlyin fasting.
Figure 38.1.Glucoseproductionandutilizationintheresting,fastedstateinnormalman.AA,aminoacids;FFA, freefattyacids.(ModifiedfromBjorkmanO,WahrenJ.In:HortonE,TerjungR,eds.Exercise, nutrition, and energy metabolism.NewYork:MacmillanPublishing,1988;100115,withpermission.) P. 650 The sour cesofe nerg yusedby sk eletalmusclevar ymarkedlybet we ent imesofr estan dexe rcise .At rest ,only10%ofthe e ner gyproducedinske le talmu scle isfromg lu coseoxidation,wh ereas85%to90% isfromfatt yacidsan d1%to2%isfromaminoacids(10).C arbohydr ate metabolismincr ease s significantlywithth eonsetofexer cise asth ebreakdown ofglycogeninmuscleincre ases. Th isis associate dwith the r apidgen erat ionoflactat e,whiche nter sthebloodst ream.With in minut esoft he onsetofexe rcise ,an aer obicme tabolismswit chestoae robicmetab olism,andup take ofglucosean d oxygen in tomuscleincre asesasthebloodflowt omuscleincreases.Th ecir culatingglucose concen trat ioniskept e ssent iallyconstantasaresu lt ofar egulat edmatchingofth ehepaticproduction of glucosetothe r ate ofglucoseupt akeby themusclefromt hecirculat ion. In addition tothesh ift in glucoseme tabolismduring exercise, break down oftriglyceridesinadiposet issu ereleasesfatt yacidsin to th ecir culation asanalter nat ive met abolicfue l.Glycerolr eleased fr omthe triglyce ridebackb on eist aken upby theliveranduse dasapr ecur sorforgluconeogen esisalong with ther ele aseofamin oacid sfr om th eskeletalmuscle. Once exercisest ops, t heincr easeinglucoseu ptak econ tinue sforatimetorebu ildglycogenstore sint he muscle.The rate ofre plet ionofgly coge nstorescanvar ydramat ically,de pending onint akeoffood.Th is occursqu ite slowly in thefastedstate;inth efedstate, glycogen gene rallyisre ple nishedwithin12 hour s.Glycogen stor esin skeletalmusclear ereplete dmorerapidlyt han are thoseinthe liver . Multiplecomple xneu rologicandh ormonalresponse splayimportantrole sin fuelhome ostasis d uring exe rcis e.The sein clu deact ivation ofth esympath eticner vou ssysteman dachange in t heratiosof insulinan dthe cou nter regu lator yhormone s.Thesh ift sin t hebalanceofthe sehormon es,plusincre ased sympath etictone, alterth emetab olismofgluc ose, freefattyacids, andaminoacidsan dchangeth e body'sabilitytoutilize oxyg enandtomain tainfluidstat us. Atth eon setofexer cise ,the sympathe ticn ervoussy stemisactiv ated, wit hare sultan tin creaseinhe art ratean dcon striction ofth ebloodvesse lssu pplying thesplan chn icbe d,the kid neys, andmusclesn ot involv eddirectlyinthe exer cise. Thiscause sanincr easeinbloodflowt oth etissuesmostin nee dth e exe rcis in gmus cles. Inadd ition,e pin ephr in ean dnorepineph rineplayv italr olesinstimu latingbre akdown ofadipose t issu e[-adr ene rgicst imulation(11)]an dsuppr essin gin sulin secre tion(-adren ergic stimu lation ).Catech olamin esar ealsoimport ant in stimulat in gglycogen olysisduring e xercise. Adjustmen tsin in sulin secret ionarecriticalforth ere gulation offu elmetabolismdu ringexe rcis e.As mentionedabov e,th esympath eticner vou ssystemsuppr essessecr etion ofinsulinat theonse tof
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exe rcis e.Becauseinsu linn ormallyin hibit shepaticglu cose p rodu ction ,the decreaseininsulinallowsth e P. 651 live rtoin crease glu cose ou tput. Insulinalsosuppre sseslipoly sis, andt husth edecr ease in insu linleve ls promote st hebr eakdownofadiposetissuetr iglycer ide s.Aswillb ediscu ssedlate r,th emolecular mechanismsofglu cose uptakedur in gexer ciseareinde pende ntofin sulin ,sot hede creasein seru m insulinconcen trat iondoesnotaffectth eabilityofth emu scle totakeu pglu cose fromthe circu lation (12). Glu cagonisimportan tinthe regu lationofglucosele velsduringvigorousor prolonged e xercisebu tplays asmallerrole in mild-t o-mod erat eexer cise .Asthe p lasmaglu cose conce ntr ation beginstofall, glu cagon act sasacoun terr egulat oryh or mone, con tributingt oth eact ivation ofglycog enoly sisandtothe in crease ingluconeogen esis t hrough acceleratedu ptak eofaminoacidsbyth eliver (13).Theroleplayed b y glucagon isgen erallylarge rin people wh oh ave notund ergoneph ysicalt rainingt han in thosewhoare train edathletes. Cortisolan dgrowthhormon ealsoactascou nter regulator yhormone sthathelptoblock th eeffectsofin sulinduring exercise. Th eymaybe e specially impor tan tin ant agonizingth eeffectsof insulinintissuest hat aren ot d ire ctlyin volvedine xercise,t husincr easingth eamount ofglucose av ailable forth eact ive lye xercisingmuscles. Seve ralfactorscan alter fu elutilizationandth eext entofinflu en ceofth ehormon aland neu rologic reg ulators.The seincludeph ysicaltraining, in ten sity ofexe rcise ,dur ation ofe xercise,andth edietth at pre cedesex ercise.Physicaltrain in glowersth eper centageofthemax imumaerobiccapacity (VO 2 m ax ) th atisreachedwh endoin gan equivalen tamount ofwor k.Train edin dividu alsdepen dmoreh eav ilyon ut iliz ation offre efatt yacidsthanofglu cose forfu el. Thisappearstobeimportantindev eloping en durance, becau semusclegly coge nstoresintr ainedindividualsdonotbecome depletedasquicklyas th oseinu ntr ainedindividuals. The int ensityofexer cise ,definedasaper centageofVO 2 m ax ,alsoinflue ncesfu elmetabolism. Ast he inten sit yrises,th erole ofglucoseinprovidin gfueltothee xercisingmu scleskeeps incr easing(Fig. 38.2),withth eimportanceoflipolysisdecre asing. Th euse ofaminoacidsremainsrough lyt hesame. Once theVO 2 m ax isgreatert han 75%, carbohydr ate becomesth emainfue lconsu medby musc leandth e rateofg lycogen olysisisincre ased.
Figure 38.2.Leguptakeofglucoseduringbicycleergometerexercise.Mildexerciseis25%to30%ofmaximal capacity,moderateexerciseis50%to60%ofmaximalcapacity,andsevereexerciseis75%to90%ofmaximal capacity.(FromFeligP,WarrenJ.Fuelhomeostasisinexercise.N Engl J Med1975;293:10781084,with permission.Copyright1975MassachusettsMedicalSociety.)
The d urationofexer cise affectsfu elmetabolismasaconsequ ence ofat ime-dep ende ntshiftfromt he ut iliz ation ofcarbohydratestoth eutilization offree fatty acids.Glycogen stor esbecome depletedafter seve ralhoursofmoder atecont in uousexe rcise ,an dlipolysisbecomesthe main sou rceoffu elfor exe rcis in gmus cle. Aft erdep let ionofgly cogen stores,h epat icglucoseprodu ctionviag lu con eoge nesisis esse ntialformaint enanceofbloodglu cose con centr ations.Somet imesinprolon gedexe rcise suchas marathonru nning ,gly coge nstoresaredeplete d,th elive risu nablet okee pupwithglucose req uirementst hrough glu con eog enesis,andh ypoglyce miadev elops. The composition ofth edietpre cedingexe rcisecan affectfu elmetabolismdu ringact ivity. Ad iet highin car boh ydratesisassociatedwithagreaterrateofglu cose oxidat ionandincreasedmuscleglycog en stores. Th ismay cont rib utet ogen erallygre ater endu ran ceinin dividu alswhohav ehadacar boh ydrat e-
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richdietth an in thosewithacarbohydr ate-r estricted d iet .Someathlete st her efor euseatech nique calledcarboh ydrateloadin gbeforeex ercisetoimproveen durance. Skeletalmuscleisabletotak eupglucosefromt hecirculat ionpre dominan tlyviathe GLU T4transporte r protein(14). P. 652 Du ringex ercise,GLUT4istranslocated fr omanint race llularlocation tot heplasmamembran e,similart o whatocc urswithinsu linstimulation .The reisnowabun dant evidence toindicateth atth einsulinmediatedandcontr action-me diatedmech anismsaredistinct (15). Insulin-mediate dsign alin gin volve s bindingofin sulin tot heinsu linre ceptoran dcau sin gitsautophosph orylationandacascade ofre action s, includingactiv ation ofinsu linre ceptorsubst rate protein-1(IR S-1)an dphosphatidylin ositol3-kin ase. Exe rcise-induce dglu cose tran spor tdoesnotin volve eit her IR S-1orphosphatidylinositol3-kin ase, alth ou ghth eremaybe activat ionofthe sign alin gserinekinaseAkt, whichislocate dfarth erdowninth e insulinsignalingpathway. Numeroush ypot heses h ave been proposedt oex plain themech anismofexe rcise-in duce dglu cose transport. Calciumflux int hemusclecellh asbe enimplicate d,becauseglucosetr ansp ort d ecreaseswhe n calciumrelease isblock edpharmacologically(15). C alciu misalsothough ttop layanimport an trolein th eactivationofen zyme ssuchasproteinkinaseC,wh ich aret hought tobe upstr eamofth emobilization ofGLU T4.Anoth erth eor yimplicatesn itr icoxideasapote ntialme diatorofcontr action-induce dglu cose transport, becau segen erationofnitricoxideincr ease sduringex ercise(16).Although theu ptakeof glucosebymuscleafte rcon traction isnotaffe ctedbyinh ib itionofn it ricoxidesyn thase,basalrate sof glucosetransportinmuscleappe art obede creased(17).Itispossibleth atn itr icoxidemodu latesa un iqu epathway thataffect sg lu coset ran spor tin depen dent ofeith erth ein sulin or t hee xercisepat hway . Eviden cealsohasimplicat edmitogen -activat edprotein(MAP)kinaseinth eprocessofe xercise-indu ced glucosetransport. Th eMAPkinase sign alin gpat hwaycont ainsseve ralenz yme cascad esthatare act ivatedwithe xercise. Th isappearstoinclud ebot hth eERK 1/2andJNKMAPkinases(18).In addition topot ent ialeffe ctson glu cose uptake,t heMAPkinasepat hwayslikelyregu lategen e-tr anscr iptioneve nts th atareinvolve din mu scle growt han drepair. The recurr ent lyisstronginte restint hehy pot hesisthat5 -aden osine monophosphate-activ ate dprot ein (AMP)kinaseserve sasametabolicfuelgaugeandke yregu lator ofglucoseupt akedu ringexe rcise. AMPkinaseactivityincre asesmark edlywith exer cise. Studieswithactivatorsan din hibitor sofAMP kinasein dic atet hat t hisiscausallylink edtothe t ran slocat ionofGLU T4transporte rs(19,20).Fatt yacid oxidation andinsu linse nsitivit ymayalsobe affecte dbyexer cise viathispat hway. Severale xcelle nt rev iewarticle shav ecov eredt hesignalingpathwaysimplicatedinex ercise-induce dglu cose transport (15,21,22).
EXERCISE AND GLUCOSE METABOLISMIN PATIENTS WITH TYPE 1 DIABETES

Ph ysicalexerc iseincr ease sinsu lin se nsitivit yin in dividu alswith diabete s(Fig.38.3).Thisincreased insulinsen sitivityisthough ttobecau sedbyth eincre aseinglucoseup take v iaGLU T4resu lt in gfromth e effect ofexe rciseon the e xpressionan dtranslocation ofth etransporter t oth eskelet almuscleplasma membr ane (23).Thisstat eofalt eredse nsitiv ity canlastforsev eralhour s(24). High lyt rained ath let es havebet terglucosetolerance,-ce llefficie ncy,andglucoseut ilizationthandoun traine din div idu als (25).In addition ,ath le tesmayex hibit agreaterglyce micresponset ooralglucosesecondaryto adaptationsinglucoseabsor ption(26). Th ead aptation sassociatedwithtr ainingrev erserapidlyonce at hletesst opth eirexer cise progr ams(27).
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Figure 38.3.Theeffectofinsulinonbloodglucoseatrestandwithexerciseintype1diabetes.(FromLawrenceRD. BMJ1926;1:648650.)
Inindividualswitht ype1d iabetes, unliketh osewith ou tdiabete s,regu latoryeve ntsinth epan creatic isle tsin duced b yexerc isecann otde creasein sulin secret ion, becau seinsulinis d erivedbyinjection. Becauseinsu linleve lsar esust ained, thesu ppressivee ffe ctofinsu linont helive rcontinue sand hepatic product ionofglu cose remainslowat thesame timeth atu tilizat ionofglu cose bymu scle rise s.This resu lt sin asubst ant ialriskofhypoglycemia.Ther iskofhypoglycemiain patien tswith diabete sise ven gre ater ifth eyhaveinjecte din sulin in toasubcu tan eou ssit ein an exercisinglimb,be cause in creas ed bloodflowcan acceler ateinsu linabsor ption (28). Thiscanbe particularlypr oblematicwhe nver y-shortact in gin sulin ,such aslispr ooraspart, isuse d(29).Becauseofthe incr ease drisk ofhy poglycemia secondarytorapidabsorp tionofrece ntlyadmin is tered insu lin, it isre comme ndedt hat v igorousexe rcise beavoidedfor1to1.5h ou rsaft erinjection .The site ofinsulinadministrat ionisalsoimport ant and shouldbech ose nwit hreg ardtoth epart icu laractivitysoastoavoidin je ctinginsulinintoanactively exe rcis in garea. Because, asdescribed above,insu linlevelsdonotdeclin einresp ons etoactivityin patien tswit htype 1 diabet es,th enormalupre gulationofglycogen olysisandglucone oge nesisdoesnotoccur,t herateof muscleglucos euptakemayn otbe matched ,an dhypoglycemiaislik ely t ode velop. Th iscancause problemsparticular lyinpatientswh oh avet igh tglu cos econ trol, becau seth eymayhavegre ate r hy poglycemiaun awar enes sandre duced count erreg ulatoryre spon ses(30).The presen ceofautonomicn europat hymayfu rthe rcon tribute toa decr eased cou nter regulator yresponse, aswellastoadiminished abilitytosen sehypoglycemia. Asan approach tod ecreasin gthe risk ofhyp oglycemiaduring exercise, patien tswith type1diabet es oftenbe nefitfromlowe ringth eir doseofshort-actinginsulinbeforee xercisean din gestingcarbohydr ates beforeordur in gexer cise. Itoft eniseffectivet ode crease theinsu lindoseby 25%to50%be fore exe rcis ean dtoavoidex ercisefor atleast anh ou rafte rtak in gin sulin .Patientssh ou ldch eckth eirblood glucoselevelsbeforeth eyexe rcisean dcon side rasupp lemen tary carbohydr ate snackwh ent heirblood glucoselevelisbe low100mg/dL.The responseofbloodglucosetoexercisemayvarysignificantly amongpat ie ntswithdiabe tes,andth uspre cise adjustmen tsin in sulin and carbohydr ate int aken eedt o beindividualized. Insomepatien tswit htype 1diabet es,impr ove din sulin sensitivitymayper sistforseve ralhoursafter th eystopexer cising(Fig.38.4),an dthe seeffectscanlastforup t o24hour s(31).Themechanismis notfullyun derstood,but t heincre ased se nsitivit yisth ou ght t obe d uetoare lativelyhighrateof glucoseupt akeby thee xercisedmusclesan dlowerh epat icpr odu ctionofglucoseasth eglycoge nstores ar ereplete d(24).Thismayresu lt int hede velopment ofhy poglycemiaseve ralhoursaftere xercise. The refor e,itisofte nadv isable tode creas edose sofsh ort -andint ermediate-actinginsulinbefore exe rcis e(asnote dabove),andcarboh ydrateintakeshouldbeincr ease dafter exercise. Asst ate dearlier, th etreatment r egimen nee dstob etailore dtoe ach p atient on thebasisofhisor herr esponseto P. 653
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exe rcis e.
Figure 38.4.Glucoselevelsduringbreakfast(BKF)andlunchwithrestandwith45minutesofmoderateexercise starting30minutesafterbreakfastinpatientswithtype1diabetes.(CopyrightAmericanDiabetesAssociation. FromCaronD,PoussierP,MarlissEB,etal.Theeffectofpostprandialexerciseonmeal-relatedglucoseintolerancein insulin-dependentdiabeticindividuals.Diabetes Care1982;5:364369.ReprintedwithpermissionfromtheAmerican DiabetesAssociation.)
Itisimportan ttorecognizeth atdiffere ntty pesofe xercisecanhavedistincteffe ctson bloodglu cose levels.Wh ereasmoderate, sustain edactivitymaylowe rplasmaglucosecon cent rationsan dresu lt in hy poglycemiainpat ien tswithtyp e1diabe tes,sh or tburst sofhigh-int ensitye xertioncan actu ally increaseglucoselevelsan dcau sehype rglycemia(32)(Fig.38.5).Theglu coseleve linindividuals withoutdiabe teste ndstorisemodest lydu ringbriefinte nsiveexe rcise ,wit hape akleve loccurring upto 15minu tesafterces sation ofactiv ity .Theglucoseleve lth engr aduallydropsdu rin gthe next h ou r.Th e riseinglucoseconcen trat ionisatt ribu tedt oanin creaseinhe paticproductionofgluc oset hat exceed s th erat eofglucoseu ptake byexer cisingmuscle. Th islikelyreflectsth edramaticst imulationof th ecou nte rregu latoryhormon esecre tiondu ringinten seexe rcise,whichsu ppresse sin sulin release .Once exe rcis eiscomp let ed,th ere isacompensatoryin creaseininsulinsecre tion. P. 654
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Figure 38.5.Glucoseconcentrationsincontrolanddiabeticsubjects10minutesbeforeintenseexercise,thenan exerciseperiodat80%VO2max,then2hoursofrecovery.Group1consistsofthediabeticsubjects,allofwhomhad plasmaglucosevaluesof70to120mg/dLbeforetheexercisetest.(CopyrightAmericanDiabetesAssociation. FromMitchellTH,AbrahamG,SchiffrinA,etal.HyperglycemiaafterintenseexerciseinIDDMsubjectsduring continuousinsulininfusion.Diabetes Care1988;11:311317.ReprintedwithpermissionfromtheAmericanDiabetes Association.)
The r ise inb loodglucosewithint ensiveex ercisemaylastlon gerinindividualswitht ype1diab etesth an inth osewith out diabete s.Onest udyfoun dthatthe poste xerciseh yperglycemiareachedh ig herleve ls an dlastedforafu ll2-h ou rob servationpe riodinpatie ntswitht ype1diabetesafterth eyex ercisedat 80%VO 2 m ax (32). Th ehigh erglucosele velsan dprolongedh yperg lyce miainpatie ntswitht ype1 diabet esare likelydu etoinc rease dhepaticprod uction ofglucoseinth esett in gofcount erre gulatory hormon erelease.Thisisfollowedbyaninabilit ytoin crease in sulin release after comple tion ofexe rcise inresponse tot hee lev ated b loodglucoseleve ls. Ofn ot e,th ecat echolamine responseinpatientswith diabet esappe arst oben or mal(33). Although h yper glyce miacanoccuraft erinte nseex erciseindiabet icpatie ntswithe xcelle ntglycemic control,pat ien tswithpoor con trolwhoexe rcise ofte nexp erience anev enmor emarkedincr easeinblood glucoselevels,whichcanbeaccompaniedbyket osis(Fig.38. 6).In the settingofin sulin deficie ncy, fat tyacidoxidation andglucosepr odu ctionb ytheliverarestimu lated, con tributingt oincre ased ket oge nesisan dhyper gly cemia(34). Th ere alsoap pear st obe decreasedclear ance ofket on esin pat ien ts withpoor lycontr olleddiabete s,becauset hisisaninsulin-stimu latedre spon se(35).Itisrecommen ded th atpatie ntswitht ype1d iabetesch eckbotht heirbloodglucosele veland t heirur in eor serumfor ket on esbeforeexe rcisin g.Ifthe ir se rumglucosecon cent rationis250mg /dLorh ig herandke ton esar e pre sent, the yshouldpost pon eexer cise andadministe rin sulin .Ifnoketone sarepr esen t,itisge ner ally safe forth emtoe xercise.In deed, moderateex ercisemaybeh elpfulin improvin gthe serumglucose level.
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Figure 38.6.Glucoseandketonelevelsduringexerciseinpatientswithdiabeteswithgoodversuspoorblood glucosecontrol.(FromBergerM,BerchtoldP,CuppersHJ,etal.Metabolicandhormonaleffectsofmuscularexercise injuveniletypediabetes.Diabetologia1977;13:355365,withpermission.Copyright1977bySpringer-Verlag.)
Rec omme ndat ionsforpat ien tswithtyp e1diabe tesshouldalway sbein dividu aliz ed,bu tthe rear esome un iv ersalprinciples(Table38.1).First ,pat ie ntsshouldalway scheckbloodglucoseleve lsbefore exe rcis e.Ifth eir glu cose leve lislessthan100mg/dL, they sh ou ld t ake su ppleme ntalcarbohydrate beforeinitiatinge xercise.Th eyalsoshouldexer ciseabou t1t o3hoursaft erameal. Ift heyt akesh or tact in gin sulin with me als,the yshouldplantolower theirdoseofin sulin atth eme albeforeinitiating act ivity. Ag ener alruleistolowerth eshort-actin gin sulin byat least50%.Ifthe ytake on ly inter med iate-actin gin sulin ,th eymaywishtolowerth edoseby30%to35%onth emorning ofth e plann edex ercise.Ifpatie ntsareinvolv edin high-inte nsityexe rcisewit haVO 2 m ax gre ate rthan80%, th eymayne edsupplemen talin sulin afte rexer ciset ocoun terpostexe rcisehype rglycemia.Forpatients P. 655 onan in sulin pump,th ebasalratesh ou ldbe lowered andt hepre mealb olusdecr ease dtoavoid hy poglycemia.In addition ,patien tsmayne edtotake supplement alcarbohydr ate sb efor eexer cisingand at in tervalsdu ringan dafte rexe rcise .Itisimportan ttocon side reach patien t'spe rson alexpe rie nce whe ndeve lopingan appropriat eregimenandmakingad ju stme nts. TABLE 38.1. Insulin Regimen for Exercise
Multipledailyinjections Decreaseshort-actinginsulindoseby3050%beforeexercise Adjustpostexercisedosesbasedonglucosemonitoringandexperiencewithpostexercisehypoglycemia Insulinpumptherapy Decreasebasalinfusionrate Decreaseoromitpremealbolusesbeforeexercise Adjustpostexercisebasalrateandbolusesbasedonglucose
EXERCISE IN PATIENTS WITH TYPE 2 DIABETES

The rear emanyh ealthbe nefitsofexerciseforpat ie ntswithty pe2diabe tes, includ in gimprovementin th ecir culatinglipidpr ofile andbloodpr essure .Inaddit iontoth eben efit sofacu teex ercise,pr olon ged phy sicaltr ainingcanimproveinsu linse nsitiv ity andboth fastingandpostprandialglu cose lev els(36, 37). Itisthough tth atth egreater insu linse nsitivit yfromphy sicalcondition in greflectsanincreaseinglucose upt akeb yskeletalmusclerather thanade crease in hepaticglu cosep rodu ction .Thismaybelin kedto au gme nte dtran slocat ionofGLU T4glucosetransporte rstot heplasmamembran e,th usimpr oving per iph eralglucoseupt ake(38). Unfortu nat ely,muchofthiseffect d isappear son ceexer cise trainingis discon tinue d,oft enwithindays(39,40).In are centmeta-an alysisofstu diesfocusingont heeffe ctsof exe rcis etrain in gon g lyce miccon trol, theh emoglobin A 1 c leve lwass ign ifican tly lowerinth eexer cise groupth an in thecont rolgroup(41),indicatin gthatexe rcise isbe neficialt olon g-ter mglycemiccont rol. Numerousstu die shav eevalu ate dthee ffectivene ssofex ercisein the preve ntion ofty pe2diabe tes. Becauseinsu linre sist ance playsan impor tan troleint heprogre ssiontotype 2diabet es,te chnique sto improveinsu linse nsitivit yshouldtheore ticallydelayorr everse thisprocess.On estud yshowedthat
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Jap ane sepersonslivin gin Hawaiiwe remuchmorelike lyt han thoseliving in Japan tod evelop d iabetes. Thiswasth ou ghtt obeassociat edwithdecr ease dphysicalexe rcise andch an gesindietinindividu als whohadimmigratedtoHawaiiascomp aredwith t hosewholived inJapan (42).Subse quen tly ,mu lt iple stu die scon firmedth atph ysicalactivityhasaprotect ive effectagainstth edev elopmentofdiabet es (43,44,45, 46).Sever alimportan tfin dingshaveemerge dfromth esestu die s.First ,the bene ficialeffect ofp hysicalactivityap pear st obe in depen dent ofcorrectionsinth eriskfactorsfordiabete s.Inone stu dy,th eincidence ofdiabet eswasre ducedby 24%fromt heh igh esttothe lowestactiv ity grou pin menathighriskfordevelopin gdiabete s[based onobesity, highbloodpres sure, andfamilyhistory (44)].In anoth erstu dy,women whoparticipate din physicalact ivitywer efou ndtohavead ecreased occurre nceofdiabete s,indepe nden tofoth erriskfactors(45). More recen tly,th reeimp ort ant c linicaltrialsevalu ated thee ffe ctsofe xerciseandlifest yle modificat ion onth epreve ntion ofty pe2diab etes. Th efirststu dy(the DaQingSt udy)lookedat577C hinese p atient s withimpair edglucosetoler ance .The su bjectswer ediv ide din tofourgr ou psaccordingtothe clinicthe y at tend ed:acontr olgroup,agrouptre ate dwith die talon e,a P. 656 grouptr eat edwit hexe rcise alon e,andagr ou ptreatedwithboth die tand e xercise. Pat ie ntsre ceiv edan oralglu cose toler ance testev ery2year sforatot alof6year soffollow-u p.Allofthet reat me ntgroups hadasignificantd ropinth eincidence ofdiabe tescomparedwithth econtrolgroup.In tere stin gly,the groupwithonlyexe rciseasaninter vent ionhadth ehighest ove rallr educt ionindiabe tesincidence after adju stme ntforbase line b loodglucoseandbodymassindex(47). Asecondstu dy(th eFinn ish Diabe tesPr even tion St udy)ev aluat edpat ie ntswithimpair edglucose tole ran ce.The subjectswe rerandomlydivide din tot wogroups :atreatment g rou poffer edinten siv e lifest yle chan ges, includ in gdie tand exercise, andanontre atmen tgroup.Att heen doft hestu dy(afte r an ave rageof3. 2ye arsoffollow-up), theinciden ceofd iabetesint hetr eatmen tgroupwasr educe dby 58%.Theriskre ductionwasmost sign ifican tin thosepatientswh oex ercisedformoreth an 4hour sp er week andint hos ewhohadt helarg estweightloss(48). Fin ally, the Diabet esPre ven tionProgram,alar gemu lt ice nter clinicaltrial,ex amin edthe in cide nceof diabet esinpat ien tswithimpair edglucosetoler ance whowe rerandomizedt oplace bo, lifestyle inter vent ion, andmetformin treatme ntgr ou ps.Thelifestyletre atment grouphada58%redu ctionint he incidence oftyp e2diabe tescomparedwithcontr ols.Thiswassignificant lybe tter thanthe 31% red uction achiev edwit hme tfor min. Inalloft hese s tudies,itiscle arth atpr even tionorre ductionofobesityplaysanimportantr oleinth e pre vent ionoftype2diabete s.Exe rcise mu stbecombine dwith calor ier estriction in orde rtotip t he en ergybalanceint hedirect ionofener gyexpe nditure . The rear esever aluniver salrecommendation sthatshouldbegiven topatient swith type2diabete s beforeth eybe gin ane xercisereg imen. Individualsolde rthan35shouldbegiven ane xercisete stto scree nforpot entialun derlyingasympt omaticcoron ary arte rydisease (49). Patie ntssh ou ldu nder goan ophth almologicevalu ation toe nsu reth atprolifer ativere tinop ath yisaddresse dbefor ethe ystar tto exe rcis e.Inaddition, testsformicroalbuminur iaandpe ripheralandautonomicne uropat hyshouldbe per formed.E xercisere gimen sshouldthen beindividualized.Ide ally ,aer obicact ivitysh ou ldbe ofaleve l th atcanbesu stained foratle ast30min ute s,an dthemax imumheartrateshouldnotbe h ig hert han 60%to70%abovet here stin gheartrate. Itisimp ort ant toallottimeforwar m-up andcool-down stre tchinge xercisestoavoidmu scleinju rie s. Forpatient stoachievet hehe althbe nefitsofexercise, itissugge stedth att heypartakeinphy sical act ivityatleast3dayspe rweek, an dthey s hou ld beencour agedt oincre aseth efreq uen cyto5to7 day sperwee k,ifp ossible .Ifpat ien tsar erece ivingoralh ypoglycemicagen tsorin sulin ,th eyshouldbe awareofthep ote ntialfor d evelop in ghypogly cemiad uringorafte rexer cise .They may needt oinge st add itionalcar boh ydratetopreve ntlowbloodglucoselevels,andadju stmentst oth eirme dicationsmay becomenece ssary.
CONCLUSION
Ith aslon gbeen k nownthatexe rcisehasb eneficialeffectsforpeoplewit hdiabet es.Int hepast,itwas oftendifficulttoavoidt hehazar dsofex ercise,particularlyinpat ie ntswithty pe1diab etes. More rece ntly,agreateru nder stan din gofen ergymetabolismandfue lh omeostasishasmadeitpossibleto includee xerciseasarealisticgoalforalmostallpat ie ntswithdiabe tes.Improvemen tsin glu cose mon itoringte chnology h ave furth ercontribu tedtothe feasibilityofactiveph ysicalexercisepr ogramsfor peoplewit hdiabet es.In p articular ,personalbloodglucosemon it orsh ave allowedpat ie ntstofollowth eir bloodglucosele velscloselyan dthu sreadilydeve lopindivid ualizedexe rciseregime ns.Th ish asmadeit muche asierforin div idu alswith diabete stoparticipateincompetitivesportsorendu ran ceact ivitiessu ch asmar ath on r unn in g.Itisimportanttoaddr essstrategiesforavoidin ghypoglycemia(both during and aft erexe rcise ),aswe llash yperglycemiaan dketosis,wit hallpatient sbeforeth eyembark onr ou tin e exe rcis e. Patient swith type2diabete sclearlyben efit fr omfrequ ente xercise.Physicalac tivityp laysanimport ant
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par tin the treatme ntstr ate gyin the sepatien ts,asitde creasesobe sit yand lowersbloodpre ssurewh ile improvinginsu linsen sit ivity, long-t ermglyce miccon trol,an dblood lipid p rofiles.Becauseofthe risk of exe rcis eunmask in gisch emiaaswellascausing softtissue and join tinjuryorre tin alhemorrhage,itis criticalthatallp atient shav eacomplete histor yan dphysicalexaminationbe fore the yengagein moder ate orvigorousactivity. Forallpat ie ntswithdiabe tes,ph ysician-patie ntinte ract ioniskeytoestablish in gasucce ssfulexercise program.Ate amapproach thatinvolve scoordinationamonge xercisephy siologists,n utritionists, diabet esedu cators,t heph ysician ,an dthe patien tisu suallythe mosteffect ive waytocreatean individ ualizedexe rciseregime nth atprovidesbe nefitstothe p atient whileavoidingpoten tialhar m.
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ske let almu scle. Am J Physiol En docr in ol Me tab1999;277:E390E394. 17.HigakiY,Hirshman M, Fu jiiN, etal.Nitricoxideincr eases g lu coseu ptak ethr ou ghamech anism th atisdistin ctfromth einsulinan dcon tractionpathwaysinratskeletalmuscle.D iabetes 2001;50:241247. 18.AronsonD,Violan MA,Dufre sneSD,etal. Exer cisest imulate sthe mitog en-activ ated prot ein kinasepat hwayinh umansk ele talmuscle.J Clin Inve st1997;99:12511257. 19.Hayash iT,Hirshman MF,Ku rth EJ,et al.Eviden cefor5AMP-activate dproteinkinaseme diation of th eeffect ofmusclecon tractiononglucosetr ansp ort .Diabe tes1998;47:13691373. 20.Ku rth -Kracz edEJ, Hirsh manMF, Goody earL J,etal. 5AMP-activate dprot einkinase activat ion causesGLUT4tran slocat ioninske let almu scle. Diabet es1999;48:16671671. 21.R yderJW, C hibalinAV,Zie rat hJR.In tracellu larme chan ismsun derlyingincreasesinglucose up take in responsetoinsulinorexer ciseinsk ele talmu scle .Acta Physiol Scand2001;171:249257. 22.Sakamot oK, Goody earL J.Intr acellularsignalingincontr actingske le talmu scle .Rev iew. J Ap pl Physiol2002;93:369383. 23.Goodye arLJ, Hirsh manMF, Valy ou PM,etal. Glucosetr ansporte rnu mbe r,fun ctionand su bcellu lardist rib ution in ratsk ele talmu scle after exerc iset raining. Diabete s1992;41:10911099. 24.Bogar dusC, Th uillezP,RavussinE ,etal. Effectofmu scle glycogen depletion in viv oininsu lin actioninman .J Clin Inve st1983;72:16051610. 25.R yanAS, Mu llerDC,E lahiD.Seq uen tialh yperg lyce mic-eug lyce micclampt oassess-celland per iph eraltissue :studiesinfemaleathletes .J Appl Physiol2001;91:872881. 26.R oseA, HowlettK, Kin gD, etal.E ffectofp riorex erciseon glu cose met abolismin traine dmen . Am J Physiol E ndocrinol Metab2001;281:E766E767. 27.LipmanR L,Raskin P, L ove T, etal.Glucosein tole ran ceduringd ecreasedphy sicalactiv ity in man . Diabetes1972;21:101107. 28.Koivist oVA,Felig P.E ffe ctsoflege xerciseoninsulinabsorptionindiabet icpatients. N E ngl J Med1978;298:7783. 29.Yamakit aT,TomofusaI, YamagamiK ,etal. Glycemicr esponsedu rin gexe rcise after administrationofinsulinlisprocomparedwithth atafteradministration ofre gularh umaninsu lin. Diabetes R es Clin Pract2002;57:1722. 30.Amie lSA,Tamborlane WV,Simon son DC ,etal. Defe ctiv eglu cose cou nter regu lationafterst rict contr olofinsu lin-de pende ntdiabe tesmellitus. N E ngl J Me d1987;316:13761383. 31.MacDonaldMJ.Postex erciselate-onse thypoglycemiain in sulin -depen den tdiabeticpat ie nts. Diabetes C are1987;10:584588. 32.MitchellTH, Abrah amG, Sch iffrinA, etal.Hype rglycemiaafter in tense exerciseinIDDMsubject s du rin gcon tinuoussu bcutaneousinsu lininfu sion. Diabet es Car e1988;11:311317. 33.PurdonC ,BroussonM,Nyvee nSL,et al.Therolesofinsu linandcatech olamin esinthe glucoregu latoryresponse duringint ensee xerciseandearly r ecoveryininsu lin-de pende ntdiabe tic and contr olsubjects. J Clin Endocrinol Metab1993;76:566573. 34.Be rgerM,Ber chtoldP,Cu ppersHJ, etal.Metabolican dhormonale ffe ctsofmuscu larexe rcise in juve nile t ypediabe tics. Diabet ologia1977;13:355365. 35.Fery F,de MaertalaerV,BalasseEO. Me chan ismoft heh yperke ton ae miceffectofprolonge d P. 657
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ex ercisein in sulin -deprived typeI(insu lin-de pende nt)diabe ticpatient s.Diabe tologia1987;30:298 304. 36.BjorntorpP,deJoun geK,SjostromL,e tal.The effectofphysicaltrain in gon in sulin prod uction inobesity.Metabolism1970;19:631638. 37.Maioran aA,O'DriscollG, Good man C,e tal.Combin edae rob icandresistancee xerciseimproves glycemiccont rolan dfit nessintyp e2diabe tes.D iabete s Res Clin Pr act2002;56:115123. 38.Ke nne dyJW,Hirshman MF,Gerv in oEV, etal.Acu teexe rcise in ducesGLUT4translocationin ske let almu scleofnormalhuman subjectsandsu bje ctswit htype 2diabet es.D iabetes1999;48:1192 1197. 39.Bu rsteinR ,Poly chronakosC ,Toe wsCJ,et al.Acute rever salofth een han cedinsulinact ionin tr ainedathlete s.Diabe tes1985;34:756760. 40.Mikin esKJ,Sonn eB,Farr ellPA, etal.E ffectofp hysicalexer ciseonse nsitiv ity and re spon sive nesst oinsulininhu mans.Am J Ph ysiol1988;254:E248E259. 41.BouleNG,HaddadE,K enn yGP,etal. Effectsofexe rcise on glyce miccon trolandbodymassin typ e2diabe tesmellitus:ame ta-analysisofcontr olle dclinicaltrials.JAMA2001;286:12181227. 42.Kawate R,Yamak idoM, Nish imot oY,et al.Diab etesmellitu sanditsvascularcomplicationsin Japane semigrantsonth eislandofHawaii.Diabe tes Care1979;2:161170. 43.FrischRE ,Wysh akG,Alb righ tTE, e tal.Lowerpre valen ceofdiabe tesinfemaleforme rcollege athletes compare dwith nonat hletes. Diabet es1986;35:11011105. 44.Helmric hSP, R aglan dDR, Leun gRW,e tal.Ph ysicalactivityan dredu cedoccurre nceofnoninsu lin-de pende ntdiabe tesmellitus. N E ngl J Me d1991;325:147152. 45.Man son JE,R immE B,StampferMJ,e tal.Ph ysicalactivityan din cid enceofnon-insu linde pende nt diabe tesmellitusinwome n.Lancet 1991;338:774778. 46.Man son JE,NathanDM,K rolewskiAS,etal. Ap rospe ctivestud yofex ercisean din cide nceof diabe tesamongU. S.male physicians. JAMA1992;268:6367. 47.Pan XR ,LiGW, Hu YH,etal. Effectsofdie tan dexer ciseinpr even tin gNIDDMinpe oplewith impair edglucosetole ran ce:the DaQingIGTan dDiabe tesStu dy.Diabe tes C are1997;20:537544. 48.Tu omileh toJ, Lin dstromJ, ErikssonJ,et al.Pr even tionoftype 2diabet esme llit usbych ange sin life styleamon gsubjectswith impairedglucosetolerance.N E ngl J Med 2001;344:13431350. 49.American CollegeofSpor tsMe dicine .Guidelin es for e xercise te stin g an d prescription,6thed . Philadelphia:LippincottWilliams'Wilkins, 2000.
Chapter39 Principles of Insulin Therapy

Alice Y. Y. Cheng Be rnard Z inman
HISTORICAL BACKGROUND
The isolation ofinsulinfromdogpan creasandd emonst rationofitsbiologice ffectivene ssbyBan tin g, Best, Collip ,an dMacLeodin 1921atth eUn ive rsit yofToron torepre sents one ofth egreatest medical discove riesofmod ernmedicin e(1).Thisant idiabe ticsubstance, in itiallycalle disletinby Bant in gand Bestandlate rnamed ins ulin b yMacLeod,waspu rified su fficien tly byCollip,the bioche mistmembe rof th eteam, s oth atitcouldbeinjectedint oh umans(2).The firstinject ionwasg ive ntoapatie ntwith
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diabet es,Le on ardThompson ,on Jan uar y11,1922,at theTorontoGe ner alHospital(3). Impr ove men tsin insulinext ractionan dpurificationfollowed, facilitatin gthe wide spreaduseofin sulin forpatientswith diabet es. In1936, Hagedorndiscovere dthatthe addition offishprotamineke ptin sulin in suspen sionsoth atit wasabsor bedslowlyfromsu bcutaneoussites, thu sprolongingth eeffect ofinsulin(4). Scott andFisher (5)d iscovere dthatzinccouldfurth erex tendt heactionofprotamineinsu lin,leadin gtothede velopmen t ofp rot amin ezincin sulin.In 1946, NPHin sulin (neu tralprotamineHagedorn), amore stableformof protamineinsu lin, wasin troduce dand r emain sin uset oday(6). Fort hefirst60yearsoft heinsu liner a,insu linwasavailableonlyin bov in eor porcine preparations.In th e1980s,hu maninsulinwasintr odu ced(7),makingan imalinsulinessen tiallyobsole te.In the1990s, insulinan alogu eswithph armacokineticsth atwer emoreappropriate forbolu s(premeal)th erapywere introduce dan dfacilitat edth eimprovement ofsub cutaneousinsu linre gimens(8).Ove rthe last80year s, gre atstr ides h ave been mad etoimproveth etreatmentofdiabet eswit himprovedinsu linformulation s, increasedeaseofself-monitor in gofbloodglucose,andab etter unde rstandingofphysiologicinsu lin req uirements. Unfortu nately,alth ou ghwearemuchclos ertothe g oalofphysiologicinsu linr eplacement , th isgoalremainselus ive owingtothe in here ntlimitat ionsofadmin iste ringinsulinat anonph ysiologic site(sub cutaneoustissue )(9).
TYPES OF INSULIN
The lab oratoryproductionofh uman in sulin in t heearly1980shasgr adu allyre sultedinth erep laceme nt ofanimalinsu linsasaviableth erapeut icch oiceforpatien tswit hdiabet es.Human in sulin san dnewer insulinan alogu esproduce dbyrecombin ant P. 660 DNAte chnologyarebe comin gthe main ins ulin su sedinth ecurr ent t reatme ntofdiabete sin most count rie s.Insu linsforclin icalu secan becharact erizedaccordingt oth eirpharmacok in eticprofiles.The y ar eavailab leinrapid-acting, short-actin g,inte rme diate-actin g,andlon g-actingpr epar ation s(10).Table 39.1showstheonse t,peak,anddur ationofaction after s ubcut ane ou sin je ctionsofthe in sulin sused common lyint herapy.Th ediffe rent time-action p rofilesmakeitfeas ibletopursu eth egoalofsimu latin g phy siologicin sulin secret ion, asshowninFigu re39.1;however ,thisgoalremainsdifficu lt toachieve withth ecurr ent formulations.In sulin replacemen tshouldbeth ou ghtofin termsofmealt ime(bolu s)and bas alins ulin s.Themealtime in sulin sare t herapid-actinganalogue sorsh ort -actingr egularh uman insulin.Th eseinsulinshavebee nuse dtoatte mptt osimu lateth ehighleve lsofin sulin seen in individ ualswit houtdiabe tesaft eringest ionofameal.The basalinsu linsar ethe in termediat e-an dlongact in ghuman in sulin san danalogue .They simulate thebasalle velofinsu linoccurr in gbetwee nme als, th rou ghth enight ,an dwith fasting. Insu liniscomme rciallyavailablein con cent rationsof100or 500 un it s/mL, designat edU-100orU -500.Th eU-500con centr ation ,whichisavailable onlyinshort- acting formu lation s,isu sedonlyin rare casesofin sulin resistancewhe nth epat ien treq uiresext remely large dosesofinsu lin. TABLE 39.1. Approximate Pharmacokinetic Characteristics of Human Insulin and Insulin Analogues Following Subcutaneous Injection
Insulin
Onset of action
Peak of action
Duration of action
Blood glucose targets
Mealtimeinsulins Lispro Asparta Regular Basalinsulins NPH 2.53h 57h 1316h Midafternoon(formorningNPH) Fastingglucosenextmorning(for bedtimeNPH) SimilartoNPH 1015min 1015min 1560min 11.5h 12h 24h 45h 46h 58h Postprandial Postprandial Postprandial Priortonextmeal
Lente
2.53h
712h
Upto18h
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Glargineb Ultralente Detemirc
23h 34h 23h
Nopeak 810h Nopeak
Upto30h Upto20h Upto24h
SimilartoNPH SimilartoNPH SimilartoNPH
NPH,NeutralProtamineHagedorn.
a DatafromMudaliarSR,LindbergFA,JoyceM,etal.Insulinaspart:afastactinganalogofhumaninsulin absorptionkineticsandactionprofilecomparedwithregularhumaninsulininhealthynon-diabeticsubjects. Diabetes Care1999;22:15011506.
bDatafromHeinemannL,LinkeschovaR,RaveK,etal.Time-actionprofileofthelong-actinginsulinanalog insulinglargine(HOE901)incomparisonwiththoseofNPHinsulinandplacebo.Diabetes Care2000;23:644 649.
DatafromHeinemannL,SinhaK,WeyerC,etal.Time-actionprofileofthesoluble,fattyacidacylated,longactinginsulinanalogueNN304.Diabet Med1999;16:332338
AdaptedfromHeinemanL,RichterB.Clinicalpharmacologyofhumaninsulin.Diabetes Care1993;16[Suppl S3]:90101.
Figure 39.1.Normalinsulinsecretioninrelationtomealsandtheovernightfastingstate.(RedrawnfromOwensDR, ZinmanB,BolliGB:Insulinstodayandbeyond.Lancet 2001;358:739.)
Mealtime Insulins
RAPID-ACTING INSULIN ANALOGUES: LISPRO AND ASPART
The t ime-actionpr ofile ofre gularh umaninsu linisun abletoadequ ate lymimicphysiologicins ulin secre tion .Insu lininsolu tion s elf-associat esan dformslarge raggre gate scalle dhexame rs.The selarge agg regatesne edtodissociate aftersu bcut ane ou sinject ionbe fore diffu sionofin sulin in toth ecirculat ion ispossible(11).The refore,analoguesofhu maninsulinhavebee ndeve lopedth atcandissociaterapidly fromh examerst omon omersorth atre main lessassociatedinsolu tion, thu sallowin gfaste rabsorption an don setofaction(10,11).Th efir strapidlyactin gin sulin analogue approvedforhu manadministration wasinsu linlispro, in whichthe terminalproline andlysiner esiduesofthe Bch ainofin sulin areinv erted , resu lt in gin decreasedself-associationpropert iesofthe in sulin (8,12). Lispr oinsu linisabsorbedmuch more rapidlythanreg ularinsulin.Lisprobeginsactingwithin15min utes, reac hespeakbiolog iceffe ctsin 60to90minut es,andcontinu estoactfor4to5h ou rs.In comparisontoregu larin sulin ,lispr ope aks more rapidly,ach ie veshighe rbloodin sulin con cent rationsmore rapidly,an dhasbeen shown tolower postprandialglu cose lev els andde creas erat esofh ypog lyce mia(13,14, 15,16,17).Th eimpact oflispr o comparedwithre gularinsu linonleve lsofglycosylate dhemoglobin(HbA 1 c )has b eenv ariable (18,19,20, 21,22,23).Howeve r,lispr oprovidesmore flex ibilityforpatie ntsatme altimesbe cause it d oes notn eedtobeadministere d30minu tesbeforeamealandth edosecan readilybeadju stedforchange s inth ecarbohy drate con ten tofth emeal.Randomizedcont rolledprospectivet rialsh ave demonst rat ed th atlisp roison eoft hepr eferre din sulin sforinsu linpu mpt herapywithcontinu ou ssubcu tan eou sin sulin infusion(CSII)andresu lt sin lowerHbA 1 c le velsan dlessh ypoglyce mia(24, 25, 26).Lispromust beuse d withcaution in patien tswit hgast roparesisbecauseofit srapidonsetof act ionandth epot ent ialforearlypostpr andialhy poglycemia.Patien tswit hgast rop aresiscan delayth e P. 661
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mealin sulin in je ction unt ilafte rthe yhav econ sumedth eme altor educe t heriskofhypoglycemia. Insu linaspart isanother very-r apid-acting insu linanalogue .Similartolispro,it isabsor bedvery rapidly aft ersubcu tan eousinjection ,re sultin gin higher peak conce ntr ation scompar edwit hth oseachieved with reg ularinsulin(27).Trialscomparin gin sulin aspartandregu larinsulininpat ie ntswithty pe1diabe tes showsignificantlyredu cedHbA 1 c levelswit hnodiffe rence in thefr eque ncyofhypogly cemia(28, 29,30). Int ype2diabetes, in sulin aspar tiscomparable tor egular insu lin, wit hnosign ifican tdifferen ceinHbA 1 c levelsor freque ncyofhypoglycemia(31).Bot hinsulinlisproan din sulin aspartapp eart obeassociated withalowerincidence ofnoctu rnalh ypog lyce miath anr egular human in sulin .Forth esere asons,lispro an daspartar ethe in sulin sofch oiceforusebe fore mealsinmost treatmentr egimen sand p articular lyin multipledailyinjectionthe rapy (13, 14,15,16, 17, 19,20,21,23, 28,29,30).Th esafet yan defficacyoft he use ofas partinC SIIhave alsobe ende monstrated(31a).
SHORT-ACTING HUMAN INSULIN: REGULAR

Asme ntion edearlie r,subcu tan eouslyin jectedr egularinsu lin, becau seofitsr elativelyslowrateof abs orpt ion, isun abletomimicph ysiologicinsulinsecre tionfollowin gameal.Re gularinsu linh asan onsetofact ion15to60minu tesaft erinjection ,ape akeffe ct2to4h ou rsafte rin jection ,an dadu ration ofaction ran gin gfrom5t o8hours(11).Givent hesh ort -acting nat ureofregu larinsulin,itisused primarilyasamealtime in sulin .Ther efor e,re gularinsu linsh ou ldbeadministe redapprox imate ly30to45 min utesbe fore amealin or dertomatcht hekine ticsofin sulin absorptionwithth epeakofcarboh ydrate abs orpt ionaft erth eme al(11).
Basal Insulins
INTERMEDIATE-ACTING HUMAN INSULINS: NPH AND LENTE
BothNPHandlent ein sulin sare modifiedintoasu spen sionformt odelay theirabsorp tionfrom subcu tan eoussites, t her ebyprolongin gtheiraction. NPHin sulin ,firstdev elopedin1946,h asalonger dur ationofaction t hanregu larinsulin(12).Itsonse tofactioniswithin2.5to3h ou rsofinject ion, with ape akaction5to7hour safterinject ionandadu rat ionofactionbetwe en13an d16hours(12). Lente insulin,th eothe rin termediate -actinginsu lin, wasfirstintroduce din the 1950s. Itson setofactionis similartothatofNPHat2.5h ou rs,itspeakactionis7to12hoursaft erinjection,anditsduration of act ionisupto18hours(12). Given themor eprolonge dactionofNPHandlen teinsulins,t heyaren ot idealfor con trollin gpostprandialserumglucosele vels.Whe ngiven atap propr iatetimes,th eseinsu lins ar ereason ablyeffect ive inloweringfast in gplasmaglu cose and p redinne rplasmaglucosele vels(11). The sein sulin sare usedasthebasalin sulinsan dare n ecessaryforade quat eglycemiccontr olin type1 an dtype 2diabet es.Cu rren tly,NPHinsu linisthe on lyinte rme diate-actinginsulinav ailable forth epen deliverysyst em.
LONG-ACTING HUMAN INSULIN: ULTRALENTE

The r oleoflong-actinginsulinist oachievebasalin sulin cov erage with are lativ ely smallor n o pharmacologic/biologicpeakaction.Itsonse tofactionis4h ou rsaft erinjection ,itspeakaction isat8 to10hours, anditsdu rationofaction isu pto20h ou rs(12).Inclinicalpractice, itsbiologicaction app earst obesimilart oth atofin ter mediat e-act in gin sulin .NPHan dultrale ntepr ovidesimilarglycemic controlwhen u sedasthebasalin sulin in amultip ledailyinjectionreg imenwithlisproasthe mealt ime insulin(32).Most patien ts(75%)r equireonlyoneinjectionofbasalinsulinperdaygivenatbedt ime (32).However ,NPHseemstoprovid easligh tlybette rdailygly cemicprofileth an ultralen teinth ose req uirin gtwoinject ionsofbasalinsu linpe rday(32).
LONG-ACTING INSULIN ANALOGUE: GLARGINE

Glargineisalon g-acting insu lin analogue thatwasdev elopedinanat tempttoprovide amore con stan t levelofinsu lint han thatach iev edwit hth ehu manin ter mediat e-an dlong-actinginsu linpre paration s (10,33,34, 35,36,37,38). Glar gin ehasahighe risoelectr icpoin tth anh umaninsu linandpre cipitatesin th eneu tralen viron me ntofsubcut an eou stissue, g ivingititsprolonge dduration ofac tion (10,33,34, 35,36).Glargineisabsorbe dmoreslowlyth ant heh umanlon g-act in gin sulin preparations, withnopronoun cedinsulinpeaks,decr easingt heriskofnocturn alhypoglycemia(33,34,36,37, 38). Insu linglar gin ehasagre ater affinitythanh umaninsu linforinsulin-like growt hfactor1(IGF-1) rece ptors,an dithasb eensu ggeste dthatthismayleadt oincre asedmitoge nicpot entialincelllinesrich withIGF-1rece ptor s(39).Howe ver,t heclin icalsign ifican ceofth ish ypothe sisisstillunk nown(39). De temir isanother long-actin ginsulinan alogu eth atwasd evelope dusingadiffer entapproach binding toalbumin .Analiphaticfatty acidhasbe enacylatedt oth eB29amin oacid, and t heB30aminoacidhas bee nremoved(39a). Th isr esultsinrev ersible bin din gbetwe enalbu minandth efatt yacidacylat edto th ein sulin .After in jec tion, 98%oftheinsu linisboundt oalbu min. Th egradualre leaseoftheboun d fractionfromalbumin allowsfort hesu staine d,prolonge dactionofde temir ( 39b ).Thetime-act ionprofile ofinsu lin d etemir isch aracterizedby apeakactivityat 6to8h ou rsafte rin je ctionandpr olon ged24- hour d urationofaction(39b).Dete mirhasbeen approvedforreleaseinEu rop ean dhasre ceived pre liminaryap prov alfr omthe FDAin t heU nitedStates.St udiestodate h ave shownlesshypoglycemia
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an dle ssvariat ioninbloodglucoselevelswit hdet emirasbasalinsulinininten siv eregime nscompared withNPH(39c, 39d ,39e).
Premixed Insulin
Pr emixe dpreparationsofsh or t-an din termediate -actinginsu linsareavailablein awideran geofratios (90/10to50/50) (11). Themost commonlyuse dpremixe din sulin is70/30,wh ich con tains30%shortact in gand 70%inte rme diate-actin gin sulin .Apremixedinsulinof75%NPL(n eut ralprotaminelispr o) an d25%lispro,HumalogMix75/25,alsoisav ailable (40). HumalogMix75/25p rov idesarelative ly rapidpe akininsu linactiv ity, similartolisproalon e,andth eNPLprovidesbasalcove ragesimilart oth at ofNPH(40).Thisallowsimprovedpostpr andialglycemiccont rolcomparedwithth atoffered by70/30 insulin(41,42).Apr emixedinsu linof30%aspar tand 70%protaminatedinsulinasp art(NovoL ogMix 70/30)isalsoav ailable .LikeHumalog Mix75/25,Nov oLogMix70/30providesimpr ove dpostp ran dial glucosecontrolandlessh ypoglyce miath an70/30insu lin(42a,b). Use ofpre mixedinsu linavoidsth epot ent ialproblemsofself-mixingandred ucesth enu mbe rofste ps beforeinjection,t here byredu cin gthe numberofpossibleer ror s.Thepr emixedinsu linsarepre ferre dby elderlypatie ntsandth ose with visu alor fine -motorimpairmen t(43).Howe ver, p remixe din sulin sdon ot per miteasyadjustmen tofmealtimean dbasalinsulindosesan dare in appropriat eforpatient swith type 1diabetes. Th eyarevalu ablean dfrequ entlyu sedin the treatme ntoftype2diabete s. P. 662
GOALS OF THERAPY Type 1 Diabetes

Insu linde ficien cyisth ehallmarkoftype 1diabet es.Insu linr eplacement ises sentialforlifeinpeople withtyp e1diabe testoavoidaprogressivecatab olicst ateandke tosis.Wh enu sedproperly, insu lincan eliminat eclin icalsymptomsofhype rglycemia,prev entdiab eticketoacidosis, r estorelean bod ymassand exe rcis ecapacity ,decre aset heincidenc eofcer taininfect ions, andimprov ethe patien t'ssen seofwe llbeing. Inad dition,th euse ofinsu linininte nsivetre atment regime ns,witht hegoalofachievingne arnormalplasmaglu cose con cent rations,de laysthe on setan dslowsthe progression ofmicr ovascular complication sin patien tswit htype 1diabet es(44,45).Table 39. 2itemiz essomeofthe p rin cipalg oalsof insulinth erap y.TheDiabete sControlandC omplicationsTrial(DCCT)wasamu lt icen ter, ran domized controlle dtrialcomparingmultipledaily in je ctiont herapyorcon tinuoussu bcutaneousinsu lininfu sion (inten sivethe rapy )toth erapywit honetotwoin je ctionsp erday (c onv entionalth erapy)in 1,441 pat ie ntswithty pe1diab etes, followedforamean of6.5y ears(44). Th einten sive-th erapy grou p,who ach ie vedsignificantlylowe rHbA 1 c lev elst han patien tsin the con vent ional-th erapygroups, h adarelative riskredu ction of76%forde velopingr etinopath yan da54%relativeriskre ductionfor prog ression of ret in opathy (44). Theinte nsive-th erapygroupshada39%relativer iskre ductionfordevelopin g microalbuminur iaanda54%r elativeriskredu ction forpr ogre ssin gtoalbumin uria(44).Th ein ten sive th erap ygroupalsohada64%re lativeriskredu ction forde velopingn europathyorexp eriencing progressionofd iagnosedne uropath y(46).Thu s,inte nsiveinsulinthe rapy ,whichre sultedinalower HbA 1 c le vel,wasassociat edwit hast atisticallyandclin icallysignificant reduct ioninmicr ovascular complication sin the int ensive-t herapygroup. Afollow-upstu dyoft heDCCTgr oup ,the Epidemiologyof DiabetesIn terv entionan dComplication s(EDIC)stu dy,showedth att heriskre ductionin microvascu lar complication sfrominten siv ethe rapyp ersistsfor atleast 4yearsdespiteincr easingh yperglyce mia(47). Howe ver, thebe nefitre latedtomacrovascu larcomplication sislessclear(48). Th eDCCTshoweda nonst atistically sign ifican t41%re lativeriskredu ction formacrovascularcomplicationswit hinten sive th erap y;however, the st udywasnotpowe redtodete ctadifferen ceinmacrovascu lareve nts, andt he nu mbe rofth esee vent sin thet rialwaslow(49).Ther ewasalsoare lativ eriskredu ctionof40%for deve lopingelevatedlow-d ensitylipoprotein(LDL)cholester olle velsin theint ensive-t herapygroup(49). Arece ntmeta-analy sisofin tens ive t her apyintyp e1diabe tesshowedth atint ensiveth erapydecre ased th etotalnu mber ofmacrovascu lareve ntsbu tshowednosignificante ffe cton the numberofpat ien ts affe ctedoron mortalitydu etomacrov ascular dise ase(48). Th ene edfor in sulin int ype1d iabetesfor sur viv alisap pare nt.However ,th eappropriat euseofinsulinwit hth egoalofach ie vin gnear-normal seru mglucoseconce ntration shasbe nefitsbeyond t hoseofmere survivalandsymptomrelief. TABLE 39.2. Goals of Insulin Therapy
1. 2. 3. 4. 5. 6.
Eliminatesymptomsofhyperglycemia Preventdiabeticketoacidosis Arrestseverecatabolicstateandregainleanbodymass Reducefrequentinfections Decreasefetalandmaternalmorbidityinpregnancy Preventanddelaymicrovascularandmacrovascularcomplications
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The d egree ofglucoselower in gtobe sou ghtde pendsonman yfactorsan dshouldbeindividualizedfor eachpat ie nt.In the DCC T,the meanHbA 1 c levelach ie vedbyth einten siv e-the rapy g rou pwas app rox imate ly7.2%comparedwithame anof9. 0%in theconv entional-th erapygroup(44).The refore, th emostre centclinicalpract icer ecommendation sfr omthe AmericanDiabe tesAssociation state thatthe primarytr eatmen tgoalint ype1d iabetessh ou ldbe bloodglu cose con trolapprox imating t hemedian valu each iev edinthe in tensive -ther apygroup (50). Table39.3ou tline stheglycemicgoalsfromthe Ame ricanDiabete sAs sociation.In fact,anyimp rov eme ntinbloodglucosecontrolwillslowt he deve lopmentandpr ogre ssionofmicrovascu larcomplication s.Howe ver, one mu stcon side rthe risk sof hy poglycemiawhen aimingforalowHb A 1 c leve l. Th einten siv e-tre atment grou pin the DCC Thada th reefold g reat erriskofse vere hypogly cemiacompare dwith the conv entional-th erapygroup,bu tth e rateofh ypogly cemiade creasedwit htime (44).Ther efor e,ver ytightcontr olshouldnotbeattempted in pat ie ntsu nwillin gor u nable toparticip ateactivelyin the irglucoseman agemen t.Patient swith hy poglycemiaun awar enes sorth ose suscept ibletoperman ent in ju ryfromh ypog lyce mia,su chaschildre n orthe elde rly,can bemanagedwithinte nsiveth erapywith mu lt ipledailyinjection s(MDI)orCSIIbut shouldhaveh igh erglycemict arget stoavoidh ypoglyce mia(51,52, 53).Appropriatediab etese ducat ion an dself-monitorin gofbloodglucoseareinvalu ablecomponen tsofr educingh ypoglyce mia(51, 53, 54). Clinicalju dgme ntandcommon sense arer equiredt odet ermin eth etar getpre meal, post pran dial, and bedt imeglucoselevelsfor ind ividualpatient swith ou tplacingth ematun duer iskforhy poglycemia (50,51,53, 54). TABLE 39.3. Target Glycemic Control for Nonpregnant Adults with Diabetes P. 663
Glucose level, mg/dL (mmol/L)
Measurement
Normal
Goal
Additional action suggested
Wholeblood(capillarybloodglucose) Averagepreprandialglucose <100(<5.6) 80120(4.4 6.7) 100140(5.6 7.8) <80or>140(<4.4or >7.8) <100or>160(<5.6or >8.9)
Averagebedtimeglucose
<110(<6.1)
Plasma Preprandialglucose <110(<6.1) 90130(5.0 7.2) <180(<10.0) <90or>150(<5.0or >8.3) <110or>180(<6.1or >10.0) <8%
Postprandialglucose(12hafter beginningofmeal) HbA1c HbA1c,glycosylatedhemoglobin.
<120(<6.7)
<6%
<7.0%
Copyright2004AmericanDiabetesAssociation.FromAmericanDiabetesAssociation.Standardsofmedical careforpatientswithdiabetesmellitus.Diabetes Care2004;27[Suppl1]:S15S35.Reprintedwithpermission fromtheAmericanDiabetesAssociation.
Type 2 Diabetes
The initialtre atment forty pe2diabe tesge nerallydoesnotinclude insu lin. Diet, exercise, weigh tloss, an dor alhypogly cemicag entsareinitiallyadequ ate t herapiesfor achievingglyce miccon trol. Howeve r, insulinisin dicatedforpat ien tswhoare unabletoachieve goodglycemiccontr olwith acombination of oralage nts,diet ,an dexerc ise(55). Th egoalsofinsu linth erapyin type2diabete sare s imilar t oth ose fortype1diabete s.Thee limination ofclin icalsy mptomsofhy perglycemiaisanimportantgoal.In add ition,maintain in ggoodglycemicc ont rolre ducesth eriskofmicrov ascular andmacr ovascular
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complication s.The U nitedK in gdomProspect ive Diabet esStudy (UKPDS)wasamu lticen ter, ran domiz ed, controlle dstudyde sign edtoestablishwh eth erinten siv ebloodglu cose con trolre ducedt heriskof macrovascu laran dmicrovascu larcomplication sin patien tswith type 2diabet es(56)and t ocomp aret he relat ive effectiven essan dsafet yofdifferen tpharmacologicapproach estothe rapy. TheUK PDSst udied 5, 102patie ntswitht ype2diabetesandfollowe dthe mforan aver ageof10year s(56).There wasa12% red uction in diabete s-relate dendpointsanda25%riskredu ction in microv ascular endpointsforthe inten siv e-th erapy grou p(56).The rewasn osignificant d iffere ncewith in t heinte nsive-th erapygroup (i.e. ,nodiffe rence betwee ninsulinan dsulfon ylu reas).AsmallerJapan esestu dyalsoshowedsig nificant red uction sin microvascu larcomplication swith improvedHbA 1 c le vels(57).Alt hough t heorigin alan alysis oft heU KPDSdatashowedan on statisticallysign ifican t16%risk r educt ion(p=0.052)inmacrovascular complication swith in ten sive the rapy(56), arece ntanalysisshowedasignificant relation shipbetwe en macrovascu larcomplication sand h yper glyce mia, asme asu redbyth eupd atedmeanHbA 1 c (58,59).For eve ry1%red uction in updatedmean HbA 1 c ,the rewasa14%riskre ductionfor myocard ialinfar ction (p <0. 0001),a12%riskredu ctionforstroke(p=0.035), an da43%r iskr educt ionforamputation or deathfromperipher alvascu lardise ase(p<0.0001)(58). Int heUK PDS,the in tensive-t her apygroupachieve dame dianHbA 1 c value of7.0%,compared with 7.9% inth econ ven tional-t herapygroup(56). Th issu ggestst hat thepr imary t reatme ntgoalfor p atient swith type 2diabe tesshouldbesimilartoth atforpat ien tswithtyp e1diabe tes.Th etar getHbA 1 c shouldalso beasclosetonormalaspossiblewithout p lacin gthe p atient atu ndue risk forsev ereh ypog lyce mia(60). The reisacon tinuousr elation shipbetwee nth erisksofmicr ovascularcomplicat ionsandglycemia,such th atforan ydecre aseinHbA 1 c ,th ereisacorre spon din gredu ction in t heriskofcomplications(58, 60). Although t heU KPDSprovide dsuggest ive datatos upportth eclaimth ataggressiveglycemiccont rol red ucesmacrovas cularcomplication s,alan dmarkstu dyfromDenmar kprovide dthe b esteviden ce,th us far ,thatagg ressiveglycemiccontr ol,inth econtex tofamultifact orialappr oach,canre duce car diovas cularoutcome s(60a).On ehu ndre dandsixty p atient swith type2diabete sand microalbuminur iawererandomized t ore ceiveinten siv emu lt ifactor ialtr eatmen tor con vent ionaldiabe tes car ebyth eir familyphysician orspe cialist.Th etar getHbA 1 c levelin the in tensivegr ou pwaslessthan 6. 5%.In addition t ointe nsiveglycemiccont rol,bloodpre ssure andch oleste rollevelswere aggre ssive ly tre ate d.Afterame anfollow-upof7.8year s,th ein ten sive lyt reat edgroupex perience da53%relative riskredu ction (p=0.007)in thecompositepr imary out comeofcardiov ascular deat h,myocardial infar ction, stroke,r evascu larization,andamput ation.Micr ovascularcomplicat ions, includ in g ne phropat hy,r etinopath y,andau tonomicneu rop ath y,were alsosignificantlyre duced. Thisstudy providedfur ther supporttothe recommend ation foraggressiveglyce miccon trolamongpatientswith diabet es. Aggre ssive ther apywithinsu lininpatie ntswitht ype2d iabetesappearstobepart icu larlyin dicated followingmyocardialinfar ction. Th eDiabetesMellitu s,Insu linGlucoseInfu sioninAcut eMy ocardial Infarction (DIGAMI) t rialsh owe dthatin ten sive in sulin the rapyfollowin ganacute myocar dialinfarction decr eases p atient mortality(61,62). Th euse ofanin sulin -glucosein fusion foratleast24h ou rsafte ran acu temyocardialin farct ionfollowe dbyinten siv ein sulin the rapyr educe din -hospit alall-causemor talit y by58%(p<0.05)and1-year all-causemor talityby52%(p<0.02)(61).Th eben efit p ersistedfor seve ralyearsafte rthe even t(62).Ofinter est,t hemostp rofoun deffectwasseeninpatient swith the lowest apparent risk atth etime ofpres entation (61) .
TREATMENT STRATEGIES
The appropriate in sulin regimen for anindividualpatie ntsh ou ldt akeint oaccoun tth epat ien t'slifestyle, age ,motivation, gene ralhealt h,se lf-man agement skills,an dgoalsoftre atment (18,63).Pr iorto initiatinginsu linth erapy,th epat ien tshouldrece ive appropriat eedu cation and supportreg ardingth e car ean duseofin sulin ,th erecognition and treatme ntofhypoglycemia,an dthe man age men tofsick day s(18,63).
Type 1 Diabetes
Asprescr ibe dbydiabetologistsanden docr in ologists, thecommonlyused insu linp rot ocolsforindivid uals withtyp e1diabe tesar eMDIan dCSII.Th eDC CTcle arlyshowsthatinte nsivethe rapy with MDIor C SII coupledwithth eappr opr iateedu cationan dfrequ entse lf-mon it oringofbloodglucose(SMBG)ach ie vesa significantlowe rin gofHbA 1 c levelsan dredu ction in t heriskofmicrovascu larcomplication scompare d withth atachievedwith lessfre quen tinjection s(44).Un fort unately,e veninth einte nsivelytreated cohortoft heDCCT, after t hecomp let ionofthe clinicaltrial,glycemiccont roldete riorated, pointing out th enece ssit yofcontinu in geduc ation and closeclin icalsu rveillance(48).Th erefore, MDIorC SII,along withapprop riateed ucat ion,coun selin g,an dsupport, isth epre ferredt herapyforpatien tswit htype 1 diabet es.
MULTIPLE DAILY INJECTIONS

Itisbesttoth in kaboutinsu lint herapyaccordingt oth epharmacokin eticsofth eav ailable in sulin pre parationsandth ephy siologicsecre tionofin sulin in in div idu alswith ou tdiabet es.Thu s,wete ndto
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th in kofbasalin sulin admin ist rationfor theover nightandpostabsorpt ive state sandb olusinsulin administrationformealtimesasan atte mpt t ore produceacute -ce llinsulinrelease.Thismealtime -basal routine usuallyre quiresat le astfourinjectionsperd ay.Arapid -actingmealtime in sulin analogu e(lispro orin sulin aspart)isthepr eferre din sulin beforeeachmeal.Asdescr ibe dearlier,t herapid ons etof act ionoflisproor ins ulin aspar tproduceslesspostprandialhypoglycemiaan dlessn oct urn al hy poglycemiacomparedwithre gularinsu lin, wh ich makesth emidealforanMDIregimen. NPH, ultrale nte ,or glarginecanbeu sedasth ebasalin sulin ,classic allyatbedtime;however ,diffe ren t reg imensarebeing u sed(32,37, 43).Itislikelyth atglarg in e(an dperh apsdet emir)willbecome the bas alins ulin ofchoicefor MDIther apybe cause ofth eirpharmacokin eticprop erties. P. 664 Glargine, asthe basalinsu lininaMDIregime n,h asbeen associatedwith improvedfast in gbloodglu cose levelsan dle sshypogly cemia(36, 37).Theadministration ofar apid-act in gin sulin analogue (lisproor insulinaspart)pr iortoeach mealcont rolspostprandialseru mglucoseconcen trat ions, andt he inter med iate-orlong-actinginsu lincontr olsfastingse rumglu cose con centr ations.Asshowninth e DC CT,th eriskofh ypogly cemiaisgreater with MDIthanwithlessfreq uen tin je ction s,primarilybe cause oft hetigh terglycemict arge tsan dimprovedcontr olachiev ed(44).The refore,patiente ducation, selfmon itoring, andaself-dire ctedman agemen tapproach are fundame ntaltoach ie vin gsucce sswith this th erap y.Bot hclin ician and p atient hav etobepreparedt omakeadjustment stot here gimen as ne cessar y,includingad ju stme ntofgly cemictargetst oavoidseve rehy poglycemia.Sincelisproand insulinaspartaresuch rapidlyact in gin sulin s,asec ond in jec tionofNPHorultralen tebe fore b reak fast mayber equiredt oprovidebasalin sulin ove rthe d ayan dbett ercontrolofpre din ner se rumglucose concen trat ions. Howeve r,acont rolledclin icaltr ial(32)de monstr atedt hat mostpat ie nts(75%)requ ire d onlyon ein jection ofinte rme diate-actin ginsulin.The actu aldose sofinsulinuse dmu stbead ju stedonan individ ualbasis.However ,the followingisane mpiricalguideforchoosinginitialin sulin dos esforMDI (Fig. 39.2). Th eap prox imate tot aldailyinsu lin(TDI)requ ire me ntsforan in dividualn ot previou sly rece iving in sulin are0.5u nits/kg. Ift hepatientisalreadyre ceiv in gin sulin ,the TDIisthesu mofallt he cur rent in sulin dose s.Approximat ely 60%sh ouldber apid-acting mealt imeinsulin(lisproorin sulin asp art)given beforeeachmeal.The breakfastmealusu ally require sadisprop ort ionatelyhigher dose of insulinth anothe rme alsfort hecaloriescon sumed.Th eremaining40%oft heest imate dTDIshouldbe givenasthe basalinsulin(NPH, ultralen te,orglargin e)atbe dtime. Closese lf-mon it oring ofblood glucosean dfrequ entadjustment saren ecessarytoopt imizeglycemiccontr olwith the fewestep isodesof hy poglycemia.
Figure 39.2.Initiationofmultipledailyinjectioninsulintherapy(fourinjectionsperday).(FromChengAY,Zinman B.Insulinfortreatingtype1andtype2diabetes.In:GersteinHC,HaynesRB,eds.Evidence-based diabetes care. Hamilton,Ontario:BCDecker,2001.)
Many differ entMDIregime ns,some ou tline din Table39.4, havebeen used b yvariousindivid uals. Howe ver, allMDIre gimen sfollowthe samebasicprinciples.Mealtimein sulin s(lispro,insulinasp art, or reg ular)areuse din combin ationswithbasalin sulin (NPH,ultrale nte ,or glargine)inanat temptto simu latephy siologicin sulin secret ion. TABLE 39.4. Various Multiple Daily Injection Regimens
Before breakfast MI MI+BI MI+BI
Before lunch MI MI None
Before dinner MI MI MI
Bedtime BI BI BI
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MI+BI
MI+BI
MI+BI
None
MI,mealtimeinsulin(lispro,aspart,regular);BI,basalinsulin[NeutralProtamineHagedorn(NPH),ultralente, glargine].
TWICE-DAILY DOSING
Twice -daily (BID)injection sare notrecommen dedfor patien tswit htype 1diabet es.Such are gimen providesne ith eroptimalglycemiccon trolnorsu fficient flex ibilityforadju stme ntsofin sulin dose .Itis importanttonotet hat NPHgiv enbefored in nerincr easest heriskofhypoglycemiaduringth enight ;thu s bedt imeNPHinsu linismoreappropriateboth tocont rolfast in gblood glu coseleve lsandtoredu ceth e riskofn oct urn alhypogly cemia(11).
ADJUSTMENTS TO INSULIN FOR EXERCISE

Exe rciseise ncouragedforpatien tswit htype 1diabet esan dshouldbepre scribe don the b asisofth e pat ie nt'sfunct ionalstatusandpre sence ofcomplication s.Patient sreceivinginsu linmayex perience hy poglycemiadur in g,immediatelyafter, orman yhoursafterex ercise.Thiscan beav oidedbyadjusting insulinth erap yandn utr itionalintaketoaccommodatee xercise. It isess entialforthep atient tocollect self-monitoredbloodglucosedatatodet ermin ehisor h erre spon setoexer cise .Theglycemiclev elatth e startofe xercise, p reviou sly measure dresponset oex ercise,andinten sit yan ddurationofplann ed exe rcis enee dtobe con side redtomakeappropriatech an gesin in sulin dose ort oincre asefoodint akeas ne cessar y(64).
Type 2 Diabetes
Insu linisindicate dwhen adequ ate glyce miccon trolcann otbe achieve dwit hdiet,e xercise,andmultiple oralage ntsinpatie ntswithty pe2diab etes(55,65). Insulincan beuse din con ju nctionwithoral hy poglycemicagen tsor alon e.Oralh ypog lyce micagen tsincludebiguanides, sulfony lu reas, -glucosidase inhibitors,th iazolidin edion es,andmeglitinides. St udieshavesh ownt hat regime nsofinsu linplusanoral age ntareequ iv alentt oorbett erth aninsu lin-onlyre gimen sinsomecir cumstan ces(55,66,67, 68,69,70). Infact,addin gme tfor mintoin sulin for P. 665 pat ie ntswithpoorlycont rolledtype 2diabet eslower sg lu coseandlip idleve lsmore effectivelyth an increasingth ein sulin dose alon e(67).Differe ntcomb in ation sofinsu linandoralage ntshavebe enu sed totreattype 2diabe tes.Acommon ly usedre gimen isbed timeNPHinsu linincombination with me tfor min withbre akfastan ddin ner. Thiscombin ationprovidesimprovedg lyce miccon trol, lessh ypogly cemia, and lessweightgain compar edwit hsomeoth erbedt imeinsulinregimens(55, 66). Insu linglargine can b e use din placeofNPHin sulin atbed timeincombination with oralagen ts(38).Infact,bed timeglarg in e cau seslessnoctur nalhy poglycemiaan dprovide sbette rpostdin ne rglu cose con trolcomparedwith bedt imeNPH(38).An ot hercommonlyusedcombin ationregimenisBIDdosin gwit hinter med iate-ac tin g insulingivenint hemorn in gan datbe dtimeincomb in ation with me tfor min.Th ethiaz olid in edion esalso havebee nstu die dforpatient swith type2diabete s,an dagen tsfromth isclassofdru gsarecu rren tly beingu sedasmonother apyorincombinationt herapy(68,69,70, 71,72).The sedru gsofte nare refer red toasinsu linsen sit ize rsan dactth rought hepe roxisome p roliferat or-activate drecep tor -(PPAR),a nu cle arre ceptorth atre gulate sthee xpressionofse veralge nesinvolv edinglucosean dlipidmet abolism (71,72). Th eystimu lateadip ogen esis,red uceplasmatr iglycer ide andfre efatt yacidcon cent rat ions,and improveinsu linse nsitivit y(71,72).Ininsu lin-t reatedpatie ntswithty pe2diab etes, theadditionof th iazolidin edion essignificantlyimprovedglyce miccon trolandallowe dforasign ifican tredu ction ofdaily insulinrequ irements(68, 69,70). Insu lin-onlyre gimens canalsobeuse din type2diabete sin amann ersimilartothatuse dfort ype1 diabet es.Itisimportanttonotet hat in sulin d eficien cyin type2diabete sispr ogre ssive ,an dthe like lihood t hatapatie ntwillrequ ir ein sulin con tinue stoincr ease over time. BI Ddosin gregime nscan be use din type2diabete s.Freque ntly,pr emixed 70/30insu lin(consistingof70%NPHinsu linand30% reg ularhu maninsu lin)isgiv eninth emorn in gand b efor edin ner .Thisregime nissuboptimalbe cause NPHinsu lingiven befor edinne rcan leadtohypogly cemiad uringth enight .Howe ver,t hisregime nis simpleandmaybeth ebest optionforpatien tswhohavedifficultymixin gin sulin .Usu ally twoth ir dsof th etotaldailyin sulin isadminister edin the morningandth eremainingone thirdisgive ninth eeven in g forBIDdosin gregimens. Th epremixedinsulinan alog ues(HumalogMix75/25or Novolog70/30)can be use din thesame fashion,bu tit isinjecte dimme diatelybeforeameal,allowingalittlemoreflexibility (41,42). Th ispr emixedinsu linpr ovidessimilarover allglycemic cont rolwithimpr ove dpost pran dial glucosecontrolandlessn octu rnalh ypoglyce miacomparedwith BIDdosin gwith 70/30in sulin ( 41, 42). The r oleofin sulin glargineforprovid in gbasalrep laceme ntwithlessn octu rnalh ypoglyce miah asbee n
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establish edintype 2diabet es(38).
COMMON DELIVERY SYSTEMS

Seve ralin sulin delive rysyste msarecommon lyu sed,andch oicesshouldbemade on thebasis of per son alprefere ncesandn eeds.Part icu laratt ent ionsh ouldbepaidtoindividualswh ohaveimp aired vision, problemswithmanu aldext erity,ordifficu lty mixin gvar iousformu lation sofinsu lin.
Syringe and Needle

The t radition alin sulin delive rysyste misthe syringeandne edle.Thisdeliverysyst emisflexible ,allows dosagest obe adjuste dread ily,andallowssome ofth ein sulin formulat ionstobemix edfor fewer injection sperday.The limitationst oth isde liver ysystemare ther equiremen tfor g oodeyesigh tand fine-mot orskillst oen sure thatappropriat edose sofinsu linaredrawnan dadmin ist ered. Thevial, syringe ,an dnee dle sneed tobe availablewhe neve rin sulin admin istrat ionmigh tbere quired, andsome individ ualsmayfindth eapparat uscumbersome.
Pen Devices
Pe n-cartridgedev ice sarebe comin gmorep opu larthanth esyringe -and-n eedlesyst em.Replace able insulincar tridgescontain in g150to300un it sofre gular, aspar t,lispr o, NPH,orpremix edinsulinare use din thepe ndev ices. Thedoseisdiale din tot hede vice ,an dnee dle swith aver yfin egau gear eused tominimize t hediscomfortofin je ction. Th ismeth od ofinsulinadministrat ioniscon ven ien t,u nobtru sive , easytocarry, an dveryu sefulfor MDIregime ns.However ,in sulin scan notbemixe d,sotwoinjections ar enece ssary wh enboth rapid-act in gand int ermediate -actinginsu linsarereq uiredun le sspremix ed insulinsar eused (73).
Continuous Subcutaneous Insulin Infusion

Ext ern alin sulin infu sionpu mps firstbe cameavailable int heearly1980sandh ave evolve drapidlysin ce th en. L isproorregu larin sulin isst ore din arese rvoir ofth epumpan disinfus edthr ou ghacathe terinto at ran scutaneouscathet erplaced s ubcut ane ou sly(73). Apr eprogrammedbasalr ateofinsulinis delivered cont in uously.The patien tcanpr ogr amt hepu mpt oprovidemore thanonebasalrate ove ra 24-hourp eriodtobest mimicthe nee dsofth ein dividu al.The reiscomple teflexibilityinth etimingof mealsbecauseth ebasalr ate maint ainsglycemiccont rolan dboluse sofinsu linaredeliv eredbe fore the meal.The amou ntofmealt imeinsulingivencanalsobead ju stedaccording t oth epre pran dialblood valu e.Asinallint ensivet reat men treg imens, carefu landfre quen tself-monitorin gofbloodglucose levelsis e ssent ial. Ade quatesup port mus tbeprovidedforthep atient with CSII.Although either lispro, asp art, orr egularinsu lincanbeu sedforCSII,th ere isev iden ceth atlis proandaspartaresu perior to reg ularinsulininter msofgly cemiccontrol,postpran dialb loodg lu coseleve ls, andr iskofhypoglycemia (24,25,26, 31a).Th erefore, lisprooraspart isth epre fe rredinsu linforCSII. The rear esever aladvantagesoft heinsu linpu mpoverMDI.Patientsaresparedth ebur denof administeringMDI.Also,th epumpprovidesgre atflexibilitywithre specttome altimingan dexe rcise programs.In sulin -pumpthe rapy curre ntlyis t hemost physiologicwayofre placin gbasalinsu lin, becau se ratesofbasalinfusioncan bechanged t omatch diffe rent physiologicr equiremen ts. CSIIcarriessomepatientr isksanddisadv ant agesth ataren ote ncount eredwithMDI.Sin ceonlyshortact in gin sulin sare u sed, anyint erru ptionofinsulindeliv erybypu mpmalfun ction ,cath ete rblockage,or displacement ofth esubcu tan eou scath ete rcan r esultinar apiddete riorationincont rolan dthe deve lopmentofket oacidosis .Howev er,t hen ewerpu mpswithsafetyalarmsindicatin gin terr upte dflow havedramaticallyde creasedth ein cide nceofthiscomplic ation (73).Somestu die shav eshownth at inter rupt ionofCSIIusinglisp roisassociated with ane arlie ran dgreatermetabolicdeter iorat ionth an th atwithre gularinsu lin(74, 75).Howev er,oth erstu die sh ave notshownasignificant differ ence (76). The corre ction ofan yme tabolicde terior ation appe arstobefasterwithlisprot han wit hregu larinsulin (74,75,76). Specialatte ntion toself-careisessen tial toavoidsubcut ane ou sin fection s.Thesu bcutane ou scath etersh ou ldbe chan gedev ery2days. Some pat ie ntsfindth eext ernalpu mpcu mbe rsome. Curr ent ly, themainbarriertoCSIIu seist hesu bstan tial costofe quipme ntan dsupplies.C SIIu sedbyawell-trainedpatientcanbeaneffec tiv eme thodof providin gmoreph ysiologicinsulinrep laceme nt. P. 666
PRACTICAL ASPECTS OF INSULIN USE Storage

Insu linpr epar ation sare stableatroomtemperature .Insu lininu semaybeke ptatr oomte mpe ratu refor 30day s;h owe ver, ther emaybeaslightlossin pote ncyifthe same vialisuse dformor ethan30days (77).Ifpatie ntse xperience une xplainedde terior ationoft heirglycemiccontr ol,th eyshouldbeinst ructe d toin spectt heirinsulinan dpossiblytochan gevialsin an atte mptt oimpr ove con trol. Vialsofinsu linn ot inuse shouldberefriger ated .Ext remetemperatur esan dexcessagit ation shouldbeav oided. Th einsulin
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shouldbevisuallyinspe ctedbeforee achu seforchan gessu chasclumping,frosting, precipit ation,ora change inclar ity orcolor.
Mixing Insulin
Many in sulin regime nsrequ ir eamixt ure ofdifferen tin sulin formulat ionsadminister edat t hesame t ime. The sein sulin formulat ionseith ercan beadministere dastwoseparate subcut ane ou sin je ction sorcanbe mixe dforasin gle in je ction. Commercially availablepre mixedinsu linsmaybe appropriate forpatient s withtyp e2diabe tesiftheinsu linr atiomatc hesth epat ie nt'sin sulin r equiremen ts.Pende vice sdon ot allowformixinginsu lins, sotwoin je ction saren ecessary.However ,con ven tionalinsu linadministration withsyring ean dneed ledoesallowformixing .NPHan dregu larin sulin when mixedmaybe used immediate lyorstoredforfut ureu se.Similarly,rapid-actinginsu linanaloguesmayb emixedwithNPHor ultrale nte in sulin andu sedwithoutfearofs ign ifican tly chan gin gthe phar macokine ticsofeach componen t(77).Mixin gregu larin sulin wit hlente oru lt ralent eisn ot recommende dexcept forpatient s whoseglucoselevelsar ealreadywellcontr olle dwit hsuch amixtu re(77). Th ezincpre sentint helent e insulinscan bin dwit hth eregu larin sulin ,th ereby delayingitsonsetofactioninan unp redictablefashion (77).NPHinsu linsh ou ldn ot bemixedwith len teinsu linsbe cause zin cphosphatemaypre cipitate.In sulin glargine cann ot bemixed with oth erinsu linsbecause itisin solut ionatan acidicpHandwillprecipitate ifmixedwithpH-bu fferedinsu lin.
Insulin Injection Technique

The followin gdescriptionappliestotheconv entionalsyringe -an d-nee dleadmin istr ation ofinsu lin. Th e topoft heinsu linvialshouldbeclean edwithanalcoholswab.Ifthe in sulin isinsusp ension ,th evial shouldbege ntlyrolledbe tween theh an dstoe nsur ethatth esuspe nsion isun iformbeforeth esyringeis loaded.Be fore t heinsu linisdrawn in tothesyr in ge,anamount ofairequ altothedoseofin sulin should beinjecte din tothevialtoavoidcreatin gavacuum.Th eproperamount ofinsulinisthen drawn in tothe syringe ,an dthe airbubblesareexpe lled. Ift woinsu linty pesare tobe mixed, airshouldbeinjecte d intobot hbottlesan dthe clearrapid-orshort- actinginsu linsh ou ldbe d rawnfirst. Insu linsh ou ldbe in je ctedintoth esubcu tan eou stissue. Th eskinsh ou ldbeg entlypinch edbetwe enth e th umbandforefinge ran din je ctedataper pendicular angle. Th eplung ershouldbepu sheddown, the skinre leased, andth ene edlethe nwithdrawn. In thinpe opleorchildren, the need lemayn eedt obe insert edat a45-degre ean gle toavoidanintramu scularinjection.Painfu linjectionsmaybemin imizedby injectingth einsulinat roomt emperat ure ,makingsure the rear enoairbubblesinth esyring ebefore injection ,kee pin gmu scle sin theinject ionarear elaxed, pene trat in gskin quickly,an dnotreu sin gdull ne edles. Insu lincanbeinject edintosit eswit hthe mostsubcu tan eousfat ,whichinclude t heabdomen ,an terior an dlater alt high,b uttocks,anddorsalar eaofthe arm.Withinth eabd omen, acircle with a5.08-cm(2 in.)radiusar oun dthe nav elsh ou ld b eavoided.In je ctionint oareaswith littlesubcu tan eousfat may resu lt in in tramuscu laradministrat ion, wh ich ispainfulan dmayresu ltinfasterinsu linabsorp tion(78). Insu linisabsorbe dmorerapid lyandconsisten tly fr omthe abdome nthanfromt hearms, thighs, or but toc ks(79)andfromane xtremitythatissubsequ ent lye xercised, probablybyin creasin gbloodflowto th eskinan dperh apsbyloc almusclecontr action(77).Massageofalocalar eath ath asbee ninjecte d can in creasethe rate ofinsu linabsorp tion, ascan in creasedlocalskinte mpe ratu re. R ot ation ofinjection siteisimportan ttopreve ntlipohy pertr oph yorlipoatrophy(77). Rot ation wit hinon ear eais recommen dedasopposedtorotat in gtodiffere ntareaswith in thebody(77).
Blood Glucose Monitoring

Allinsulin-u sin gpatien tsshouldbeen cou rage dtope rfor mSMBG. With SMBG,patientscanev aluat ethe ir goalsofth erapyan dadjustt heirinsulinregimensaccor din gly. Awr it tenorelectr on icre cord ofth edaily bloodglucosele velsisaninvalu abletoolfor theph ysicianan dpat ien tfor guidin gadjust men tofthe insulinregimentoaccommodat eflu ctuations ininsu linr equiremen ts.Man yofth ecurr ent lyavailable glucoseme tersh ave memor y,whichsimplifie srecordkee pin g.The fr eque ncyofmonitorin gdepen dson th ein sulin regime nuse d.The useofMDIofinsu linre quiresmultipled ailyglucosemon it oring, specificallybe fore every mealandatbedtime.Specificsitu ations,su chaspr egnancyandillne ss,may makemor efrequ ent monitorin gnece ssary.
Implementation
One ofth emostcriticalcomponen tsfor successfu limplemen tationofanyinsu linre gimen ised ucat ion an dsupport. Thisisespe ciallytru eforimpleme ntingMDI orC SIIt herapy(44,50, 51). Allpat ien tsmust bee ducat edabout thebasic sofinsulinth erapy ,in cludingallthepr eviou slydiscu ssedpracticalt opics an daboutt hecomp licationsan dhowtoman age t hem.In addition, patien tsrece ivingMDIorC SI Ish ou ld learn howtose lf-man aget heirinsulinth erapy .They sh ou ld learnabou tme alplann in gand carbohydr ate count in g,howtoiden tifybloodglu cose patt erns, pot entialhy poglycemicsitu ations,andth eprinciple sof insulindoseadjust me ntsan dhowtomak eappr opriateadju stme ntsforexer cise ,sic kdays, andt rave l. The yshouldle arnh owt odev elopan dadjust theirownvariablein sulin dose scales(VIDS). Th esest eps
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willempower patien tsan dallowthe mtoactivelyparticipatewitht heirdiabet escar eteaminth eir th erap y.Edu cationan dsupportonacon tin uousbasisn otonlyimproveover allglycemiccon trolth eyalso can decre aseh ypoglyce miaan dot her adver seeven ts(48,50, 51, 80).
P. 667
COMPLICATIONS OF INSULIN THERAPY Hypoglycemia

Hypogly cemiaisth emostfre quen tan dfeare dcomplicationofinsulintre atment ,wit hpotent iallyser ious sequ elae(52,81). Poor t imingofmeals, exercise, andinsu lint reat men tcan le adtohypoglycemia(82). Pr eviou sepisode sofrep eate dsever ehypoglycemiarequ iringassistan ceor h ypogly cemicun awar ene ss ar eriskfactorsforsever ehypoglycemia(80,82).In theDCCT, thefr eque ncyofse vere hypogly cemia wasincr eased t hre efoldinth ein ten sive -the rapygr ou p(82).Theriskofsever ehypoglycemiawas inver sely relate dtoHbA 1 c levels(44,52,82). When sever ehypoglycemiaoccu rs,onesh ou ldinve stigate th especificcircu mstancesofthatepisode,poten tiallyr aisegly cemictargets, and improveedu cationto av oidfutu reepisodes(51,53,54, 80).Also,aperiod ofme ticulou spreven tion ofh ypoglycemiamay rev ersesome hypoglycemiaunaware ness(51).Th erat esofh ypoglyce miainty pe2diabe tesaremu ch lower thanthoseinty pe1diabe tes(56,57, 83).Inth eUK PDS, the fr eque ncyofmajorhy poglycemic episodeswas1.8%per year int heinsu lin-tr eat edgroup(56).In the st udybyOk huboetal. (57),no majorh ypoglyc emicepisod esoccu rred with in sulin -med iatedinte nsivecontrolover 7yearsoffollow-up. Howe ver, thesame gene ralprinciple applie sin type2diabete s;n amely,th eriskofh ypoglyce miais inver sely relate dtot heHbA 1 c (84).Most patien tsexper ie ncesymptomswh enth eirplasmaglucosele vels decr easet o60mg/dL(3. 3mmol/L ).Asplasmaglu cose lev elsd ecline furth er, moreseve resymptoms, specificallyn eur ologicsymptoms, appear(85).Acomplete d iscu ssionofhypoglycemiacanbe fou ndin Ch apte r40.
Weight Gain
Weight gainisanoth erpotent ialadverse effectofin sulin use. Inthe DC CT,th ein cide nceofbecoming overweight duringt hemedian6.5year soffollow-u pwas41.5%int heinte nsive-th erapygroups comparedwithonly26.9%inth econven tion al-the rapygr ou p(p<0.001)(82).Theriskofweightgain withinsulinuse in type2diabete salsoh asbee nwelldocument ed(56,57,82, 86).Inth eUK PDS, the insulingroupgain ed4. 0kg(8.89lb)moreth an theconv entional-th erapygroup(p<0. 001)(56). Seve ralme chan ismshavebee nproposedtoexplainth eweightgain associatedwithinsu linu se. Improv edglycemiccontr oldecre asesglycosuria, ther ebydecr easingt helossofcalor ie st hrough the ur in e(87).Thed ire ctlipogeniceffect sofinsulinonadiposetissue cont rib utet oweight gain(87).Also, increasinginsulindosesmaycau serecu rren tmildhypoglycemiathaton ly man ife stsitselfashu nger . Thismayresu lt in int ake ofexce sscalories. Th ere fore ,dietth erapy andwe igh t-lossprogramsin conjunct ionwithappropriate g lyce mictar getsar eext remely impor tan tin the man age men tofdiabetes. The r esultofweigh tgain ininsu lin-t reatedpatie ntsisfurth erinsu linre sist ance ,le adingtoth enee dfor more in sulin andapot entiallygreaterwe igh tgain. Obesityis assoc iatedwithdec rease dresponsiven ess toin sulin in mu scle ,liver ,an dfat(88)(discusse din detailin Chapter31).
Lipoatrophy/Lipohypertrophy
Inject ionofle ss-purifie din sulin in tosu bcut ane ou sfatcan sometimesle adtolocalizedloss ofth efat. Withth ecur rent more-pu rifiedinsu lins, thisproble misun common. Ifinsu linisinjectedint oth ear ea sur rou ndingth eaffe ctedsites, t hesu bcutaneousfatwillberest ore dove rseve ralmonth stoyear s. The opposit eoflipoatrophy, lipoh yper trophy,may occu ratsitesofin sulin in je ction .Loc alize dareasof increasedswellin gofsu bcutaneousfatcan d evelop with repeatedinject ion.Th esensitivitytopainmay decr easeint hese areas,an dmassesoffibroust issu emaydeve lop.In sulin absorption fromsitesof lipohyp ertrophy maybeerr atican dunr eliab le. Rotatinginject ionsitescanpre vent t hede velopmen tof lipohyp ertrophy .Thee xcesstissuewillre gressgraduallywithtime.
Atherosclerosis
Foranumber ofyears,th ere hasbe enacon cernt hat in sulin p romotesan dacceler atesathe roscler osis. Somestu dieshaveshownanassociation betwe enhigh in sulin lev elsandmacrovasculardisease (89,90,91, 92,93,94,95). Othe rshav eshownth ath yperinsu line miaisnotan in depen dent riskfactorfor macrovascu lardisease (96, 97,98,99, 100).Ith asbee nsug gestedt hat hyper in sulin emiamere lyr efle cts insulinresistance, whichiscloselyassociatedwithoth erriskfact orsformacrovascu lardisease (91,92,96, 97,98,99,100).The refore,insu linpr obably d oesn ot d ire ctlypromoteat her osclerosis. There is clearlyn oev ide nceth ate xoge nousinsulinuse isassociate dwith macrovascu lardise ase, and its app ropr iateadministrationsh ou ldn ot bediscou raged (60). TheU KPDSshowe dnoin creasein car diovas culareve ntsordeathine ith erth einsulinorsulfon ylu reagrou pthaninth econven tionally tre ate dpatien ts,despite higherplas mainsu linleve ls(56). Asacon seque nce, on ecan safelycon clude th atex oge nou sin sulin isn ot ariskfactorforath erosclerosis.
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Alternative Routes of Insulin Delivery

The b enefitsofachieving tigh tglycemiccontr olare wellest ablish ed,andth ein sulinan alogu esplayan importantrolein me etingapprop riatebolusan dbasalinsu linre quirement s.Howe ver,forth isgoaltobe ach ie ved,MDIofinsulinorCSIIar erequ ire d.Despiteth ewide spreaduseofin sulin pende vic esthatar e lesspainfu landuse smallergauge n eedles, in je ction-r elatedanxiety remainsacommonproblem(101). Sinceth e1920s,th ereh aveb eenman yatt emp tstofind alt ern ativerout esofinsu linde livery ,in clu ding oral,re ctal,transde rmal, nasal, an dpulmonaryroute s. Atte mptst ode velopaneffect ive oralinsu linbe ganin1923(102).Todate, t hese atte mpt sh ave been large lyu nsucce ssfulbecau seofthee xten sive enzymat icandche micaldegr adat ionth atoccur sin t he gas troin testinaltr actandth evar iable tran sit timeofthegastrointest in altract (103).R esearcher shave triede nclosinginsu linwithinmic rosph eres andconcu rren tadministrat ionofprot eolyt icen zyme inhibitors,withmin imalsucce ss(104).Re ctalinsulinhasbeen in vestigat edbutitsvariablepoor bioavailabilityandlackofpatien taccep tan cemaketh isrout eofde liver yimpractical(105). Tran sdermaldeliveryofin sulin isanat tract ive opt iongiven thee asyaccessib ilit yofskin;h owe ver, succe sshasbe enlimitedbe cause ofth erelat ive impermeabilityoft heskin. Met hodsusedt otr yto improvet hepe rme abilityofskinin clu deion tophoresis,low-fre quen cyultrasou nd,couplingwith transfer omes,andth eapplicationofph ot omech anicalwave s(103,106,107). Theinitialobse rvat ionsin an imalsan dhu manshavebee nen cou raging;h owev er,fu rthe rclinicalstu die sarer equired . Int ran asaladministrationofaer osolize din sulin seemedlike anothe ratt ract ive option.However ,the disadvantagesar ethatth esurfacear eaofthe nasalmucosaisrelat ive lysmall,atapproximat ely150 cm 2 ,an dabsorptionmu stoccurqu icklyorthe drugwillber emovedt oth eback ofth enasoph aryn xby th emu cociliaryclearance mech anismsand swallowed(108). Clin icalstu die sdemon strat epoor bioavailabilityandar apidbutsh or t-livedh ypoglyc emiceffect ( 108).Largedosesar erequ ir ed, despite t headdit ionofenh an cers,andpatie ntsex perience irr it ation tot hen oseandn asalcongest ion (108). Forth esere asons,intr anasaladministrat iondoesnotappear tobe aviableroute forde liver in g ae rosolize din sulin . Beginn in gasearlyas1925,inve stigatorshavetriedt odev elopaneffectivemeansofint rapu lmonar y deliveryofin sulin (108).Th esurfacear eaofthe alveolarregionoft helung isve rylarge(75to100m 2 ) an dish igh ly permeable(0.1m)(103,108).Itiswellvascularizedandh asmin imalmu cociliary clearance .Allthe sefeature sfavorthe lu ngasaneffe ctiv ean defficien tme ansofdeliv eringinsulin. Howe ver, effectivede livery ofae rosolize din sulin tot healve olarr egion ofth elu ngre quiresappropriate ae rosolpart iclesize,aerosolvelocity ,an din spir atoryflowrate(103).Cu rren tdelive rysyste msinclude dry-p owder in halat ionsyst emsandaqueousinsu linaerosoldevices. The d ry-powderinsulininhalation systemusesaholdingch ambertocap ture theinsu lincloudan dallow forslowdeepinh alations.C ompar isonwithsu bcutaneousre gularh umaninsu linde monstr ate dfaster onsetofact ionan dtime tope akeffe ct.Thed urationofactionwasbe tween thatoflis proandre gular insulin(109, 110).An ope n-label,proof-of-concep tstudy in73patientswith type1diabete s,compar in g pre pran dialinh aledinsulinplusbedt imesub cutaneousultr alente in sulin andu sualMDIofsubcu tan eous insulin,de monstr ated n odiffere nceinHbA 1 c ,fastingorpost pran dialbloodglucoselevels,andfre quen cy orsever ity ofhy poglycemiaafte r3mon ths(111).Anopen -label,noncontr olle dstudy of26pat ie ntswith type 2diabe tesusingpr eprandialin haledinsu linplusbe dtimeu lt ralent einsulindemon strateddecr ease d HbA 1 c afte r3mon ths(112).Inh aledinsulinwaswelltoler ated inb oth studies, andt here wasnochange inpulmon aryfu nction . The aque ou sin sulin aerosoldev ice isbre ath -activat edan dreleasesin sulin when in spir atoryflowrate an dvolu meareoptimal. Acleardose -response curve andarapidonsetofact ionascompare dwith that ofsu bcut ane ou sregularhuman in sulin hav ealsobe ende monstr ate d(113,114).Bothinsulin formu lation sh ave relativelypoor b ioavailab ilit yascomparedwitht hat ofsubcu tan eousinsulin. En hancersh ave b eenincorporat edtotrytoimproveb ioavailabilit y,an dear lyr esultshavebee n promising(115). Improv edae rosolandde liver ytech nology,easeofuse, andpatientsatisfactionmakeintr apulmon ary insulinth emostpromisingalte rnativeroute ofinsulindeliveryatthistime .Adequ atepatient education toensu reproper techn iqu eiscrit icalt oth esucce ssofinhale din sulin .Itisimportan ttonoteth at clin icalstu diestodate h ave been performe din patien tswit hnormalpulmonaryfun ctiont ests.Dataare un availableforpat ie ntswithabnormalp ulmonar yfunct ion. Inaddition,smoke rsare knowntohavemore rapidabsor ption ofintrapulmonarysu bstan ces,andth ismayaffectitsclinicaluse in thispop ulation (108). There isalsocon cern aboutth epoten tialofhighconcen tration sofinsulininthe lu ngstocau se pulmon aryvascular d iseaseorot here ffects(116). Nomajor adver seeffectsh ave been d emonst rate dto dat e,bu tlong -termsafet yand e fficacystudiesarere quiredbeforeinh aledinsu lindeliverysy stemscan berout in elyin corp oratedintoclin icalpr actice. P. 668
CONCLUSIONS
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The d iscovery ofinsulinbyBan ting,Be st,Collip,andMacLe odin1921repr esen tson eoft hegre ate st medicaldiscoveriesofmodern me dicine .Insu linandinsulinan alog uesre main afun damentalcompon ent ofd iabetesman agemen t.In sulin saren owavailablein awideran geoftime-action profiles,anda nu mbe rofdiffere ntdeliverysy stemsareavailable.MDIorCSIIisconsideredt hestandardofcarefor type 1diabe tes.For type2diabete s,an umberofdiffer entinsu linsplusanoralage ntorinsulin-only options may beused .Regardlessoft here gimen chosen,pr ope reducation and s upportar ecritic aland th egoalsh ou ld alwaysbetoach ie veth ebestglycemiccon trolwitht hefewe stadve rseeve nts. When use dproperly,insu linth erapyeffectivelyre ducesmor bidityandmort alit yin pate ntswithdiabe tes. Th e challen geforthe fu tur eist ocontinu etoimproveinsulinrep laceme ntandtoach ie vethe elusivegoalof phy siologicreplace men tofinsu lin.
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101.Zamban in iA,NewsonRB, Maise yM, etal.In jection relate danxiet yin in sulin -treateddiabe tes Diabetes R es Clin Pract1999;46:239246. 102.Win terL B. Onth eabsorptionofins ulin fr omthe s tomach .J Ph ysiol1923;58:1821. 103.Cefalu WT.Nove lrout esofinsu linde livery forpatientswith t ype1ort ype2diab etes. An n Med 2001;33:579586. 104.ModiP,MihicM. Replacemen tofscinject ionswithOralinint reat men tofd iabetes. Diabet es Care 2001;50:179. 105.Yamasak iY,Sh ich iriM,KawamoriR,et al.Thee ffectivene ssofre ctaladmin ist rat ionofin sulin su ppositoryonnormaland d iabeticsubjects. Diabet es Care1981;4:454458. 106.LeeS, McAuliffeDJ, Mu lh ollandSE ,etal. Photome chan icalt ran sdermaldelive ryofinsu linin vivo.Lase rs Surg Med2001;28:282285. 107.Kan ik kann an N, Sin ghJ,RamaraoP. Tran sdermaliont oph ore ticde liver yofbovineinsu linand mon omerichu maninsulinan alogu e.J C on trol Re le ase1999;59:99105. 108.Lau beBL.Tre atingdiabe teswithaerosolizedinsulin.C hest2001;120:99S106S. 109.Heineman nL,TrautT,He iseT. Time-act ionprofileofin haled in sulin .Diabe t Me d1997; 14:63 72. 110.Lau beBL,Ben edictGW,DobsAS.Timet opeakinsulinlevel,re lativ ebioav ailability,andeffe ct ofsite ofdep osition ofne buliz edin sulin in patien tswit hnoninsu lin-de pend entdiab etesmellitu s.J Aerosol Med1998;11:153173. 111.SkylerJS,Ce faluWT,Kour ide sI A, etal.E fficacyofinh aledhu maninsulinintype 1diabet es mellitus:aran domizedproof-of-concept study. Lan cet2001;357:331533. 112.Cefalu WT,SkylerJS,Kour ide sI A, etal.In haled h uman in sulin t reatme ntinpatie ntswitht ype2 diabe tesmellitus. An n In tern Med 2001;134:795. 113.Brun ner GA,Bale ntB,E llme rerM,et al.Dose-re spon serelationofliquidaerosolin haled insu lin intyp e1diabe ticpatient s.Diabe tologia2001; 44:305308. 114.FarrSJ,McElduffA,Mather L E,et al.Pu lmonar yin sulin admin ist rationusingt heAER xsystem: ph ysiologicalan dphysicochemicalfactorsin flu encinginsu line ffectivene ssin health yfast in gsubjects. Diabetes Tech nol Th er2000;2:185197. 115.Steiner S, Pfut zner A,WilsonBR, e tal.Tech nospher e/Insu lin proofofcon ceptstu dywit han ew insu linformu lation forpu lmon ary delive ry.E xp Clin Endocrinol D iabete s2002;110:1721. 116.ChanNN,BaldewagS,Tan TMN,et al.Inh aledinsulinintype 2diabet es[Lett er].Lance t 2001;357:1979.
Chapter40 Iatrogenic Hypoglycemia

Stephanie Anne Amiel Node fin itionofgoodglycemiccontr olin diabete siscomplete unlessitincludesastat eme ntabou t abs enceofhypoglycemia.Patient swith diabete sandt heirfamiliesar ewellawareofthis,andh ealthcare profession alsresponsiblefor p atient swith diabete snee dtobe equallywellinformed. Hypogly cemialite rally ,alowbloodglucoseconcen tration isr arelyen cou nte redinhe althy ind ividuals.
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Glu cose isnormally themajorme tabolicfue lforth ebrain. Becau seth ebrainst ore son lyt rivialamount s ofg lu coseasgly coge n,th ebrain isde pende ntfornormalfu nctiononan adeq uat esupplyofg lu cose fromitscirculat ion.Both t hee ntryofglucosein tothecircu lationanditsremovalthe refromvarywidely withfast in gan dfe edingandwit hrest and e xert ion.E labor ate andse nsitiv eme chan ismsexistto maintain glu cose conce ntr ation sin the p lasmawith in nar rowlimitst oohighaconce ntr ation upset sthe wat erbalan ceintissue s,cau sesglycosu ria,andacce le rate stis sueglycosylation ,wher eastoolowa concen trat ionre sultsincere braldysfun ction andu lt imate lycomaan ddeat h.In healt h,h ypoglyce mia sufficientt ocauseclin icallysignificantcognitivedy sfunctiondoesnotoccurbe cause ofth eefficie ncyof th eend ogen ou sme chan ismsofg lu coseh omeostasis.On cethe semechanismsareupse tbydiabet esan d its treatment ,clinicallyproble matich ypoglyc emiacanoccur. Hypogly cemiacanbe d efin edinbioch emicalte rmsasaplasmaglucoseconcen trat ionbe lowthe n or mal range. Itshouldbenote dthatglu cose con centr ationsin plasmaare approximately10%highert han th oseinwh olebloodbecauser edcellscont ainrelat ive lylowconce ntr ation sofglucose;arterialglucose levelsare higher thanven ou slev els,an dcapillar yle velsarebe tween the arte rialandve nouslevels. Res earch studiesofhypoglycemiain human subjectsoften usearterializedve nousglucosecon cen trat ions becauset heyapproximat ethoseofthe arte rialsy stem(andt here fore the g lu cosesu pplytoatissue)and makearter ialsamplingun nece ssary(1). Fastingplasmaglucoseconce ntration sareconsider ednormalifth eyar ele ssthan6mmol/L,alth ou gh levelshighe rthan5.5mmol/Lare r are lysee ninhe althyindividuals(2).The lowerlimitofn ormalityis more equivocal.Health ypeoplerar ely h ave aplasmaglucoseconcen trat ionlowe rthan4mmol/Lafte ran overn igh tfast, butleve lsof2.8mmol/Lh avebe enre cor dedinhealthype opleaft erprolon gedfasting (3). Spon tan eous,pathologichypoglycemia,such asmayoccurinth epre sence of insulin-orin sulin -likegr owth factor(IGF)-se cretingt umors, requ ire sfordiagn osisth edemon strationof plasmaglucoselevelsoflessth an 2.8mmol/Loreve n,according t osome aut horit ie s,le velsle ssthan 2. 2mmol/Lin women(4).Howe ver, detailedphy siologicstudiessh owadetect ableimpairmen tofh igh er cere bralfun ction atplasmaglucoselevelsof3mmol/L(arterializedve nousplasma)(5), an dther eis eviden ceth atre curre ntplasmaglucoselevelsof3mmol/Ldamageth een doge nousprotective mechanismsagainstmor esever ehyp oglycemia(6). Nonpancre aticcounte rregu latoryresp on sesto hy poglycemiastartat 3.5to3.6mmol/L(see b elow).Thu s,in th e con text of th e tre atment of diabe tes mellitus, hypogly cemiaisdefine dasaplasmaglucoseconce ntration of3. 5mmol/Lorless. Indiab etes, hypogly cemiaisalsoofte ndefined byit sclinicalprese ntation. Acuteh ypoglyce miais symptomatic, and Whipple 'striad ,although definedby asur geon in tere stedininsu linomas,remainsa use fulguidefor defin in gepisod es.The triadreq uires(a)sy mptomsattr ibu tabletoalowplas mag lu cose concen trat ion, (b)ameasu rablylowplasmaglucoseconcen tration(lessth an 3.5mmol/Lindiabet es), an d(c)rapidre solutionoft hesymptomsaftercorre ctionofthe bioche micalabn or mality(7).Howe ver, aswillbede scribedlater ,pat ie ntswithdiabe tes(an dindeed thosewit hinsulinomas)canlosethe ir abilit ytog ener ateandde tectth esymptomsofear lyh ypog lyce mia(see Hypoglyce miaUn awarene ss), an dWhipple'sorigin altriadisbestmodifiedbyth einclusion ofth eter mandsignsinth efirstcriterion (Table40.1). TABLE 40.1. A Modification of Whipple's Triad for Diagnosis of Hypoglycemia in Diabetes Therapy P. 672
Presenceofsymptomsand/orsignscompatiblewithalowplasmaglucoseconcentration Demonstrablylowplasmaglucoseconcentration(<3.5mmol/L) Rapidresolutionwithrestorationofplasmaglucoseconcentration
Pe rhapsthe mostimportantclin icalde fin it ionofacut ehypoglycemiain diabete st her apyisthe division intomildandse vere .Manyauth or itiesalsorecognizeaninte rme diatecategoryofmoderate.Mild hy poglycemiaisd efin edast hat whichisr ecognizedan dtre atedb ythepatient ,an dsever ehypoglycemia isdefin edasthatwhichth epatien tisu nable tose lf-tr eatbe cau seofcognitiveimpair men t.Some au thoritiesrest rict thet ermsever ehypoglycemiatoepisodesr equiringparen teralth erapy (intramu scularglucagonor in trav enousglucose)and/orthosere sultin gin comaorseizu re.The classification moderateh ypoglycemiau suallyrefer stoe pisodesth att hepatie ntcouldself-treatbut resu lt edinsignificantlife disru ption .The lac kofclarityinth isde fin it ionhasle dtoitsdisuse .Thet erms mildandsev ereh ypoglyce miaarenotappropriatelyap pliedtodegr eesofbiochemicalhypoglycemia (Table40.2).
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TABLE 40.2. Clinical Classification of Acute Hypoglycemia
Mild Moderate Severe
Symptomatic,self-treated,nomajorlifestyledisruption Symptomatic,self-treated,butwithsignificantlifestyledisruption Often(butnotalways)asymptomatic,butpatientunabletoself-treatbecauseofcognitive impairment 1. Third-partyhelpbutnotparenteraltherapy 2. Parenteraltherapyrequired(intramuscularglucagonorintravenousglucose) 3. Associatedwithcomaorseizure
Commonly,thequalificationconcerninglifestyledisruptionisomitted,leavingonlymildandsevere categories.
FREQUENCY OF HYPOGLYCEMIA
Formalstu die softh efrequ encyofhypoglycemice vent smu stbecomparedcarefullybecau seof differen cesindefinition s.Thisdifficultyn otwith stan din g,itisimport ant todocumen tthe fr eque nciesof hy poglycemice pisodesinorder tocomparet heeffe ctsofdiffere ntth erapeut icre gimensandto det ermin eclinicalcharact eristicsthatputpatient satrisk. Mildhyp oglycemia,alth ou ghoften u npleasant ,ten dstobeacce ptedasaninev itablecon sequ enceof glucose-lower in gther apies.However ,mildhypoglycemiashouldnotbeignored, asithast hepoten tialto increaseth eriskofse veree pisodes. Inth eDiabe tesCont rolan dComplication sTrial(DCC T) ,whichwas conduct edinpat ie ntswithty pe1diabe tes,t herateofsever ehypoglycemiain creasedfrom app rox imate ly20ep isodesper 100pat ien t-yearsdu rin gcon ven tionalt herapyto60perpatie nt-ye ar dur in gin ten sifiedth erap y(8).In con trast,th eDu sseldor fgr ou p,usingint ernallyconsisten tdefinition s but differ ent fr omthoseus edin the DCC T,reporte dadeclineinratesofsever ehypoglycemiawith inten sifiedt herapyfromratesof28to17e pisodesper 100pat ie nt-ye ars(9).
COUNTERREGULATION: THE DAMAGED DEFENSES AGAINST SEVERE HYPOGLYCEMIA IN DIABETES

Asthe plasmaglu cose con centr ationbeginstodecr ease ,an orch estratedn eurohu moralre spon seact sto pre vent h ypogly cemia. Thefirstcompone ntofthiscou nte rregu lation islocalt oth epan creaticislets,with cessation ofinsulinsecre tionandstimulationofglucagonreleasebyth epan creas.These responses promote h epaticpr odu ction ofglucose,wh ich ,in healt h,re prese ntsth emostimportantmech anismfor pre vent in ghypogly cemiab etween me als.Inpe oplewithdiabe tes,t heinsu linlevelsdonotdecre aseas glucoselevelsfall, either becau seofpe rsistent absorption ofex oge nousin sulinor becau seofn on glucose-depe nden televationofinsulinsecre tionby sulfony lu reas .Thelackofdeclin einplasmainsulin concen trat ionasglu cose lev elsde creasethe nresu lt sin iatrogenichyp oglycemia. Inadditiont oth eirin abilityt omodu lateinsu linlevelsast heplasmaleve lofglu cose decreases,patients withtyp e1diabe teslose t heabilitytoenh an ceglu cagonpr odu ctionby pancr eat ic-cellsin responset o hy poglycemia.Basalglu cagonproduct ionandglucagon responsest oothe rsecret agoguesaremaintain ed, but ther esponsetohyp oglycemiaisabrogate d.Thishappenswith in 5yearsoft heonset oftype 1 diabet es(10)an dmaybesecondarytodecre ased-ce llactivity.Glucagon responsesarealsolostlate in th eevolu tion oftype 2diabe tes,andth eglucag onr esponsetohyp oglycemiaisr educe dunde r expe rimen talconditionsinwh ich -cellactiv ity ismaintain edbysu lfonylure as(11,12). Ine xperime ntalst udies,coun terre gulation(th espon tan eouscorrectionofadecre asingplasmaglucose level)occ urseve niftheinsu linandglucagon responsesareinh ibited(13), aconsequ ence ofsecondary defe nsemechanismsinvolvin gthe aut on omicn ervoussyst emandadren almed ulla.Releasedepinep hrine an dnorepine phrine st imulate endogen ou sglu cose prod uction an dalsoinh ibitglucoseconsumption by per iph eraltissue s.These action soccu rth rou ghelevation ofsub strat esfor g lu con eoge nesis,including none sterifie dfatt yacids,whichalsoinhibitperiphe ralglucoseox idation(14). Glucoseisgene rate d initiallybyh epaticglycogen olysisandsu bsequ entlybyh epat ic(andren al)gluconeogen esis(15, 16).The act ivation ofth esympath etic ne rvoussyste mcanbedemonstratedn ot onlybyde terminingadr enalcatech olamin esecre tion asblood glucoseconcen trat ionsfallbutalsobydet ermin in gsymp ath eticactivityinmu scle (17),recording per spiration (18),or measuringn or epineph rin eass ume dtoh ave spilledoverfromsympathe ticn erve ter minals. Asig nificantandprobablygrowingnu mbe rofpatientswith t ype1diabetesde velopde fectsinth e adr enalandautonomicresponse stoh ypoglyce mia. Th eseoccur ind epen dentlyofclassicalautonomic P. 673
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ne uropat hy,t owhicht heyarenotmechanistically r elated (19)andre presen tan importan triskfactorfor susce ptibilitytosever ehypoglycemia.Thede fectsar eassociated with afailuret ogen erateth etypical symptomsofaut on omicactivation.Affect edpat ien ts,de scrib edash avingh ypoglycemia un awar ene ss, ar eatgr eat lyincre asedr iskforseve rehy poglycemia(20,21). Growt hhormon ean dcort isolareaddit ionalh ormoneswithimport ant rolesinglucosehomeost asis,an d th eir absen cecan beassociate dwith clinicalhy poglycemia.The irr olesinth eresponse toacute hy poglycemiaare le ssclear,andth eycer tainlycan notcompen sate forde fectsinepine phrinese cretion an dau ton omicresponsiven ess.
SYMPTOMS OF ACUTE HYPOGLYCEMIA

Earlyexper tsin diabete s,Ame rica'sE lliotP.JoslinandBritain'sR.D.Lawrence (22,23),dividedth e symptomsofacut ehypoglycemiaon physiologicpr in ciplesintoau tonomic(att rib utablet oactiv ation of th eau ton omicnerv ous sy stemandadren alme dulla)and n eur oglycopeniccat egorie s(relate dtoimpaired glucosesupplytoth ecereb ralcor tex).Morere cently,comple xstat isticalpackagesh ave been u sedto groupth esymptomsre por tedbypatients(orsymptomsandsignsre port edbyparent sofch ildren with diabet es)intorelate dfamilies,withv erysimilarre sults(Tables40.3and40. 4)(24,25). Clin ically,th e specificsympt omsexper ien cedarenotimportantaslongasthe patient becomesaware ofth emata glucoselevelwhen cogn it ive functionisadequ ate toe nab leaneffe ctiv eresponse (i.e .,inge stionofsome rapidlyabsorbe dcarbohy drat e).Man ypatien tswit htype 1diabet esreportagreaterde pende nceon ne uroglycope nicsympt omsthanonau tonomicsymp tomsov ertime . TABLE 40.3. Classification of Acute Hypoglycemia by Factor Analysis in Adults
Adrenergic Tremor Sweating Anxiety Nausea Warmness Palpitations Shivering Dizziness Confusion Tiredness
Neuroglycopenic Hunger Weakness
Other
Blurredvision
Difficultyspeaking Inabilitytoconcentrate Drowsiness
FromDearyIJ,HepburnDA,MacLeodKM,etal.Partitioningthesymptomsofhypoglycaemiausingmulti-sample confirmatoryfactoranalysis.Diabetologia1993;36:771777,withpermission.Copyright1993bySpringer Verlag.
TABLE 40.4. Classification of Acute Hypoglycemia by Factor Analysis in Children
Neuroglycopenic and autonomic Weakness Trembling Dizziness Poorconcentration Hunger Sweating Headache
Behavioral
Argumentative Aggression Irritability Naughtiness Nausea
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Confusion Blurred/doublevision Slurredspeech
Nightmares
FromMcCrimmonRJ,GoldAE,DearyIJ,etal.SymptomsofhypoglycemiainchildrenwithIDDM.Diabetes Care 1995;18:858861.
The e tiology ofhu nge r,whichre presen tsafr eque ntsymptomofhypoglycemiaandmostdir ectly en cou rage sresuscitativefoodintake,h asnotbe enclear lyde line ated .Thesatietycen terslat eraltothe hy poth alamusmaybe in volved. Leptindoesnotre spon dacu telyin hypoglycemia,an dthe roleofore xin isunce rtain(26, 27).
INVESTIGATION OF RESPONSES TO ACUTE HYPOGLYCEMIA

The categorizat ionofthe sy mptomsofacuteh ypoglyce miadiscusse dabovewasbasedondatacollect ed fromth edescr ipt ionofsympt omsand sign sbypatien tsan dthe irfamilymember s.More d etailedstu die s onth erelationshipsbet weensy mptomsofacu teh ypog lyce miaandth eeffectofdiabet esan ditst herapy oftenh ave inv olvede xperime ntallyinduce dhypoglycemia.Insu lininject ion(i.e. ,the in sulin toler ance test )isahigh-riskprocedu reth atre sultsin an uncontr olled,rapid ,var iable ,an dofte nprofou nd hy poglycemicch allenge t hat willmissallbu tthe mostext remevariationsinth ecount erre gulatory resp on se.Aslowdeclineinplasmaglucoselevelinduce dbyalow-d oseinfu sioncanbeu sefulfor examininganindividual'sove rallcoun terr egulat orycapacity(i.e .,th eability toarrest orre verse adrop inglucosele vel)(28).Howe ver, thecomp arison ofre spon sesbet we enindividualsorgroupsof individ ualsmaybecomp licate dbythe failu retoach ie veequ allev els ofhyp oglycemia.Asan altern ative, controlle dhypogly cemiacanbe ind ucedwithamodificationofthe euglycemicins ulin clampte chnique (29).In theslow-fallclamp,plasmaglucoseiscon trolleddu rin gah igh -dose in sulin in fu sionby meansof an adjust ableintravenousg lu coseinfu sion(Fig.40.1).Forpatientswithd iabetes, plasmaglu cose ofte n isregulateddur in gthe nightpre cedingth estud ybyan in trav enousinsulininfusion.Th isen sure sthatall subject sin agivenst udy, with orwithout diabete s,are exposedtothe samehypoglycemicch alle nge (i.e. ,similarin it ialglucoselevel,finalglucoselevel,andrateofdeclin e)(29).Insomeexper imen tal protocols,th eplasmaglucoseconcen trat ionislowere din aseriesofsteps, soth att heglucoselevel associate dwith the onse tofanyone r esponsecanbede termin edforthatindivid ualor grou pof individ uals.Thiste chnique first wasuse dtode termin eth eeffect ofth erat eofglucosedec lineonth e magnitu deoft hecoun terre gulatoryr espon sestoagiven moderateh ypoglycemicchallenge (29)and late rtoinv estigate thee ffectsofint ensifieddiabete streatmentoncoun terr egulatoryh or monere spon ses (30).Itisimportanttorealizet hat theclampte chnique doe sn ot examine count erreg ulation perse ,becauseth eglucosele velisalwaysun derth econ trolofthe in vestigat or. P. 674
Figure 40.1.Thesteppedhypoglycemicclamp:ameansofapplyingacontrolledreproduciblehypoglycemic challenge.Aprimed-continuousintravenousinsulininfusionisstartedattime=0minutes,creatingapredictable rapidsquarewaveriseincirculatinginsulinlevels(black dotted line).Thesubsequenthypoglycemiaiscontrolledby avariable-rateglucoseinfusion(bars)adjustedaccordingtotheplasmaglucosemeasurementmadeatthebedside every5minutes.(FromAmielSA,SimonsonDC,TamborlaneWV,etal.Rateofglucosefalldoesnotaffect counterregulatoryhormoneresponsestohypoglycemiainnormalanddiabetichumans.Diabetes1987;36:518522.)
Such studiessh owth atacuteh ypoglyce miare sultsinah ie rarch yofre spon ses.In healt hyvolu nte ers, epine phrine se cretionbeginsatar terializ edplasmaglucoselevelsof3.0t o3.4mmol/L,ad rene rgic
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symptomsat3.2mmol/L, andminorbutde tectablecogn it ive impairment (firstsh own asaslowin gof complexre actiontime s)at3.0mmol/L(Fig.40. 2)(29,30,31, 31,32,33).Moreext ensivecognitive impairmen thasbeen shown atlowerglucosele vels(32).Theh or monalan dsymptomat icre spon sesoccur at higherg lu coseleve lsinpatie ntswithpoorlycon trolleddiabe tes(31,34). Th einitiation ofhormon al resp on ses,an despec iallyofsy mptoms,beforeth eonsetofsig nificantcognitiveimpairmen tduring a progressivegluc osede cline iscriticaltoapat ien t'sabilitytoprev entse vere h ypogly cemia, giv in ga windowofoppor tun ity forre cogn itionofthesitu ation an dforself-tre atmen t(35).
Figure 40.2.Normalhierarchyofresponsestoacutehypoglycemia.Asplasmaglucoselevelfalls,theautonomicand symptomaticresponsesprecedetheonsetofevenmildcognitiveimpairment.
The d eline ationofcognitiveimpairme ntdu rin gacu tehy poglycemiaislessclear.The brainisnota homogen eousorgan ,an dspecificbr ainfun ctionsu sevariousbr ainreg ionsth ath avediffere nt susce ptibilitie stoh ypoglyce mia. Th edet ection ofhy poglycemiabyglucose-sen sin gneu ronsan dthe initiation ofth eau tonomicresponsesn or mallyoccurat orbe fore theonse tofcognitivech ange s (typicallyatarte rializedplasmag lu coseleve lsof3. 4mmol/L). Forexample, theslowin gofch oice reaction timeoccursatglucoselevelsof3mmol/L,andth eslowingofasimplemot oractivit ysuchas fingert appingoccursat2. 4mmol/L(Fig.40.3).
Figure 40.3.Glucosethresholdsforonsetofcognitiveimpairmentinhealthyvolunteers.Thedataareacquiredfrom clampstudiesinwhichtherateofglucosedeclineispreciselycontrolled.Itisimportanttonotethatdifferent cognitivefunctionshavedifferentsusceptibilitiestohypoglycemia.Dataforthetwomemorytests(immediateand delayedrecall)andthecompositeStroopscorearefromCryerPE,ScottA,SegalMD,etal.Bloodbrainglucose transportisnotincreasedfollowinghypoglycemia.Diabetes2000;39[Suppl1];thezscoresarefromFanelliCG, EpifanoL,RambottiAM,etal.Meticulouspreventionofhypoglycemianormalizestheglycemicthresholdsand magnitudeofmostofneuroendocrineresponsesto,symptomsof,andcognitivefunctionduringhypoglycemiain intensivelytreatedpatientswithshort-termIDDM.Diabetes1993;42:16831689;andthefingertapping,trailB, Stroopreading,and4-choicereactiontime(4crt)arefromHopkinsDFC,EvansM,LomasJ,etal.Effectsof antecedentcontroloncognitivefunctionandsymptomsduringhypoglycaemiaintype1diabetes.Diabet Med 1998;15[Suppl]:S4.Theshadedbarsrepresentcognitivefunctionsthathavebeenshowntomanifestadegreeof resistancetohypoglycemiainpatientswithhypoglycemiaunawareness.
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P. 675
HYPOGLYCEMIA UNAWARENESS
The b estdefe nseap atient with diabete shasagainstse vere hypogly cemiaissubject ive awar enes sofan early fallinplasmaglucoseconcen trationsandth eimmediate ing estion ofar apidly available car boh ydrate.Lossoft heabilitytogene rate and/ orpe rceivesuch symptomst hesyn dromeof hy poglycemiaun awar enes sisaseriousclin icalproblem,in creasin gthe risk ofseve rehy poglycemiaby about 10-fold(20,21).Suc hun awar enessp lacesthe patien tin dan ger,asheorshe mayexper ien ce bloodglucosele velslowenoug htoimpairbasiccognitiveprocessessu chasreact iontimes(5), makin g common taskssu chasdriv in goroperatingh eavymach in erypoten tially let hal.Le ssdramatic,bu t equ ally d evast ating, isth esudd eninabilit ytosustain logicalt hought ort hesu ddenonse tof un characte rist icaggression,wh ich c anh avese riouspr ofes sionalandsocialconseq uen cesfor t he individ ual.Because ,bydefinition ,apatientwith hypogly cemiau nawaren esscan notrecognizeh isorh er state,afullassessmentofapatient'sexpe rie nceofhypoglycemiacanbe comple tedonlybyinte rviewin g th epeople closetothe patien tin ever ydaylife:the partn er, oth erfamilymembers, orclosefrie nds(36). Animpairedabilit ytod ecreasein sulinle velsin responset oh ypoglyce miaisin tegralt otr eatmen twit h insulinorasulfonylure a.Failureofthe glu cagonre spon sein type 1diabet es(an dlateinsulin-deficient type 2)isapparent lyu niversal, and earlystu die salsosh owedamarkeddimin ution oft heepine phrine resp on setohypogly cemiainpatient swith long-st anding(10ye arsormore )type1diabete s(10). Howe ver, mostpat ien tswithlon g-standingtype 1diabe tesdoretain anabilitytorecognizee arly hy poglycemiaan ddefen dagain stsever eepisode s,at leastmostofthe time. Lossofawar ene ssof hy poglycemiaisce rtain lymor ecommon in long-du rationtype 1diabet esth anindiabe tesofshorter dur ation(it hasn ot beenwe lldescribedint ype2diabetes), with 25%ofpatien tsinon egen eral diabet esclin icwithadurationofdiabet esofmor ethan15yearsrep ort in gthisproble m.Su chpatie nts ar eatmuch higher riskofseve rehy poglycemia(20,21).Similarly,mor ethanadecade ago,pat ie nts withah ist ory ofre curre ntsev ereh ypoglyce miawere fou ndtohavedefect ive cou nter regu lation, with impaire dhormonalr esponsesandan in ability t oarrest aglucosefalldu ringlowdoseinsulininfusion indepe nden tofd iabeticneu rop ath y(19). Int erest int hepr oblemsofhy poglycemiaawaren essin creasedwithth erecognition thatboth asy mptomatic(37)an dsevere sympt omatic(8)h ypogly cemiawe remore commoninpatie ntswitht ype1 diabet esran domizedtorece ive in tens ifiedinsulinth erapy in thelar getrialsofpr even tionofchr onic complication s(38).Inve stigationshowedth atpatientsr eceivinginten sifiedth erapywere lessable than th oser eceivingstandar dthe rapyt oproduce acount erreg ulatoryre spon sein the faceof insulininfusion(aswer eprev iouslystud ied p atient swith recu rren thypoglycemia)(39).Thede fectwas foundt obealoweringofthe plasmaglu cose lev eln eede dtoinitiat ethe adre nergican dsymptomat ic resp on ses(30),closing, ifnotoblite rating ,the gapbet weent heonset ofsymptomaticprot ective resp on sesan dofcognitiveimpairmen t(Figs.40. 3an d40.4). P. 676
Figure 40.4.Disturbedhierarchyofresponsestoacutehypoglycemiaafteraprecedingperiodofhypoglycemia. Counterregulatoryfailureismanifestasaloweringoftheglucoselevelthatinducesanadrenergiccounterregulatory responsetoward,orevenbelow,thatassociatedwiththeonsetofcognitiveimpairment.
The reislittledoubtt hat t hede tectionofh ypoglyce miaandth ein it iation ofth eau ton omicand adr ene rgicr esponsesarecen trallyme diated. An imalstu die sshowt hat main tenance ofglucosesupplies inabr ainregionar ou ndth even tromedialhy pot halamusdu ringsyste michypoglycemiapreve ntsth e count erreg ulatoryre spon se(40)an d,con verse ly ,thatlocalizedintr acellularglucosedep rivation (by deoxyglucose)inth atbr ainregionalonecaninduce aper iph eralhy perglycemic cou nter regu lator y
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hormon alresponseine uglycemicanimals(41). Ne uronsfromt heseandre latedbrainare ascanbe excite dbychangesinglucosesup ply(42). Inan exper iment ofnatur e,ap atient with asarcoidlesionin th esamereg ionshowedabnormalitiesofglu cose homeostasisandcount erre gulationun tilhislesion reg ressedwitht herapy(43).Glucose-sensing neu ron salsoarepre sentint heh epat icportaltr act, as shownbyanimale xperimentsinwh ich port alperfusionwithglucoseamelioratesth eau tonomican d adr ene rgicr esponsestosyste michypoglycemia(44,45),bu tthe irr oleinmaintain in gglu cose su pplie st o th ebraing lu coseisun cle ar.On ehy poth esisisth att hese neu ron smonitorglu cos ein putfromthe gas troin testinaltr actandmaybeable tomoderateace ntrallymediate dcou nter regu lator yresponset o syste michypoglycemiaon ceeatin gstar ts(46). The reisg oodcir cumstan tiale vid encet hat thet rigg erfor aut on omicandadren ergiccou nter regu lationis aslowin gofmetab olicr ateint heglucose-sen sin gneu rons.Su pply in gthen on glu cose substr ateslact ate or3-h ydroxybut yrat etosupportmetab olismdur in gexper iment allyindu cedh ypoglycemiadelay s(i.e ., shiftstolower g lu coseleve ls)th eonset andmagn it udeofthe epin eph rin eresp on se,ad rene rgic symptoms, andcognitiveimpair men tofacut ehypoglycemiain volun teer s(47,48,49).On epopular cur rent theoryt oexp lain thech an gein hypoglycemiasensitivityoft heglucose-sen sin gme chan ismis th atanupr egulat ionofglu cose t ran spor tersandofg lu coseu ptakebyth ebrain occur sasar esultof prior exposure toh ypog lyce mia(50,51, 52).Astudy inpatient swith diabete sandh ealth yvolun tee rsthat calculat edglucoseconsumption bythe brainfrommeasure men tsofc erebralb loodflowand ar teriov enousdiffere ncesinglucoseconcen trat ionsacross t hebr ainshowednoeffect ofhy poglycemiain diabet icpatientswith ahistoryofh ypogly cemiau nawaren ess,wh ereashypoglycemiawasassociated withad ecline in glu cose uptakebyth ebrain in s ympt omaticdiabet icandnondiab eticsubjects(53). A similarapp aren tadaptationint hehandlingofg lu coseby thebr ainalsowasinduce din healt hy volu nte ersbyex posu reto56hoursofin duced moderatehy poglycemia(54).The con ceptth atth ehu man brain canadapt toante ceden thypoglycemiabyupre gulatingitsabilitytoextractglucosean dthu sfails totriggercoun terr egulat ionbecause met abolismint hecer ebralglucosesen sorisbet termaintain edisan at tract ive on e.However, recen tdat aobtaine dwith positrone missiont omogr aph y,measu rin guptakein th ebrainofglucoselabeledwithapositronemitter ,havebee nun abletocon firmth edatafromth e stu die sofar teriovenousdiffere nce(55,56). Th ediscrepanciesremaint obee xplained. Onepossib ilit yis th atadaptation alchan gesar eregionalallth edescribedst udieshavemeasu redonlyglobalglucose upt akeb ythebr ain.R egion aldiffer encesinse nsitivit ytoh ypoglyce miaitselfhavealreadybee n mentioned, andr egion aldiffer ences with in themetaboliccapacity ofth ebrain ande venofju stth e cere bralcortexh ave b eensu ggeste dbyfurt herst udiesofn on glucoseme tabolicsub strat esin acu te hy poglycemia(57). The alt eredse nsitivit yofth ebrain 'shy poglycemiasen sin gmech an ismsin the hypogly cemia un awarene sssyndromeiswe lldocu me nted .Ther eisde bate aboutth eext entt owhich t hiseffectoccurs inth ecereb ralcor tex.Th ediscrepanciesin the literatur eare almostcert ainlydue todiffere ncesinth e cognitivefun ctiont estsuse dtoassesscorticalfun ctiondu ringacu teh ypoglyce mia someofwh ich adapt (i.e. ,don ot showe vid enceofdete riorationu ntilamore profoun dhypoglycemiahasbe enre ach ed)an d someofwhichdonot.Itiscleart hat ,inpeople with cou nte rregu latoryfailu reandhy poglycemia un awarene ss,the glu cose lev elr equired t oinitiate thesymptomaticcou nte rregu latoryresponse sis red ucedbe lownormalt oag reat erext ent t han an ychan geinglucoselevelassociated with detect able cognitivemalfu nction,n arrowingoreven closingth ewin dowofopp ort unitybe tween subjective awaren essan dcon fusion . Itisnotknownh owantece dent hypogly cemiaalt ersth eresponse tosu bsequ ente pisodes. Ase xplained above, in con nect ionwithth emechanismsofhypoglycemiaunaware ness,aposs iblemechanismis upr egulat ionofglu cose tran spor tersin resp on setotheinitialhypoglycemicep isodes;another ishy poglycemia-ass ociate dapoptosisofglu cose sen sin gcells(58).Asu ggeste dfactormaybeth ead renocorticotr opichormon eor cort isolr esponseto th ein it ialinsu lt(59, 60),alth oug hhowthismigh tbeinvolv edin long-t ermhypoglycemiaunaware nessis un cle ar. Whateve rthe mech an ism,th elin kbetwee nth edefect ive cou nter regulator yresponsesofhypoglycemia un awarene ssandh ypoglyce miaitselfiss trong.Aser iesofrese arch studieshavede monstr atedind uction ofcoun ter regulat ory failu rean ddiminishedsy mptomaticresponse stoe xperime ntallyinduce d hy poglycemiainbothhe althyv olun teersanddiabe ticp atient sasaconse quen ceofe xposuret o hy poglycemiadur in gthedayornightbe fore thet eststimu lu s(61,62,63, 64, 65).Such tran sie ntde fects inth eneu roendocrinere spon setohypoglycemiaare v erysimilartoth osefirstde monstr ated in inten siv elycon trolleddiabe ticpatient swith hypoglycemiaunaware ness:aloweringoftheg lu coseleve l req uiredtoin it iateth esymptomat icandhormon alresponse s(particularlyt heep in ephrine response )and adimin ution ofth ehormon alresponse atan ygivenglucoseleve l. Th erelevancet oth eclin icalsyn drome ofh ypogly cemiau nawaren essindiabet icpatie ntsisconfir med b ythe d emonst rationth atbotht he un awarene ssandt hen eurohu moralfailure aree ith erpartially(66)orcomplete ly(67)r eversibleby scru pulou savoidance ofhy poglycemiain dailyliving.It isimportantt on ote thatthe ind uction of temporar ycou nter regu lator yfailu reinexp erimen talstu die scanbe gene rate dbymodest priordecr ease s P. 677
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inplasmaglucoseconcen trat ions(Tab le40. 5)an dthatrev ersibilityinpat ie ntswithdiabe tescanbe ach ie vedbysu ccessfulavoidan ceofbloodglucoseconcen trationslowerth an3mmol/Lonhome mon itoring. Th isillu strat esthe dan gerofu singdefinition sofhy poglycemiacoin edfor thediag nosisof pat hologicspon tan eoushypoglycemiain the c ont extofdiabete sther apies. TABLE 40.5. The Hypoglycemic Stimuli Associated with Subsequent Counterregulatory Defects
Healthyvolunteers 3.9mmol/Lfor2h 3.3mmol/Lfor2h 3mmol/Lfor2h 2.9mmol/Lfor2h(residualeffectat3d) Patientswithdiabetes 2.8mmol/Lfor2h 2.8mmol/Lfor2htwiceaweek 2.7mmol/Lfor3hatnight DatafromDavisSN,ShaversC,Mosqueda-GarciaR,etal.Effectsofdifferingantecedenthypoglycemiaon subsequentcounterregulationinnormalhumans.Diabetes1997;46:13281335;GeorgeE,HarrisN,BedfordC, etal.Prolongedbutpartialimpairmentofthehypoglycaemicphysiologicalresponseforfollowingshort-term hypoglycaemiainnormalsubjects.Diabetologia1995;38:11831190;HvidbergA,FanelliCG,HersheyT,etal. Impactofrecentantecedenthypoglycemiaonhypoglycemiccognitivedysfunctiononnondiabetichumans. Diabetes1996;45:10301036;GeorgeE,MarquesJL,HarrisND,etal.Preservationofphysiologicalresponsesto hypoglycemia2daysafterantecedenthypoglycemiainpatientswithIDDM.Diabetes Care1997;20:12931298; OvalleF,FanelliCG,ParamoreDS,etal.Brieftwice-weeklyepisodesofhypoglycemiareducedetectionofclinical hypoglycemiaintype1diabetesmellitus.Diabetes1998;47:14721479;andFanelliCG,ParamoreDS,Hershey D,etal.Impactofnocturnalhypoglycemiaonhypoglycemiccognitivedysfunctionintype1diabetes.Diabetes 1998;47:19201927.
Itisimportan tnottoassu me t hat cou nter regu lator ydefect sind ucedbye xpos uret ohy poglycemiaitself ar erestr ict edtoin tensifiedinsulinthe rapy regime nsan dtightglycemiccont rol.Th estudy byCranston etal. (67)in clu dedsixpatien tswit hpoorlycontr olle ddiabete sreceivingconve ntion althe rapywh o, despite h ig hlevelsofglycosylatedh emoglobin andge ner allyh igh plasmaglu cose con cent rations, ne verth elessexpe rienced int ermit tent severe hypoglycemiawith nowarning .These patient salso recover edsymptomaticn eur oh umoralre spon sestoin duce dhypogly cemiaafteraperiodofhy poglycemia av oidan ce,su ggestingth att heet iologyofthe ircoun terr egulat ory failur ewasth esameasthatin pat ie ntsre ceiv in gin ten sive ther apy. The failur etogene rate anadequ aten eur oh umoralre spon setoin duce dhypogly cemiaindiab eticpatien ts withhy poglycemiaun awar ene ssisprobablye nhancedb yadiminishe dsensitivit ytoadren ergic stimu lation .Redu cedcardiovascularre spon sestoin fused-agonistshav ebeen demon strat edinpat ie nts withdiabe tesprone t ore curre ntep isodesofsevere hypoglycemia(68,69),an dperh apslossofboth epine phrine se cretionan dit seffectsarereq uiredtocreateth efullsy ndrome ofhy poglycemia un awarene ssandh igh riskofsev ereh ypoglyce mia. Th eredu cedsen sit ivityt oadrene rgicstimulat ion mayber eversible;onestu dyth atattemptedt ocorrect cou nter regu lator yfailu rebyh ypoglyce mia av oidan cedemon stratedre stor ation ofadren ergicsympt omsbut n ot ofepine phrine responsest oindu ced hy poglycemia(70). Variationinadren ergicsensitivityalsomay explaindifferen cesinthe suscept ibility ofpatie ntswith classicaldiabeticau tonomicneu ropath ytoh ypogly cemiau nawaren ess.The sepat ie ntshavedimin ish ed count erreg ulatoryhormon eresp on sestohypogly cemia(71)andincre asedr iskofsever ehypoglycemia (72),bu tthe reisnodire ctlin kbetwee nclin icalautonomicne uropath yan dcou nte rregu latoryfailu re (19).Patien tswit hau ton omicneu ropathy maybemore s ensitivetoan yadre nergicstimu lation thatthe y can ach iev e(73).The failur eofsu bjectiveawaren essofh ypoglyce miainth esepatientscanalsobe par tiallyre storedbyavoidan ceofhypogly cemia(74), whichdoesnotcorrectt hen europathyitself. Rec entdatasu ggestge notypicvariationmaycont ribu tetoth eriskofsev ereh ypoglyce mia. I npar ticu lar, variantsofthe ACEgen ehavebe endemonstratedinsome popu lation stobe excessivelyre presen tedin pat ie ntswithse vereh ypoglyce mia(75).
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CLINICAL CAUSES OF HYPOGLYCEMIA AND APPROACHES TO MINIMIZING RISKS

Itisimportan ttorecognizeth atacute hypoglycemiain d iabetes, wheth erornotcomplicate dby hy poglycemiaun awar enes s,iscaused b yexcessiveinsu linaction .Ther eare man yimportantdifferen ces bet we ent herapeu tice xoge nousinsulinan dendogen ou sin sulin :exogenousinsu linisdelivered per iph erallynotportally,hasvar iable andn on physiologicp har macodyn amics, andisun responsivet o change sinb loodglucoseconce ntration s.
Meal-Related Insulin and Hypoglycemia

Rapid-acting(re gular)insu lin, designedforprandialuse, hast oolowape akan dtoolon gadu rationof act iontomimicth eshort, sharp,prandialburst ofinsu linproduce dbyth ehealt hypancreasin response toeat in g.Thu s,ife noughinsu linistakent opre vent ane xcessiveincreaseinglucoselevelwit hameal, toomuch in sulin mayremaininth ecir culation 2to4h ou rslater .Thepr oblemmaybecompoun dedifan inter med iate-actin gin sulin isadministe redwithth eprepr and ialre gularinsu lininanefforttocov erth e subse quen ttwome als(e.g., the useofapre break fastmixt ure ofregu laran din ter mediat e-act in gin sulin tocov erbreakfast andlun ch).Pat ien tstry in gtogain con trolofimmediatepostpr andialglycemiaalmost invariably need bet we en-mealsn ackstoprev enth ypoglyce miabe fore then extmeal(76).Th isre presen tsoneofthe mostt rou ble someasp ectsofsuchdiabe testr eatmen tregimens.Th euse ofultra-short-actinginsulin an alog uesmayre ducet hedep ende nceonsnacksbet we enmeals(77,78), asmayth euseoftwice-daily inter med iate-actin gin sulin toprov ideb asalinsulincoveragean dredu cethe depen dence on ame alrelat edreg ularinsulinbolu stop rovidee noughinsu lint olastfromon eme altot hene xt(9,79). P. 678
Basal Insulin Replacement and Nocturnal Hypoglycemia

Basalinsu lincover ageovern ig htoftenr eprese ntsaneve nmore sign ifican tproble mindiabe tes management .Ithaslongbe enkn own thatappr oximately50%ofinsu lin-tr eate dpatien tsexpe rie nce noctu rnalh ypoglycemia(80),andth ish asrece ntlybee nconfirme din s tudiesinchildren (81, 82,83).In oneofthe sestudies, themedian glu cose nadirwas1.9mmol/L(range, 1.1to3.3mmol/L)andth e mediandu rat ionwas270minu tes(range, 30to630minu tes)(82).Noctur nalhyp oglycemiaisoften asy mptomatic,possib lybe cause itpr odu cesamuch les sv igorouscount erre gulatoryh ormon ere spon se dur in gsle epthandu rin gwake fulness(84,85). Thislackofav igoroussympath eticresponse mayexplain th eprolonge dduration ofepisodesofn oct urnalh ypogly cemiae pisodesobserv edin childr en(82)and whyn oct urn alhypogly cemiacanbe p rofoun denough tocause conv ulsionsandseizur es.Ith asbee n sur pris in glydifficulttod emonst rate deleteriouseffect sofn octu rnalh ypog lyce miaoncognitivefun ction th enex tday(82, 86),excep tfort hefindingofasignificantde cline in fe elin gsofwell-beingan dmood . Howe ver, nocturn alhypoglycemiaiscapableofind ucingdefe ctiv ecou nte rregu lation thefollowin gday (32)an dshouldbeav oidedforthisreasonalon e. Significantdifficu lt iesr esultfromt heuse ofconve ntion alin termediat e-act in gin sulin sforovern igh t insulinreplaceme ntinpatie ntswitht ype1d iabetes. Allhav eamark edpeak-an d-troughe ffectth atdoes notmatch the p hysiologicpatter nofn on pran dialins ulin se cretionfromth ehe althypancre as.Th e pre dicte dpeakaction is4to8hours afterinject ion, with thesu bsequ entde creasedlevelslikelytoleave th epat ien twit hinsulindeficiencyandhy perglycemiathe next morning. Wit hinthe ran geofisophaneand lente in sulin s,th erearesubt le differ ences inph armacodyn amicsth atsometime scanbe exploitedbu tth e differen cesar enotgreat(87).Le sspureandanimalinsu linsmaylastlonger t han the equivalen thu man insulins,withone studysh owingt helowe stfastingglucoseleve ls,d ose-for-dose,with b ovine ins ulin (87);howeve r,are cent studyspe cificallyofn octu rnalglycemiccon trolwithe quivalent human and porcineinsulinsshowedn odiffere nceinglycemiccont rolorin thefr eque ncyofe pisodesofnoctur nal hy poglycemia(88). De layingth eadmin ist rat ionofeven in gin termediate -actinginsu lint odefe rthe peakaction in tot hetime oft hedawnphe nome noncan ofte nbeu seful(89),an don estu dyshowedred ucedratesofhypoglycemia whe nnoctur nalinsulinrep laceme ntwasbysin gle -rat econ tinuoussu bcutaneousinsu lininfu sion(90). The reisalsoasu ggestionth atth eriskofn oct urn alhypogly cemiamay b ediminishedwh enbasalin sulin rep laceme ntisprovid edbytwice-dailyinter mediat e-act in gin sulin srath erth an byon eeve ningdose (9, 79).Then ewinsulinan alogu es,glar gin ean ddete mir,wh ich arede sign edtohaveaflatt er,more prolong ed,insu linactiont han con vent ionalisop han ean dle nteinsu lins, hav ebeen associatedwith red ucedn octu rnalh ypoglyce mia(91,92), although the firstclinicaltrialshavenotshownamajorimpact onhyp oglycemiain gene ral(93). The r egular in sulin give nbeforeth eeve ningmealcan beasignificant con tributortonoctur nal hy poglycemia.Thishasbeen shownbystu die ssuggest in gthatth ebloodglu cose testbe fore t hebe dtime snackmaybeagoodpred ictorofnocturn alhypoglycemia(94,95),alth ou ghth isisnotau niversal finding(81).C on vertingt oanultra-short-actin gin sulinan alogu efor mealsr educe sther iskofnoctur nal hy poglycemia(96),alth ou ghth isre sultsinsignificanth yperglycemiadur in gthee arlypar tofth enigh t (97,98). Adju stin gbedtimesnackin gprocedur esmayprev entsu chh yperglycemia,bu tthishasnotbeen
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confirme din con trolledstu die s. Bedt imesnackingisalong -estab lished compon ent ofdiabet estre atment regime nsthatiswide ly acce ptedasanapproach topr even tin gnoctur nalhy poglycemia.Itmostofte nisusedt ooffsetth elate act ionofthe r egular in sulin take nbeforeth eeve ningmealasfoodin tak eisn ot likelytohav ea significante ffe cton bloodglu cose lev elsafter3or 4hour s.Inclusion ofu ncooke dcorn starchinth e bedt imesnackhasbeen showntoredu cerat esofn octu rnalh ypoglyc emia, butth emechanismis un certain (99).Becauseth eamount ofcornstarchinge stedisvery small,itisu nlik ely tofu nction asa sourceofcar boh ydrat eslowlyabsorbedover manyhour s.Thesu ggeste din clu sionofsubstr atesfor gluconeogen esisin t hebe dtimesn ackh asalogicalappealbu thasn ot been formally tested (100).The use of-ag on istsatbedt ime,e ffe ctiveinare sear chsett in g,demon stratedn oeffect in aclin icaltr ial (101).
Posthypoglycemic Hyperglycemia and Hypoglycemia

Belie fin theSomogyiphe nomen on ,lite rallytheoccur rence ofke ton uriat hemorn in gafte ran igh ttime hy poglycemice pisode, asan explan ationfor diabeticin stab ilit yand fastinghy perglycemia,h asacyclic popularity(102).Asdiscussedpr eviou sly, itislike lyt hat morningh yperglycemiaresu lt sfromawaning oft heinsu line ffe ctfromth eprev iousday,withth eearlierpe akactionofth atsameinsu lincausingth e prior hypoglycemia(103).E arlymorn in gketonu riaislikelytoarisefromth esameinsu lindeficiency , alth ou ghket osisalsoisun dou btedlyaugmente dbyelevationsinst resshormon es.Despiteth efrequ ent importanceofin sulin deficie ncy,posth ypog lyce michype rglycemiad oesoccur andmaye xplainwhy succe ssfulresolu tionofrecu rren thyp oglycemic e pisodesoften isassociat edwit hlower in gof glycosy latedh emoglobinvalu esan dimprovedbloodglucosecontr olov erall. The mech anismsofposthy poglycemichyper glyce miainclude aten denc ytoover treatthe hypoglycemic episodean dthe g ener ation ofinsu linre sist ance asar esultofh ypogly cemiacoun terr egulat ion.C on trary totraditionalte aching, the e ffectofasingleepisode ofh ypoglyce miamaybeman ife staspostprandial hy perglycemiathe next d ayrathe rthanasfastinghy perglycemia(104).Th ein sulin resistancedu etothe cat echolamine response istransien t(105,106);amore prolonge deffectappear stobe attr ibu tableto growthh or mone(107).Thiseffectmayb epart icu larly pron ou nced inch ildre n,wh osecoun terr egulat ory hormon eresponse toh ypoglyc emiaisgreater t han thatinadu lt s(108),e speciallywh englycemiccont rol isgene rally poor.The proble miscompou nde din adole scents, who,in addition toh aving avigorous count erreg ulatoryre spon se,arealsorelativelyinsulin-res istant(109).Not herapeu ticcompensation can bemade forth isavoidanc eofth ehy poglycemiaist hee ssentialth erap euticmane uver . Parad oxically,th eot herch an geinbloodglu cose le velsthatshouldbean ticipatedfollowin ga hy poglycemice ven tis P. 679 an ot herh ypoglyce micepisod e.Thisappliestomorese veree pisodesofhypoglycemiaandispres umably relat edtoacount erre gulatoryde ficitinduce dbythe in dexepisode(110). Patie ntsre ceivin gin sulin shouldbeaware ofth eriskofasecon doccu rren ceofhypogly cemiawith in 24h ou rsofasin gle sever e episode.
HYPOGLYCEMIA IN TYPE 2 DIABETES MELLITUS

Comp ared with theinformationavailab leabou thy poglycemiaintype 1diabet es,kn owledgeabout hy poglycemiaintype 2diabet esislimited. Se vere hypogly cemiaismuchlesscommonin type2 diabet es,inwhichinsu linr esist an cean dresidualpancreaticfunct ionpre sumablycon fersome prot ection . Howe ver, with progression ofth edisease proce sstoaninsu lin-re quiringstate,t hepatie ntwitht ype2 diabet esmayassu me risk sofhy poglycemiasimilartothoseinpat ie ntswithty pe1diabe tes. Th e an alysisofth eeffects ofbloodglucosecon trolint ype2diab etesinth eUn it edKingdomProspective DiabetesStu dy(UK PDS)clearly demonst rat edan in crease driskofsev ereh ypoglyce miawith inten sificat ionofcon trolandth eintroduct ionofin sulin (Fig.40.5)(111).
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Figure 40.5.IncidenceofseverehypoglycemiaintheUnitedKingdomProspectiveDiabetesStudy.(FromUK ProspectiveDiabetesStudyGroup.Intensivebloodglucosecontrolwithsulphonylureasorinsulincomparedwith conventionaltherapyandriskofcomplicationsinpatientswithtype2diabetesmellitus:UKPDS33.Lancet 1998;352:837853.)
Patient swith type2diabete swhosethe rapyislimit edtodie tan dexercisedonotexp erience sign ifican t hy poglycemia,anditise xtremelyrareinth oser eceivin gme tfor minorthiazolidened iones, becau seth ese dru gsactasaninsu linse nsitiz eran dthu sdon ot preven tade creasein the patien t'sen dog enousinsu lin oran incr ease in glu cagonasleve lsofplasmaglucosedeclin e.Withinsu linse cretagog ues, h ypogly cemia can occu ran dcan often besev ereen ou ghtoproduce n eu roglycopen icsymptoms(112-114).Th elongact in gsulfon ylu reasareparticular lypr oblematic,andth eoccu rren ceofcon fu sionine lde rly p atient s rece iving sulfony lu reasmust alwaysraise suspicionofhypoglycemia.Shorter -actingsu lfonylur easand th eme tig linidescarryalowerriskofh ypoglyce mia(Fig .40.6)(114,115).
Figure 40.6.Incidenceofseverehypoglycemiaondifferentoralhypoglycemicagents.(FromShorrRI,RayWA, DaughertyJR,etal.Antihypertensivesandtheriskofserioushypoglycemiainolderpersonsusinginsulinor sulfonylureas.JAMA1997;278:40-43.)
Hypogly cemiaind ucedbysu lfonylur eascanbepr olon gedandcan recu rafte remergen cytreatment asa consequ ence ofper siste ntdr ugact ion. Pat ien tspre sentingwith severe hypoglycemias econ dary to sulfonylure atre atment shouldbehospitaliz edfor obse rvation;th eyoftenr equireparen teralglucose th erap y. The reisc ont rov ersyconcer ningth ediffe ren cesbetwe enth ecount erregu latoryresp on sesto hy poglycemiaintype 1an dtype2diabete s.Patient swith type2diabete sarege ner allyolderth an pat ie ntswithty pe1diab etes, andn ormalag in ghasbe enassociat edwit hredu cedcoun terre gulatory hormon eresponse stoind ucedh ypoglyce mia(116-118).Symptomge neration andcognitiveimp airme nt inhyp oglycemiaoccu rmore closelytogeth erinhealthyold erindividu als,andth ismigh tbee xpected to increaseth eriskofse vereh ypoglyce miainold erpat ie ntswithty pe2diabe tes(119,120).
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The reisg oodeviden cethatcount erreg ulatoryresp on sesin patien tswit hpoorlycontr olle dtype2 diabet esare in it iatedat highglucoselevels,withadecreaseinth ele velsofglucoseth atareassociate d withhormon alresponse sandsu bjectiveawaren essascontr olisimprov ed,atle astwithinsu lin(Fig. 40.7)(121).Preliminaryeviden cesugge ststhatth resholdsforatleastsomecogn it ive dysfun ctionsare notsimilarlymobile (121).Symptomsofhypoglycemiain patien tswit htype 2diabet esrece ivinginsu lin differlitt le fr omthoseofpatien tswit htype 1diabet es(122), although elde rlypatien tsmorer eadily pre sentwith n eur olog icsymptomssu chasincoordinat ion,blur redvision ,or slu rredspe ech(122).
Figure 40.7.Arterializedplasmaglucosethresholdsforepinephrinereleaseandslowingof4-choicereactiontime(a verysensitivemeasureofpsychomotorcoordinationinhypoglycemia)duringacuteinducedhypoglycemiainpoorly controlledtype2diabetesmellitusandafterimprovingglycemiccontrolwithinsulinontheright.(DatafromKorzonBurakowskaA,HopkinsD,MatykaK,etal.Effectsofglycemiccontrolonprotectiveresponsesagainsthypoglycemia ontype2diabetesmellitus.Diabetes Care1998;21:282-291.)
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EXERCISE AND HYPOGLYCEMIA

Exe rciseisanimportantcont ribu tortoepisodichypoglycemia.The e ffectsofexerciseonbloodglucose ar eimmediate(asexer cisingmuscleuse sglu cose ),inter med iate(lastingfor18to24h ou rsift he exe rcis eisvigorousor prolonged ),an dchronic(in the senset hat mus cleismore s ensitiveth anadip ose tissue t oinsu linandth atafitbodyismoreinsu lin-se nsitiv ethananun traine dbody )(123-125). The immed iatehy poglycemice ffectofexercisecanbeaccommodatedbyre ducingth edoseofinsu lint hat willbeact ive atth etime ofplan nede xercise.Altern ative ly, rapidlyavailablecarboh ydrate(fru it ju iceor glucose)can betakendu ringan dafte rthe exercise. Judiciousu seofh omebloodglucosemon itoring he lpst hepatie ntassesshisor herownre quirement sforgiven in ten sitiesofexer cise . Vigorousorprolon gedexe rtion willde ple telive ran dmu scleglycogen ,an dthe d emandforglucoseto rest ore the sepoolslastsatleast24hours. Peoplewhoexer ciseint ermitt ent ly, eit herv eryvigorou sly or overprolon gedper iods,ar elike lytoreq uiresignificantlylessin sulin thr ou ghth efollowingn igh tan d possiblyev enth ene xtday .Insu linre quirement s,in clu dingbasalr equiremen ts,du rin gspor tingholidays (e. g.,skiing)can fallby 30%to50%(126).Foramorede taileddiscussion ofexe rcisein diabete s,see Ch apte r38.
ALCOHOL AND HYPOGLYCEMIA

Alcoh olicbe veragesoftencont ainglucose,andth eimme diatere spon setoalcoh olingest ion,e speciallyof bee ran dcide r,isofte nhyp erglycemia.Theh yperg lyce miceffectofwin eisverysmall. Alcoholisalsoan insulinsen sitize r(127).It suppre ssesglu con eogene sis, ane ffe ctth atcancau sedelaye dhypoglycemia, ast hebodynormally activat esglu con eogene sisafterse veralhour soffast in g.Thiscan ,for example, cau sesignificanth ypog lyce miath emorn in gafte reven in gdrinking. Th eeffect isdose-dep ende nt,and oneortwodrinksar ethe reforeun likelytohaveamajoreffect. Howev er,individualsintigh tgly cemic control(andt heirfriends andre latives)ne edtobeawareofther isk. Th elike lihoodofhy poglycemiais gre atest in you ngpeoplewhocombinealcoholint ake(n ot neces sarily e xcessive)withe xerciset ypically at ove rnightpartiesinvolvin gdan cin g.You ngpeoplehavediedasaresu lt ofth iscombination .Advisin g red uction in ove rnight insu linaftere vening orall-night partieswh erealcoholand/orexe rcisehavebee n involv edan dwarn in grelativesorfriendsofth erisknext daysh ou ldbe advised. Acut ely ,alcoh olhasbeen showntodiminishappr eciation ofh ypog lyce micsymp toms(128)and count erreg ulatoryhormon eresp on ses(129)andcan the reforebeacon tributortosever ehypoglycemia withoutwarningsigns.
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DRUGS AND HYPOGLYCEMIA

The r iskt hat -blockersmay dimin ish appr eciation ofsymptomsofhypoglycemiahasn ot b een subst ant iatedinex perime ntalstu die sin dicatingth ate xagger ate dsweating e nhance dsubjective awaren essofh ypoglyce mia(130).Theu seof-b lockersindiabe ticpatient swith cardiovascu lardisease shouldnotbeavoide don thebasisofthe ris kofhy poglycemia,alt houghitmakesse nset ouse car dioselectiveagent swhere appropriate . Considerablediscussion aboutth erebe in gasignificantlyincre asedr iskofhypoglycemiawith the useof an giote nsin-conver tin genz yme (AC E)inhibitors(131)wasfollowedbye vide nce(inamixedgroupof pat ie ntswithty pe1andtyp e2diabe tes)th atth eassociationwaswithantihyp erten sivethe rapy p erse (132). ACEinh ibitorsdoappeartoenh ance in sulin sensitivity,bu tthe effectissmall.The rewer e sugg estion sthatthe relationshipwasindirect eithe rthr ou ghcomorbidit yfort hecondition sforwh ich th eACEinh ibitorswere beinguse dorasaconsequ ence ofmode rndiabe tesmanagement with in ten sified insulinth erap yandv igoroususe ofACE in hibit ors. Ar eportofanassociationbet we ene nalap rilan drisk ofh ypogly cemiaspe cificallyin patien tsrece ivingasulfon ylu rea(133)wasfollowedbyafailur eto observe inc rease dhypoglycemiarate sin usersoframiprilinth eHOPE (Heart Outcome sPrev ention Evaluat ion)tr ial(againamixture ofpatie ntswitht ype1andty pediabet es)(134). Th epossibility that hy poglycemice ffectsofAC Einhibitorsare drug-spe cificrat her t han class-specifich asn otbe enex clu ded byavailablestudies. At presen t,cautionisadvisedwhe nintroducingorincre asingth edoseofanACE inhibitorin apat ie ntwithtight lycont rolleddiabet es,withadvicegiv entoincreasehomeglu cos e mon itoringu ntilt hedoseisestablishe d.Thisisgoodpract icewh enmakinganyadjustment inmedicat ion forapatie ntwithdiabe tes. Th edat adonotin any waysupp ort theavoidanceofACEinh ibitorsin pat ie ntswithdiabe tes. Thyr otoxicpatien tshaveacce le rate dhepaticdegradationofinsu lin. Treat men twithhy pot hyroid drugs mayth enincre aset heriskofhypogly cemia, especiallyifth epatie ntbe comessignificantlyhyp oth yroid (135). Fin ally, it h asbe ensu ggested t hat chan gesinth enature ,an dpart icu larlythe sp ecie s,ofe xog enous insulinuse dbyapatientwithdiabetescanbeassociat edwit hincre asedriskofhypoglycemia.In par ticular,conce rnsh avebe enrais edthatsyn thet ich umaninsu linsmaycarrygre ate rriskthanolde r an imalinsulinsofp roblematichy poglycemia.Are centsys tematicreviewofavailablepu blishe dstudies foundn oev ide ncetosupp ort t hisclaim,alth ou ghitwasn ote dthatan ystudy mayfailtopickupan idiosyncr aticeffect with relevan cetosomeindividuals(136).Ther eisn oev ide nceth atv ariou sin sulin speciesh avediffere nteffe ctson response st oh ypog lyce mia(e. g.,differe ntiallydisposingto hy poglycemiaun awar enes s),butitisgoodpracticetouseaninsulinspecieswithwh ich thepatientfe els mostconfiden t.
MANAGEMENT OF HYPOGLYCEMIA The Acute Event

Acut ehypoglycemiaismost safelytre atedwith 15t o20goforalglucose ide allyasglu cos etablet s; jelly, orglucose-cont ainingdrinkssu chas150to200mLoffresh fruitjuice,n on die tle monade,n on die t cola,or asligh tlyle sseramount ofLucozade(100to130mL).C hocolate isbe stavoidedbecauseth efat conten tten dstoretardglucoseabsorption.Ifn omealisplanne dwith in the houraft erah ypoglyce mic episode,addit ionalcomplexcarbohydr ate(10to20g)shouldalsobein geste d.Thep aren teralr ou te shouldnotbeu sedifthep atient isconsciou san dabletoswallow. Itisusefu lifthe patien tcan c onfirmthe blood g lu coseconce ntration priortotre atmen t,sinceitwill he lpsu bseque ntman agemen ttoknowtheleve latwhichth epat ien texpe riencessy mptomsof hy poglycemia.Tre atment ofnonh ypoglyce mic,appare ntlysymptomat ic, episode s(b loodg lu coseh igh er th an3.5mmol/L)shouldbeavoidedu nlessth epat ien tne edstobesur ethe g lu coseleve lisnotfallin g fur ther orisabout t odrive . Ifthe patien tist oocon fusedt oswallowsafely ,correctivet herapymustbeadministe redparent erally. Absorption ofhone yor glu cose g elt hrough thebu ccalmu cosacan sometime sbetriedifthe situ ationis nottooe xtre me. Intramu scularglucagon(1mg)can beadministere dbytrain ednonpr ofessionalsan d shouldbee ffe ctivewit hin10minu tes(137).Theaction hasbe ensaidt obeasrapidasint rave nous glucose,alth ou ghanecdotally,intr aven ou sglucosehasb eenr eportedtobefaster. Ad ministrationof glucagon shouldbefollowedb yoraladministration of20gofglu cose aftert hepatientisalert enough to swallowandth ereafterof40gofast arch ycarbohy drate tomaint ainrecover y.The action ofglucagon depe ndsonstimu lation ofglycogenolysis, anditth ereforemay n ot beeffect ive after p rolongedfastingor inalcohol-indu cedhy poglycemia. Int rave nousglucosesolut ionssh ou ldbe give nwithcare.The oldregimenof50mLof50%glucose providestoomuch glu cose in afor mth atisvery t oxictotissues. What mattersisth etotalquantityof glucosegiven, and 75t o100mLofa20%solution or even 150to200mLofa10%solu tionofglucose ismu chsafer .Ther eisareportoftissuen ecrosisre quiringamput ationofahan dasacon seque nceof
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ext ravasationofa50%solution ofglucoseadminister edin travenously(138).
Prevention
Aspectsofhyp oglycemiapreve ntionhavebee ndiscussedint hesect iononmin imiz ation ofrisk, butitis importanttonotet hen eedtoreviewth eth erap euticreg imeninpatientswith p roblemat ichy poglycemia. Thisin clu desepisodesofhypogly cemiawith ou tpatien tawarene ss;episode sthatath ird party hadt o he lptr eat ;episodeswh ent hepatie ntlost self- con trol,r esultinginembar rassment ,un derper forman ceat work,oracciden tswit horwith ou tphy sicaldamagetothe patient oranothe rperson;andepisodeswhe n th epat ien tlostconsciousne ssorh adas eiz ure. Comorbiditiesthatmigh tin creasehypoglycemiarisk(deficien cie sofcortisol,gr owth hormone ,thy roid hormon ean dcau sesofmalabsorptionsuch ascoelicdisease,anorexia,orgastropare sis)sh ou ldbe exclud ed.However, the p rin cipalcause ofhyp oglycemiaise xcessinsulin,andadju stmentofthe in sulin reg imenorchange sin insu linse cretagog uesmustbe con side redinan ysuch patien t.Thisshouldbe coupledwithedu cationonproperman agemen tofothe rriskfactors,su chast het imin gan dcon tent of mealsan dsnack s,managementofexer cise ,an dthe e ffectsofalcoh ol.Adjustmen tofdiabe tesre gimens toelimin ate bloodglu cose valuesofle ssthan3mmol/Lmayhelpah ypogly cemia-u nawarepatient r egain hy poglycemiawarn in gsan dcanfr eque ntlybeaccomplishe dwit houtworsening t heaverageglucose control.Examination ofapatient 'styp icaldayinter msofmealt imesan dexer cise patte rnsoften can rev ealeasilyremediableriskfact ors. Itisofte nwor thcomparingth epat ien t'sinsu lindistribu tionwith th enormand, ifth ereisabigdiscrepancy, t ryingtoredistribu teth etotaldose in linewith textbook descr iptionsofrequire men ts(e.g .,inmultip ledailyinsu linre gimen s,40%t o60%ofat ot aldosesh ou ld beadminister edasbasalin sulin ,withth eremainde rdivide dbetwee nmealsmos tforbr eakfast,least forlu nch). Aschemaforalter in gther apytorev erseproblematichypoglycemiais illustr ate din Figure 40.8. Forpat ie ntswithty pe2diabe teswhoar erece ivingsu lfonylur eas, reduc ed doses,administration ofother hypogly cemicag ents, and c onv ersion tosh or ter-actingage ntssh ou ldall beconsidere d.Ultimately,jud iciou suseofcon tinuoussu bcutaneousinsu lint herapy(insulinpump th erap y)iseffe ctiv e(139, 140).Islett ran splantationr emain sare searc hprocedur ewhichcanbe effect ive in reducing hypogly cemiabu rden in in sulin -sensitivety pe1patientswh enallelsehasfaile d (141). P. 682 P. 683
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Figure 40.8.Aproposedplanforthemanagementofpatientswithproblematichypoglycemia.
Driving and Hypoglycemia

The reisn ocleareviden cethatpat ie ntswithdiabe tesh aveanoverallhighe rris kofau tomobilecollisions th andoother in dividuals.Howe ver,h ypoglyce miaisimplicatedasacau seofaccident s(142),anditis possibleth atdr ive rswit hdiabet esfollowparticularlysafe driv in gpract icest ocompe nsate.Much ofth e eviden ceonthe in cide nceofau tomobilecollisionswascolle ctedbeforet hewidespre adintrodu ctionof inten sifiedinsu lint herapy,andne wstudiesth ereforearen eeded(143).Ultimately,de cisionsabout the fitnessofpat ien tswithdiabe testodrivemustbemade on anindividualbasis. Patient swith recur ren tsever ehypoglycemiaand t hosewhodon ot r ecognizehy poglycemiashouldnotbe per mittedt odrive. Ifthe secir cumstan cescan bereve rsedbyimprov in gthemech anismofsubject ive hy poglycemiarecognition ,itisr easonable toconsider ther esumption ofdriving.It isagoodstrategyfor such patien tstoverifythe ir bloodg lu coseleve lbe fore d riv in gandat90-minu teinte rvalsdu rin galon g drive. Th edriver with diabetessh ou ld alwayscar ryglucosefor r apidmanageme ntofhypoglycemia shoulditoccu r.Ifahypogly cemicepisodedeve lops,th epat ie ntsh ouldstopth ecarwith out delay,t reat withglucose,wait 20minute s,an drech eckth ebloodglu cose beforeresu mingdr iving .Thisisimportant , becausecognitivere cove ryfromacute h ypogly cemiamayb edelaye d(144).
LONG-TERM EFFECTS OF ACUTE HYPOGLYCEMIA

Rec ove ryfromseve reh ypoglycemiawithcognitiveimpair men t,includingcomaor seiz ure, isge nerally complete .Rarely,pat ie ntssu ffe rperman ent braindamage,obviou satth etime ofrec ove ryof consciou sness, with slowimprovement thatcan con tin ueforweek safter ward. Perman ent neu rologic sequ elaeh avemostofte nbee nrep ort edafte rmassiv edelibe rate ormaliciousoverd osagean ddelayed rest oration ofbloodglucoselevels(145). Hypoglyc emic he miple giaisanun common con ditioninwhichth epat ie ntwak esupaftern octu rnal
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hy poglycemiawit hah emiparesisthatresolvesaft erminu tesorhour s.Patientsmay p resen twit h recu rren tepisodes.Although sometimesthough ttoin dicateu nder lyingcircu lator ydefect s,in on esur vey of56r epor tedcasesin adu lt s,mostofwhichin volve daright -side dhemiparesis,onlyth reeof16wh o were in vestigat edshowedeviden ceofin tern alcarotidarte rysten osis(146) .There are n odatat o sugg estapoorprognosis. Inchildren ,the reisnorecordofaprefer enceforright -orleft-sided ne urologicsign s,an don eser iesof44childr eninclude d14wh ou nder wentcompute dtomograph icscans, whichwer enormalin allbu ton e(147).
Cumulative Damage from Recurrent Severe Hypoglycemia

The conce rnth atr ecurr entse vere hypogly cemia, from which an app aren tly full re cove ry is mad e at t he time ,migh tcau secumulativecorticaldamag ean dimpairedcognitivefu nction remainsun resolved(148). Inadults,t here aredatat osu ggestagreat erdeclineinIQscoresovert imean dimpaire ddecisiontimes onfor malte stingindiabet icpatie ntswithahistoryofr ecurr entse vere h ypogly cemia(149).The seare sugg estivedata,bu tth edecre men tinIQwascalcu lated, inarat hercomplicat edmann er,asthe differen cebetwe enth eNationalAdultRe adingTest score (whichis saidtobe resistan ttoorganicbrain disease )andt heWe chslerAdultIn telligen ceScale(rev ised )score ,adjust edtoaccoun tfort hedifferen ce inth ewayth etwotestsareper formed. Th eincreasedlosswasapproximatelyadoub lingofthe n or mal red uction in IQscore with age. Another studyfoun ddecre asedpe rforman ceinaword-re callte stin diabet icpatientswith ahistoryofse vere hypogly cemia; u lt imate ly itwasunclearwhet hert hiswas associate dwith diabete sperserathe rthanwithh ypoglyce mia(150).Similarly ,diabet eswasfoundt obe associate dwith prolongationofth eevokedpoten tialtheP300wav eon electroen cephalography, with no fur ther e ffectofahistoryofsevere hypoglycemia(151).However, an oth erstu dyconcludedt hat t her e wasde creasedpsychomotorpe rforman ceonlyin diabeticpat ie ntswithsev ereh ypog lyce miaand ne uropat hy,su ppor tin gthe possibilityofadiabe ticce ntraln eur opathyoren ceph alopathy(152).In evalu ating t hepossibilityofh ypoglyce mia-indu ceddamageoft hecen traln ervoussyste m, itisimportant torecognizeth atfactorsot hert han subclin icalorganicbraindamagemayaffe ctresu lt sofformal cognitivefun ctiont esting.In part icu lar,dep ression canh ave avery majoreffect andisrarelyfactored outofthecr oss-se ctionalst udies.Thismayex plain whyan ear lyst udyfounde quallydecre asedcognitive per forman cein patien tsfromadiabetesclinicand p atient sfromagastroent erologyclin ic(153). Neur oimaginghasnotproduced d efin it ive answe rs.Stu die sh ave gene rally been smalland cr osssect ional.On estu dyfou ndleukoaraiosisintwoeach of11diabet icpatientswith andwithout hy poglycemiabut foun dimag in gevidence ofcorticalatroph yin 5oft he11withre curre nth ypog lyce mia only(154).It ispossib let hat both chronichyp er-an drecu rren thypoglycemiahav edetr iment aleffects oncorticalfunction,asevidence dbydelaye dreactiont imesinbothve rytightlycontr olle d(and b y implication morecommonlyhypoglycemic)andver ypoorlycontrolledd iabetes(155). Non eoft hech ang esdescribedamoun ttoclinicaldement ia,but somepat ien ts,pe rhapspart icu larly th osewh ose habitsandsituation sr equireh igh cog nitive in putandfas treactiont imes,maybe disadvantaged. Frankde men tiahasbeen docu men tedinfivepatientswith se vere hypogly cemia, but adv ance dmacrovasculardise asemayh ave b eenofetiologicsign ifican ce(156). The reisc leareviden cethatinte nsifiedinsu lint herapy,de spit eit sassociation with in crease dprevale nce ofse vere hypogly cemia, doe snotcau secog nitiv eimpairment prosp ectivelyov ertime (157).Thisdoes notex on erat erecu rren tseve rehyp oglycemia,because conv entionallytreatedpatient salsodev elop hy poglycemiaan dnotallint ensivelytre ate ddiabeticpat ien tsexp erience p roblemat ichy poglycemia,bu t itprovid esreassurance. An exh aust ive break down ofth eDC CTdat a,collect edprospectively,sh owe dno eviden cefordiminishedpsych omotor performanceinpatient swith moreth an fivee pisodesofsever e hy poglycemiaascomp aredwith thosewit hfewer episodes(158). The situ ationisslightlyclear erreg ardingth eeffect sofre curre nth ypoglyce miaonth edeve lopin gbrain . Inch ildre nyounge rthan7year s,the reisevidence ofimpair edintellectu alp erformanceatlater timesif diabet esdeve lopsver yearly(be fore t heageof7years)an difth ereh asbe enre curre nth ypoglycemia with seizu res(159). Insuch you ngch ildren ,onemajoraimofdiabete sther apymustbe theavoidanceof hy poglycemia. Goodbloodglucosecon trolisimportantforthe optimization ofgrowth andforth epreve ntion oflongter mcomplicationsofdiab etes. Howeve r,itisatleast asimportanttoavoidsever ehypoglycemiain young childre n,andsligh tlyhighe rgly cemictargetst han thoseap propr iateforadu lt sandolderchildren maybeindicat ed. P. 684
SUDDEN DEATH AND HYPOGLYCEMIA

De ath fromacu teh ypoglyce miaoccursbu tisv eryrare(160,161). Hy poglycemiahasbeen implicatedin occasion alune xplainedde ath sin y ou ngpeoplewit hdiabet es(162). Th ediagn osiscan notbemade ret rosp ectively,asitisnotpossibletoobtainfirmpostmortemeviden ceofh ypog lyce mia.Typ ically,th e pat ie ntisfou ndinan und istu rbedbe dwith noevidenc eofpre cedingke toacidosis(prodromalillnes s, eviden ceofv omit in g)orahypoglycemicse izu re.R ecen tstudiesh avesh own thatacu tehy poglycemiais associate dwith le ngth eningofthe QTint ervalonth eelectrocardiogram, wh ich maypredisposetoseriou s
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ar rhyt hmias(163,164).Ithasbeen sugge stedth atth ecombination ofacatech olamin esur gean dadrop inpotassiumle velassociatedwithh ypoglyce miamaypr ecip itateafatalcardiacarr hyth miainth ese, fortun ate lyrare, cases. Itisn ot k nownifanat-riskpopulationcan beident ified,asthe p roblemisso infrequ ent ,but thepote ntialcatastrophiccomplication addstocon cern saboutavoidingproblematic hy poglycemiainthe cou rseofin sulin t her apy.
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107.Fowelin J,Attv allS,vonSch enckH, etal.C har acter ization ofth einsulin-an tagonisticeffectof growth h or moneininsu lin-de pend entdiab etesmellitu s.Diabe t Me d1995; 12:990996. 108.AmielSA, Simon son DC ,Sher winR S,etal. E xagg erat edepine phriner esponsestohyp oglycemia innormalan din sulin depen dent diabeticchildr en. J Pediat r1987;110:832837 109.AmielSA, Tamborlan eWV,SimonsonDC,e tal.Impairedinsu linactioninpu bert y:acontribut in g fact ort opoor glyce miccontrolinadolesce ntswithdiab etes. N E ngl J Me d1986;315:215219. 110.CoxD, Gonde r-Fr ederickL,Sch lu ndtD,et al.Rece nthy poglycemiainfluen cesprobabilityof su bseque nth ypoglycemiaintype 1patie nts. D iabete s1993;42[Su ppl1]:126A. 111.UKProspectiveDiabetesStu dyGrou p.In tensive b loodglucosecont rolwit hsulphony lu reasor insu lincomparedwithconve ntionalth erapy andr iskofcomplication sin p atient swith type2diabete s mellitus:U KPDS33.Lan cet1998;352:837853 112.ChanTYLeeK K,Ch an AW, etal.U tilizat ionofant idiabe ticdrugsinHongKong:re lation tot he common occu rren ceofant idiabe ticdr ugindu cedhypoglycemiaamon gstacu temedicaladmissionsan d th erelat ive prevale nceofNI DDM.In t J Clin Ph armacol Th er1996;34:4346 113.TessierD, Dawson K ,TervaultJP, etal.Glibe nclamide vsgliclazideintyp e2diabe tesoft he elder ly. Diabet Med1994;11:974980. 114.ShorrRI, R ayWA,Dau gher tyJR, e tal.In dividualsu lfony lu reasandser ioush ypog lyce miain olde rpeople .J Am Geriat r Soc1996;44:751755 115.Wolffen butte lBH,L andgr afR. A1-yearmu lt icen terr andomize ddou ble -blind comparisonof re paglin ide and g lybu ridefor thet reat me ntoftype2diabete s:Dut chan dGe rmanRe paglin id eStudy Group.D iabetes C are 1999;22:463467 116.Marker JC,C ryerPE,C lu tter WE.Att enu atedg lu coser ecov eryfromh ypoglyce miainth eelderly. Diabetes1993;41:671678. 117.Me neillyGC, Che ungE ,TuokkoH.Alte redre spon sestohypoglycemiaofh ealthy e lde rlypeople .J Clin En docr in ol Me tab1994;78:13411348. 118.Ortiz-AlonsoFJ,GaeleckiA,Herman WH,etal. Hypoglyce miacount erre gulation in elderly hu mans:re lation shiptobloodglucoselevels.Am J Ph ysiol1994;267:E497E506. 119.BrierleyEJ, Brou ghtonDL,JamesOFW,e tal.Re ducedaware nessofhypoglycaemiainthe elderly desp ite anint actcoun terre gulatoryre spon se.Q J Med1995;88:439445. 120.MatykaK,E vansM,LomasJ,et al.Alt eredh ie rarch yofp rot ectiveresp on sesagain stseve re hy poglycemiainnormalaginginh ealthy men .Diabe tes Care1997;20:135141. 121.Korzon -BurakowskaA,HopkinsD, MatykaK,et al. Effectsofglycemiccontr olon protective re spon sesagain sthy poglycemiain type 2diabet esme llit us.D iabete s C are 1998; 21:282291. 122.JaapAJ,Jon esGC,McCrimmonRJ, etal.Perce ive dsympt omsofh ypoglycaemiain elde rlytype2 diabe ticpatient streatedwithinsu lin. D iabet Med1998;15:398401. 123.CaseyA,Mann R,BanisterK, etal.E ffectofcarbohyd rate in gestion on glycogen resyn the sisin hu manliv eran dskeletalmuscle,measured by(13)CMRS.Am J Physiol En docrin ol Metab 2000;278:E 65E 75. 124.KrssakM, Pet ersen KF, Berger on R,et al. Intr amuscular g lycogen andint ramyocellularlipid ut ilizationdur in gprolongede xerciseandrecover yin man:a13C and1Hnuclearmagne ticr eson an ce spect roscopyst udy.J C lin E ndocrinol Metab2000;85: 748754. 125.KoivistoVA,Sane T,Fy hrqu istF,e tal.Fuelan dflu idh omeostasisdur in glong-te rme xercisein
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he althy su bjectsandtype Idiabeticpat ien ts.D iabetes C are 1992;15:17361741. 126.Sane T,HelveE, Pelkonen R,et al.Theadju stment ofdietan din sulindoseduringlong-te rm en durancee xerciseintyp e1(insu lin-de pende nt)diabe ticmen .Diabe tologia1988;31: 3540. 127.LazarusR ,Sparr owD,WeissST.Alcoholint ake andinsu linleve ls:th eNor mativ eAgin gStudy. Am J E pidemiol1997;145:909916. 128.Kerr D,MacDon aldIA,HellerSR,e tal.Alcoh olcaus eshypoglycaemicunaware nessinh ealthy volu nte ersandpat ie ntswithty pe1(insu lin-de pende nt)diabe tes. D iabetologia1990;33:216221. 129.Flan aganD,WoodP,Sher winR ,etal. Ginandtonican dreact ive hypoglycemia:what is importantthe gin ,th etonic,or both ?J C lin E ndocrinol Metab1998;83:796800. 130.Kerr D,MacDon aldIA,HellerSR,e tal.Beta-adr enoceptorblock adeandhy poglycaemia:a randomised, dou ble -blind, placebocon trolledcomparison ofmetoprololC R,aten ololan dpropran olol LAinnormalsubjects. Br J Clin Pharmacol1990;29:685693. 131.HeringsRM,de Boer A, StrickerBH,e tal.Hypoglycaemiaassociated with useofin hibit orsof angiote nsinconver tin gen zyme .Lan cet1995;345: 11951198. 132.ThamerM,R ayNF,Taylor T. Associationbet weenantihy perte nsivedru guseandhy poglycemia: acase-contr olstudy ofdiabet icu sersofin sulin orsu lfonylur eas. Clin Th er1999;21:13871400. 133.ShorrRI, R ayWA,Dau gher tyJR, e tal.Ant ih ypert ensivesandth eriskofser ioush ypog lyce miain olde rpersonsu sin gin sulin orsu lfony lu reas. JAMA1997;278:4043. 134.Effects oframipriloncardiovascularandmicrovascularoutcomesin people with diabete s mellitus:r esultsoftheHOPEstu dyan dMIC RO-HOPE substu dy:HeartOutcomesPr even tionE valuation Stu dyInve stig ators.Lancet 2000;355:253259. 135.DimitriadisG,Bak erB,Mars hH,etal. Effectofthy roidhormon eexce sson action ,secr etion , andme tabolismofinsu lininh umans. Am J Ph ysiol1985;248:E593601. 136.Aire yCM,WilliamsDR, MartinPG,e tal.Hypoglycaemiainduce dbyexogen ou sin sulin 'h uman ' andan imalinsulincompared.D iabet Med2000;17:416432. 137.CollierA,Stee dmanDJ,PatrickAW,et al.Comparison ofintraven ou sglu cagonanddext rose in th etre atment ofseve reh ypoglycemiainth eacciden tan deme rgen cydepar tme nt. Diabete s Car e 1987;10:712715. 138.KorenI, Sh alitin S,VardiP. Hazardou sou tcomeoftre atingh ypoglyce miawith50%IVin fusion . Diabetologia2000;43[Suppl1]:A195. 139.Bode BW,Steed RD, Dav idPC.R eductioninseve rehy poglycemiawit hlon gtermsubcu tan eous insu lininfusionintype 1diabet es.D iabetes C are 1996;19:324327. 140.RodriguesIAS,Re edHA,IsmailK, AmielSA. Indicationsan defficacyofcon tin uoussu bcutaneous insu lininfusion(CSII)th erapyin type 1diabet esme llit us:inclin icalwarded. D iabet Med2004(in pre ss). 141.RyanEA,Sh and roT,Gre enK, etal.Assessmen tofth esev erityofh ypoglyce miaandglycemic labilityint ype1d iabeticsubjectsu nder goingislettransplan tat ion.D iabete s2004;53:955962. 142.Eadin gtonDW, Frier BM.Acciden triskofth ediabet icdr ive r.Diabe tes C are1989;12:597. 143.MacLeodKM.Diab etesanddriving:towar dsequitable ,eviden ce-base ddecision-making. Diabet Med1999;16:282290. 144.EvansML,Perne tA,LomasJ,etal. Delayinonse tofawaren essofacut ehypoglycemiaand of
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re stor ation ofcognitiveper forman cedur in grecovery. Diabet es Care2000;23:893897. 145.Coope rAJ.Atte mpte dsuicide usinginsulinbyanon-diabet ic:acasestu dydemon stratingth e acuteandch ron icconse quen cesofpr ofoun dhypoglycemia.Can J Psych ol1994;39:103107. 146.ShintaniS,Tsuru okaS,ShiigaiT. Hy poglycaemiche miplegia:are peat SPEC Tst udy. J Ne urol Neu rosu rg Psy chol1993;56:700701. 147.PoceccoM, Ron fan iL. Tr ansien tfocaln eur ologicaldeficitsassociatedwith h ypogly cemiain ch ildren with in sulin depen dent diabete smellitu s.Acta Pae diatr1998;87:542544. 148.De aryIJ, CrawfordJR, Hepbur nDA, etal.Sev ereh ypog lyce miaandintellige nceinadultpat ien ts withinsu lin-tr eat eddiabet es.Diab etes1993;42:341344. 149.Lan gan SJ, DearyIJ,He pburn DA,e tal.Cu mu lativecog nitiv eimpairment followingrecu rren t sev ereh ypoglycaemiainadultpatie ntswithinsu lin-t reat eddiabet esme llitus.D iabetologia 1991;34:337344. 150.SachonC ,GrimaldiA,DigyJP,etal. Cognitiv efunc tion, in sulin -depen dent diabete sand hy poglycaemia. J Inte rn Med1992;231:471475. 151.Kramer L,FaschingP,MadlC.Previousepisodesofh ypoglyce miccomaaren otassociat edwith per manen tcog nitive braindy sfunct ioninIDDMpatien tson in ten sive in sulin treatme nt. D iabete s 1998;47:19091914. 152.RyanCM,WilliamsTM,FinegoldDN,et al.Cognitivedysfu nctionin adu lt swith type1(in sulin dep ende nt)diabe tesmellitusoflongdu rat ion:effe ctsofre curre nth ypoglycaemiaandoth erchr on ic complication s.Diabetologia1993;36:329334. 153.SkenazyJ,BiglerED.Neu rop sychologicalfin din gsin diabete smellitu s.J Clin Psy chol 1984;40:246258. 154.Pe rros P,Dear yIJ,SellarRJ,e tal.Brain abnormalitie sdemonst rat edbymagne tic r esonan ce imagin gin adu ltIDDMpatie ntswithandwithoutahistoryofr ecurr entse vere h ypogly cemia. Diabet es Care1997;20:10131018. 155.Holme sCS,TsalikianE ,YamadaT. Blood g lu cosecont rolan dvisualan dau ditoryatten tion in menwithinsu linde pende ntdiabe tes. D iabet Med1988;5:634639. 156.GoldAE,Dear yIJ,JonesRW, etal.Se verede teriorationincognitiv efunct ionandper son ality in fivepatie ntswithlong-standingdiabe tes:acomplicat ionofdiabete soracon seque nceoftreatme nt? Diabet Med1994;11:499505. 157.Effects ofinten siv ediabete sthe rapyonn europsych ologicalfu nction in adu ltsinth eDiabetes Cont rolan dComplicationsTrial.Ann In tern Me d1996;124:379388. 158.AustinE J,De aryIJ. Effectsofrepe ated h ypogly cemiaoncognitivefu nction :apsych ometr ically validat edreanalysisoft heDiabete sCon trolandC omplicationsTrialdat a.D iabete s C are 1999;22:12731277. 159.RovetJ, AlvarezM.Atte ntion alfunct ioninginch ildren an dadole scentswith IDDM. D iabete s Car e 1997;20:803810. 160.Edge J A, Ford-AdamsME,Dun gerDB.Causesofdeat hinchildrenwith in sulin d epen dent diabe tes199096. Ar ch Dis Ch ild1999;81:318323. 161.LaingSP,SwerdlowAJ, Slat erSD,etal. Th eBritishDiabe ticAssociationCohortStu dy,I:allcausemor talit yin patien tswit hinsulin-tre ated diabetesmellitu s.Diabe t Med1999;16:459465. 162.Tatte rsallRB,GillGV.U nexplain eddeathsoftype1diabeticpat ie nts.D iabet Med1991;8:4958.
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163.Marqu esJL,GeorgeE, PeaceySR, etal.Altere dven tricularre polar ization d uringh ypoglycaemia inpatie ntswithdiab etes. Diabet Med1997;14:648654. 164.Lan dstedt -HallinL,E nglun dA,Adamson U,e tal.Incr ease dQTdisper siondu rin ghypoglycae mia inpatie ntswitht ype2diab etesmellitu s.J Inte rn Med1999;246:299307.
Chapter41 Management of Hyperglycemia with Oral Antihyperglycemic Agents in Type 2 Diabetes

Harold E. Leb ovitz The man age men tofh yperg lyce miainpatie ntswithdiab etesh aschange dsign ifican tly duringth epast seve ralyearsasaresultofnumerousadvan cesinourkn owledgeaboutth edisorde ran dthe application oft hisknowle dgetothe develop men tofn ewstrategiesandtre atment s. The q uan titativer elation shipbetwee nglycemiccont rolan dthe chronicmicrovascu lar,ne uropat hic,an d macrovascu larcomplication sofdiabe teshavebe endefine dbylargelong-te rmclin ic als tudiesin individ ualswit htype 1andtype 2diabet es(1, 2,3).Acleare run derstandingofthe physiologic mechanismsinvolvedinregu latingglucosemetab olismhasprovide dthe basisforamorede taile d an alysisofth ediffe ren tpath oph ysiolog icprocesse scausingh yperg lyce mia(4,5, 6,7).Meth odsfor reg ulatingfastin gglycemiacanbe differ entiat edfrommeth odsforregu latingpostprandialhype rglycemia (8, 9). Ne wc lassesofantihyp erglycemicagent sareavailableth atprovideth eme ansforselectively amelioratingth ediffe rent mech an ismsthatcau sehyp erglycemia(10,11).Long-t ermfollow-updataare sufficientt odemonstrateth att ype2d iabetesisapr ogre ssiv edise aseandth att herapymustchange withdiseas eprogression (12).Combination soforalan tihyper glyc emicage ntsoroforal an tihyper gly cemicage ntsandinsulinar efrequ ent lyn ecessarytoach iev eappr opriat eglycemicgoals (13,14). Th eimpactsofth evariousclasse sofantihype rglycemicagents oncardiovascular r iskfactors havebee nest ablish edan dare animport ant con side rationindecidingwhichagent stou seinaparticular pat ie nt(15,16). Effec tive manag eme ntofhype rgly cemiar equiresu tilizat ionofallofthisne winformation.In itial evalu ationofapat ien trequ ir esestablish men toft hegoalsoft herapyforthatpat ien t.Diabete s edu cationreinforcest hosegoalsandh elpsthepatient learnte chn iqu esan dbehaviort hat canh elp ach ie veth ose g oals.Th eevalu ationmu stincludeanasse ssme ntofwheth erth epat ie nth asthe metab olicsyn drome and, ifso,whichcomp on entsofthe syndrome.The sele ction ofinitialp har mac ologic th erap yisde termin edbyth eseinitialevalu ation s.Long-te rmman age men trequ ir esin ter mitten treevalu ationoft hepr ogre ssionofthe dise aseprocessandmodification ofth eth erap ytoadjusttoth is changingpathophy siology. Effectiveu seofcu rren tth erape uticage ntsandtec hnique scanr esultinne ar normoglycemiccon trolinmost p atient swith type2diabete s.
GLYCEMIC GOALS OF THERAPY

Avar iet yofapproache sare u sedtodefinet hegoalsfor glyce miccon trolinpatient swith diabete s.The levelsach ie vedan dshowntodecre asech ron iccomplicat ionsininte rven tionst udiessuch asth eDiabe tes Cont rolan dComplication sTrial(DCC T)inpatient swith type1diabete sort heUn it edKingdom Pr ospe ctiv eDiabe tesStu dy(UKPDS)inpatie ntswitht ype2d iabetescandefine thegoals(1,2, 3).In th osest udies,th einte nsivelytreatedpatientsachieved meanorme dianhe moglobinA 1 c (HbA 1 c )le vels app roaching7.0%.Th eselevelswere attain ableinalar gecohortofpatient sandsignificant lyr educe d, but didn ot p reven t,ch ron iccomplicat ions. Anothe rappr oachindefiningth egoalistodet ermin eift here isathre sholdofgly cemiccontrolon ly abovewh ich chroniccomplication soccu r.Ananalysisoft here lationsh ip b etween the meanHbA 1 c an dthe deve lopmentofret in opathy, neph ropath y,orneu ropath yin the e ntireDCC Tcohortsh owed thatthe re wasn oglycemicthre sholdsh ort ofnormalgly cemiat hrough ou tthe entire r ang eofHbA 1 c (17).The data forsustain edprogressionofr etinopath y(Fig. 41. 1)sh owedacon stan t39%reduct ioninriskforeach 10%reduct ioninabsolut eHbA 1 c valu es(17).The e pide miologicd atafr omthe entireU KPDSsimilarly showe dnogly cemicth resholdfor eithe rmicrovascu larormacrovascu larcomplications(Fig.41.2)(18).
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FIG. 41.1.OutcomedatafromtheDiabetesControlandComplicationsTrial(DCCT)ontherelationshipbetweenthe riskofsustainedprogressionofretinopathyandthemeanHbA1c .Thereisnoglycemicthresholdforretinopathy developmentandprogression.Retinopathyprogressiondecreased39%forevery10%reductioninmeanHbA1c percentage.(Copyright1996AmericanDiabetesAssociation.FromDCCTResearchGroup:Theabsenceofa glycemicthresholdforthedevelopmentoflong-termcomplications:theperspectiveoftheDiabetesControland ComplicationsTrial.Diabetes1996;45:12891298.ReprintedwithpermissionfromtheAmericanDiabetes Association.)
FIG. 41.2.EpidemiologicanalysesoftherelationshipsbetweenmeanHbA1cover11yearsandtheincidenceof microvascularandmacrovascularcomplicationsintheUnitedKingdomProspectiveDiabetesStudy(UKPDS).There wasnoglycemicthresholdforeithermacrovascularormicrovascularcomplications.(FromStrattonIM,AdlerAI,Neil HA,etal.Associationofglycemiawithmacrovascularandmicrovascularcomplicationsoftype2diabetes(UKPDS 35):prospectiveobservationalstudy.BMJ2000;321:405412,withpermission.)
The lac kofag lyce micthre sholdsh or tofn ormalglycemiain dicatesth atanyleve lofin crease dgly cemia, aswe llasth edur ation ofth eincre ase,canre sultin chroniccomplication s.These datasugge stthatthe goalforglycemiccon trolinpatie ntswithdiab etessh ou ldbe lev els asclosetonormalaspossib le, providedth atth eycanbeachievedwithout causingu nacceptable sidee ffects.Forthe stan dard HbA 1 c assay,normoglyce miaiscon side redtobelessth an6.0%. Obviously,oth erclin icalfactor sneed to beconsidere din deter miningth eglycemicgoalforaparticularindividual.Th eage ofth ein dividu alan d lifee xpectancyareimportant, becau seth ebene fit sofglycemiccontr olare greatestinth ose wholive lon genough tobe nefitfromr educe dcomplications. Th each ie vement ofver ygoodglycemiccontr ol req uiresamot ivated, educated, andcooperativ epat ien t. Although iden tificationofth eide algly cemicgoalisn ear-n or malglycemia,itise quallyimportantto recogn ize t hatany improvementinglycemiccon trolde crease scomplicationr ates. Becau seth e complication rat ein creasesnonlin ear lywith theHbA 1 c ,a10%re ductioninHbA 1 c from11%t o9.9% resu lt sin aredu ction in risk ofprogressionofr etinopath yof6.57case sper100patien tyear s(17).In contrast,adecreasefrom8.0%to7. 2%redu cesth eriskby0. 95c asesper 100pat ie ntye ars(17).Table 41.1highligh tsth e9-ye arcu mu lativ ein cid enceofdeve lopme ntofretinopathyprogre ssionor microalbuminur iain patien tswith type 1diabet esatmeanHbA 1 c le velsran gin gfrom6%to8%(17). TABLE 41.1. Cumulative Incidence Rates Among Patients in the Diabetes Control and Complications Trial of Developing Complications over a 9-year Period as a Function of Mean HbA1c Values
Mean HbA1c value (%)
Cumulative incidence of retinopathy progression (%)
Cumulative incidence of risk of microalbuminuria (%)
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8.0 7.0 6.0
20.0 11.0 5.5
26.0 19.0 13.0
DatafromTheabsenceofaglycemicthresholdforthedevelopmentoflong-termcomplications:theperspective oftheDiabetesControlandComplicationsTrial.Diabetes1996;45:12891298.
Insu mmary ,the gly cemicgoalthatcan bereadilyac hievedwithanacce ptab leleve lofside effectsisan HbA 1 c of7.0%. Howeve r,inyoung patient sand int hosewhoare n ot limite dbyside effects, agoalof 6. 0%wou ldappeartobemoreacceptable.Whilean yimprovement in Hb A 1 c iswor thwh ile,ale velin t he rangeof7. 0%orlowe rshouldbesough t.
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FASTING VERSUS POSTPRANDIAL HYPERGLYCEMIA

Fastingplasmaglucose(FPG)levelsare dete rmine dprimar ilybyh epatican d,toalesser degree ,by ren alglucoseproduction(4, 19,20).Asth eplasmaglu cose le velsdecreasedur in gfasting, plasmain sulin levelsdecre asepr oportionat ely .Thede crease in plasmain sulin cause sanincr ease in adipose tissu e lipolysisandske let almu sclep rot eolysisan dadecre aseinu ptak eofglucosebype rip heralt issu e(21).At th ele velofth elive r,th ecarb on sk ele tonfromaminoacidsfrommuscleproteoly sisser vesassu bstrate an dthe freefattyac idsfromadiposet issu eserv easen ergysour cefort hepr odu ctionofglucose. Glu cose fr omgly coge nolysisan dglu con eogene sispr ovidesth een ergysource fort hen ervoussyste m, whichh asan in sulin -in depen den trequ ire me ntforglu cose .Pe ripheralt issu esuse fr eefat tyacidsand ket on esasth eirene rgysource .Theplasmaglucoselevelisdeter mined bythe r ate ofglucoseproduction fromth elive ran dkidn ey, becau sethe rat eofglucoseu tilizationbyth eperiph eralinsulin-indepe nden t tissue sisfixed.Normally, theplasmainsu linleve lst abilizesatalevelinwhichglucoseprodu ction equ alsnon-insulin-dep ende ntup take ofglucose.Fast in ghyper glyce miaoccurswh englucosepr odu ction exce edsglucoseutiliz ation ,asoccur swith absolu teorrelat ive in sulin deficien cyatt heleve loftheliver. Postpr andialplasmalevelsofg lu cosearede termin edinth ein it ialph aseby meal-mediat edsuppr ession ofh epaticpr odu ction ofglucosean dthr ou ghoutth epostprandialperiodby hepaticandmuscleup take of glucose(19,22).Glucoseupt akere quiresh igh erplasmalevelsofin sulin ( suchasthosenormally gen eratedbymeals)th and oessu ppressionofh epaticpr odu ction ofglucose.The regu lationof postprandialplasmaglu cose ther efor eish ig hlydepen dent on thequ alit ativeandqu ant itativeaspe ctsof meal-me diatedinsu linse cretion ,aswe llasbyt hesen sit ivityofmu scle toinsu linaction (8).Th ese phe nome naaccou ntforthe diffe rent ialre gulationoffastingan dpos tpran dialg lu coset hat occu rsin diabet esingen eralan din type2diabete sin part icu lar. The rear emanypoten tialcon seque ncesofthediffere ntialregu lation offast in gan dpostp ran dialplasma glucoselevels.Postpr and ialh yperglycemiaoc cursseve ralyearsbeforefastin ghype rglycemiaandisth e initialp hase ofglucoseintole ran ce.Cont rib ution sofpostprandialhype rglycemiatot heoverallglycemic control,ases timat edbyth eHbA 1 c ,willvary with theindividualandth estageofglucoseintolerance (23).Some d atasuggest thatspik esin glu cose excur sionmayh aved iffere ntqu an tit ativeeffe ctson the metab olicmech anismsin volvedinth epathogene sisofchroniccomplication s(24,25).Phar macolog ic age ntsmaydiffere ntiallyaffectfastingan dpos tpran dialh yper glyce mia(10,26, 27).Near -normal glycemiacann ot beach ie vedun le ssbot hfasting andpostprandialhyp erglycemiaare con trolled.
STAGES OF TYPE 2 DIABETES

Type2diabete sisth een dstage ofapr oce ssthatin volves p rogr essivelossofpancr eat ic-cellfunct ion (Fig. 41.3)(12). Th einitialph ase ofth isprocessinth emajorityofpat ie ntsisthed evelopmen tofinsu lin resistance(28, 29).Studiesoflow-birth-we igh tin fan tsin dicatet hat insu linr esistan cecan berecognized inchildrenasyoungas8ye arsofage(30). Th enormalcompen satoryre spon setoin sulin resistan ceis increasedinsu linsecr etion and compensatoryhyp erinsulinemia.Aslon gasth ecompen satory hy perinsulinemiaissu fficien ttoove rcometh einsulinresistance, fastingandpostprandialplasmaglu cose levelsremainn ormal.Ifth eindivid ualwit hinsulinresistanceh asth egen eticpredispositiontodevelop type 2diabe tes,th eab normalitiesinth epan creat ic-ce llwillcause aprogressivelossofinsulin secre toryfun ctionandalossoffirst-ph aseinsu linre le ase(31,32). Thisresultsinitiallyinimpaired glucosetole ran ce(IGT)andsu bseque ntlyintype 2diabet eswit honlypost pran dialh yperglyce mia(23). Aspan creatic-ce llfun ctioncont in uestodete riorate, n ot on lydoespostprandialinsulinsecre tion becomein adeq uat e,sodoe sbasalinsulinsecre tion ,an dfastingh yperglycemia P. 690
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en sues. Dur in gthe clinicalcou rseoftype2diabete s,in sulinsecre tor yfunct ioncontinu estodecre ase, an dfin ally ,afte ran umb erofy earsofclin icaldiabe tes,man ypatien tsbecome sever ely in sulin d eficien t an dwillrequire ins ulin -replacemen tthe rapy. Treat men toft heabnormalg lu cosemetabolismis det ermin edbyth estag eofth edisor der(Fig. 41.4).
FIG. 41.3.Schematicrepresentationofthestagesofglucoseintoleranceasafunctionofpancreatic-cellinsulin secretorycapacity.ThedatapointsaretakenfromtheHOMA(HomeostasisModelAssessment)calculationofpercent normal-cellinsulinsecretorycapacityasafunctionoftimeinasubsetoftheUKPDSpopulation.Thedataare extrapolatedbothbackwardbeforetheonsetofclinicaldiseaseandforwardintolongerdurationofdisease. (Copyright1999AmericanDiabetesAssociation.FromLebovitzHE.Insulinsecretogogues:oldandnew.Diabetes Rev1999;7:139153.ReprintedwithpermissionfromtheAmericanDiabetesAssociation.)
FIG. 41.4.Schematicrepresentationofthenaturalhistoryoftheevolutionofinsulin-resistanttype2diabetesand thematchingofpathophysiologywiththepharmacologyofavailabletreatments.SU,sulfonylureas.
INSULIN RESISTANCE AND ASSOCIATED ABNORMALITIES

Int here port ofth eAme ricanDiabete sAssociationExpe rtCommittee on theDiagnosisandC lassificat ion ofDiabet esMe llitus, t ype2diabetesischaract erizedasran gin gfrompredomin ate lyinsu linre sist ance withre lativ ein sulin deficie ncytopredomin atelyaninsulinsecre tor ydefect with in sulin resistan ce(33). Inpr acticalter ms,abou t85%ofpatie ntswitht ype2diab etesh avesignificant in sulin resistan ce,wh ich pre cedesth edeve lopmentoftype 2diabet esbymanyy ears, asnoted previou sly .Insu linre sist ance isa separat eent ity fromtype 2diabet es.Man yin dividu alshav ein sulin resistan cean dnev erdev eloptype 2 diabet esbecauseth eydonothaveth epan creatic -ce llabn or malities(34,35). Insu linr esist ance isassociat edwit haclust erofmet abolicabn ormalities,an dthisisreferr edtoasth e insulin resistance syn drome orth emetab olic sy ndrome (5,36, 37).Alloft hecompone ntsofthe met abolic syn drome(Tab le41. 2)ar ecard iovascu larriskfactors. Be cau semacrovascu lardise aseisresponsiblefor alar gecomponen tofmorbid ity andmor talityin patien tswit htype 2diabe tes,th eirthe rapy must be directe datcardiovascularr iskfactor saswellashype rgly cemia.Animportantissue inany an tihyper gly cemictre atment regime nisthee ffe ctthatre gimenmighth aveonth ecompone ntsofthe insulinresistancesyn drome t hat are p resen t. TABLE 41.2. Components of the Metabolic Syndrome
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Insulinresistance Hyperinsulinemia Centralobesity Increasedsystolicanddiastolicbloodpressure Dyslipidemia Increaseinplasmatriglycerides DecreaseinplasmaHDLcholesterol AnLDL-particlepatternshiftedtosmall,denseparticles(typeBpattern) Procoagulantstate Increaseinplasmafibrinogen Increaseinplasminogenactivatorinhibitor1 Vascularabnormalities Increaseinurinaryalbuminexcretion Endothelialdysfunction Hyperuricemia Non-infectiousinflammation HDL,high-densitylipoprotein;LDL,low-densitylipoprotein. FromLebovitzHE.Clinician's manual on insulin resistance.London:SciencePress;2002,withpermission.
PHARMACOLOGY AND USE OF CURRENTLY APPROVED ORAL ANTIHYPERGLYCEMIC AGENTS AS MONOTHERAPY

The d iffere ntmajorclassesoforalantihyp erglycemicagent sin curre ntuse can b ediv ide din tot hosethat increaseinsulinsecr etion ,thoset hat d ecreaseinsulinresistance, andt hosethatmodifythe rate of glucoseen tryfromt hegastroin testinalt ract(Fig.41.5).Eve nwithinth eseclasses t here are strikin g differen cesamon gage nts. Curr entdataont heeffe ctiv enes sofne werage ntsonglycemiccont rol gen erallyar ederivedfromthelar gemu lt ice nter ran domiz edplacebo-controlled p hase IIIstudies pre sente dtor egulat ory agen cie sforapproval(13,14).The sestud iesareh eavilyweighted with patien ts whohadpreviouslyreceived anactiv eage ntth atwasdiscont in ued. Inthoseinstance s,the patien ts randomizedtoplaceb ohaveaverysignificant deter iorat ionofglyce miccon trol,while thepatients int he act ive lyt reat edgroupe ith ermaintain orsh owimp rove d P. 691 glycemiccontr ol.Re sultsare reported e it herastreatmente ffect,wh ich isth edifferen cebetwe enactiv e tre atment and p lacebot reatme nt, oraschan gefrombaselin e,which isth ediffe ren cein gly cemiccontrol at thee ndofthet reat men tperiodcompar edwit hth atbe foret hetr eat men tperiod.Thed iffere nce bet we ent reat men teffect andde creasefrombaseline issignificant lylessindru g-naive patien tswit htype 2diabetes. Recen tstu die swith ant ih yperglycemicdrugsh avesh own thatthe decreasesinHbA 1 c wit h an ytre atment aredire ctly p roportionaltothe baselineHbA 1 c levels(13).Indr ug-naivepat ien tswith type 2diabe tesinthe rosiglit azoneclinicaltrials(Fig.41. 6),itwasappar entt hat thesame doseofthe samedru gresu lt edin a2.2% P. 692 decr easeinHbA 1 c comparedwithplacebot reat me ntat abas eline of10.0%bu tinonlya0. 8%decre ase
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at abase line of7. 0%.The seeffect softh enature ofth epopulation sstudiedandth ebas eline HbA 1 c levelson gly cemicre spon sesare relevantbecause t heysh owth atitisnotpossibletocompareth e efficacyofdiffe rent agen tsonglycemiccontr olunlesst hecomparison isder ive dfromdat agen erated fromth esamerandomized dou ble -blinde dstudy.
FIG. 41.5.Availablepharmacologicagentsamelioratethehyperglycemiaoftype2diabetesbymanydifferent mechanisms.Theantihyperglycemiceffectofagentswithdifferentmodesofactionareadditive.SeeTable41.9.
TABLE 41.9. Effect of Combination Therapy with Oral Antihyperglycemic Agents on Glycemic Control in Registration Studies
Drug Metformin 2,000 mg/d + Glyburide Repaglinide Nateglinide Acarbose Rosiglitazone Pioglitazone Rosiglitazone 8 mg/d + Repaglinide Sulfonylurea Pioglitazone 30 mg/d + Repaglinide Sulfonylurea
Dosage (mg/day)
Baseline mean HbA1c (%)
Additional decrease in HbA1c (%)a
Percentage attaining HbA1c 7%
20 12 120 600 8 30
8.8 8.3 8.4 7.8 8.9 9.9
1.3(1.7) 1.1(1.4) 0.7(1.9) 0.8 1.2(0.8) 0.8(0.64)
NA ~60 NA NA 28 NA
12
9.2
1.15(1.45) 1.4(1.4)
NA NA
12
9.6 10.0
2.2(1.9) 1.3(1.2)
NA NA
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Insulinb + Metformin Sulfonylurea Rosiglitazone Pioglitazone NA,notavailable.

a
2,000 8 30
9.0 8.9 9.0 9.9
0.54(2.1) 1.0(1.8) 1.3(1.2) 1.0(1.3)
NA NA NA NA
Differencefromplacebotreatment(differencefrombaseline).
bInsulindoseisusuallydecreased15%to25%whenoralagentsareaddedtoaninsulintreatmentprogramin patientswithtype2diabetes.
DatafromLebovitzHE.Oraltherapiesfordiabetichyperglycemia.Endocrinol Clin North Am2001;30:909933.
FIG. 41.6.Themagnitudeofglycemicresponsetoeveryantihyperglycemicagentisinverselyrelatedtothebaseline HbA1c.Thedataherearefromacohortofdrug-naivepatientswithtype2diabetestreatedinadouble-blindplacebocontrolledfashionwithrosiglitazoneat8mg/day.Theplacebo-treatedpatientshadthesameincreaseinHbA1c regardlessoftheirbaselineHbA1c.
Insulin Secretogogues
MECHANISM OF ACTION
The insu linse cretogoguescu rren tlyavailablestimulate t hese cretion ofinsu linbycausingclosureofthe ade nosin etriphosph ate(ATP)-depen dent potassiumch an nel(K A T P )inth eplasmamemb rane ofth e-cell (38,39,40). TheK A T P chan nelisc ompose doftwodiffe ren ttypesofsubu nitsan disassembled fr omfou r subu nitsofeach type(Fig .41.7) .TheKir-6.2su bun itsmak eupth einwar drectifie rthr ou ghwhichK + is transporte dfromthe in trace llular compart men ttothe extracellu larcompartme nt. Th eSUR -1subu nitis at tach edtothe K ir- 6.2subu nitand regulat eswhet her t heK A TP chan nelisope nor closed. Th eSUR-1 subu nitcontain sabindingsiteforsulfon ylureaan drelate dmole cules,aswe llasbinding site sforATP an dade nosin edip hosphat e(ADP).Whe nth eATP:ADPrat ioin creases,asoccu rswhen the plasmaglu cose levelise le vate dorwh ensu lfonylur easorth enewe rin sulin secret ogogue sbin dtot heSUR -1su bunit, th eK A T P ch ann elcloses(Fig. 41.8). When theK A TP channe lclose s,K + accu mu latesat thep lasma membr ane and cause sdepolariz ation ofth emembr ane adjace nttothe closedch ann els.De polar ization of th eme mbrane cause sv oltag e-depe nden tL-type calciu mch ann elsin t hemicr oe nviron me nttoopenand
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forCa 2 + toen terth eintracellu larcompartmentfr omthee xtracellu larcompar tme ntandincreaseth e cytosolicCa 2 + conce ntration in the-ce ll.The in crease in Ca 2 + stimulatest hemig rationan dexocytosis oft heinsu lingr anu le .
FIG. 41.7.Thepancreatic-cellKATPchannelisopenandextrudingpotassiumionswhentheplasmaglucoselevelis low.Theadjacentvoltage-dependentcalciumchannelisclosed.TheKATPchannelconsistsoftwotypesofsubunits: theKir-6.2subunit,whichmakesuptherectifier;andtheSUR-1subunit,whichregulatesopeningandclosingofthe channel.
FIG. 41.8.Whentheplasmaglucoselevelincreases,theATP:ADPratioincreases,causingtheKATPchanneltoclose. Thatinitiateslocaldepolarizationoftheplasmamembrane,resultingintheopeningoftheL-typevoltage-dependent calciumchannels.Calciumionsenterthecell,andtheriseincytosoliccalciumionconcentrationstimulatesinsulin secretion.
Allofthesu lfonylur easandth ene we rnon-su lfonylur eainsu linsecr etogogu es,r epaglinidean d nateglinide,actbybindingtothe SUR-1subun it softh eK A T P ch ann els,cau sin gthe mto close (41, 42,43).Differ ence sint heinsu linsecr etorycharact eristicsofth evar iousinsu linsecr etogogu es ar edepen den ton the irph armacokinet icproper tie sandt heaffin ity andkine ticsofth eir bin din gtothe SUR-1subu nit(41,42,43).
P. 693
PHARMACOLOGY
The n or malre gulationofinsu linse cretionist igh tlycou ple dtot heplasmaglucoselevel(44,45). Incr easingplasmaglucoseleve ls, su chasthoseth atoccurfollowin gin gestion offood, resu ltinan almostimmediat eincreaseininsulinsecre tion. De creasingp lasmag lu coseleve lsareassociate dwith a rapidde cline in t hese cretion an dplasmale velsofinsulin.Fast in gisaccompan ie dbyredu ctionsin insulinsecre tion su fficien ttoin crease hepaticprod uction ofglucosetomain taing lu coseh omeostasis. The idealinsu linse cretogogue, ther efor e,wouldbeoneth atr estorestonormalt hede fectiveearlymealmediatedinsu linse cretionoft ype2d iabetes, in creasesin sulin secret iontoad equatelyov ercomet he insulinresistance, stimulat esinsulinreleaseon ly in r esponsetoelevatedplasmaglucoselevels,andh as litt le orn olagtimein it sin sulin secretoryr esponsetorap idlychangingplasmaglucoseleve ls. None of th eavailab leinsu linse cretogoguesfu lfillsallofth eseproper tie s. Earlypost pran dialh yperglyce miainth ein dividu alwit hdiabet esisacon seque nceofdelaye dand inade quateearlysecret ionofin sulin (44,45,46).Latepostprandialhypoglycemiain the sesubjectswith
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type 2diabe tesresu lt sfroman in crease in drug-mediat edlateinsu linse cretion thatisfu rth er acce ntu ate difth ereisan ear lyex agger ate dpost pran dialh yperglycemia.Fast in gorn oct urn al hy poglycemiaismorelike lyt ooccurinpatientswith t ype2diabetes admin iste redinsulinsecr etogogu es th ath avelonghalf-livesan dstimu lateinsulinsecre tion int hepre sence oflowglucoselevels(45). The factorsdete rminingt heclin icale ffectsoftheavailablein sulinsecre togogu esare listedinTable 41. 3 an dtab ulatedforeachsecr etogogu einTable41.4(13,47).Th emajorfactor stoconsiderinpr escribin g an in sulin secret ogogue aret herateofon setofitsaction ,th eduration ofitsaction,t hedeg reetowhich itsactionisdepen dent ont heplasmaglucoselevel,anditsspect rumofsideeffect s,including inter actionwit hK A T P ch an nelsin oth ertissu es.The majorcomplication softh erapywit hin sulin secre togogu esar ehypoglycemiaandwe igh tgain, bot hofwh ich areman ife stationsoft heinabilityof th eseag entst osimu laten ormalphys iologicin sulin secret ion(47,48, 49,50).The c loserap articular insulinsecre togogu ecan restoreinsu linse cretoryph ysiologyt on ormalin the patien twith type 2 diabet es,th elessthe setwocomplicationswilloccur. Th eeffect ive nessofallinsu linse cretogoguesin stimu latinginsulinsecr etion andinr educingh yperglycemiaisdepen dent ofth eprese nceoffunct ioning -cells.Insu linsecr etogogu esar eineffect ive in p atient swith type1diabete s,inpat ien tswithlate nt au toimmu nediab etesofadu lts(LADA),an din the laterstagesoftype2diabete swhen pancr eatic-cell fun ction ismarke dlyd eficien t. TABLE 41.3. Factors Influencing the Clinical Effects of Insulin Secretogogues
Bioavailabilityfollowingoraladministration Timetoreachmaximalconcentration AffinityforandkineticinteractionwithSUR-1subunitofthepancreatic-cellKATPchannel Plasmahalf-life Mechanismofmetabolismandactivityofmetabolicproducts Routeofexcretion InteractionwithotherKATPchannels Sideeffects
TABLE 41.4. Characteristics of Specific Insulin Secretogogues
Drug
Dose range (mg/day) 5003,000 100500
Peak level (hr)
Halflife (h) 4.56.5 36
Metabolites
Excretion
Sulfonylurea Tolbutamide Chlorpropamide
Kidney Kidney
34 2.4
Inactive Activeor unchanged Inactive Inactive
Tolazamide Glipizide
1001,000 2.525a
34 13
7 24
Kidney Kidney80%, bile20% Kidney80%, bile20%
Glipizide-GITS
520
Constantafter severaldaysof dosing ~4
Inactive
Glyburide
1.2520
10
Inactiveand weaklyactive Inactiveand
Kidney50%, bile50% Kidney50%,
Glyburide,
1.512
23
~4
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micronizedformulation Glimeperide 18 23 9
weaklyactive Inactiveand weaklyactive Inactive
bile50% Kidney60%, bile40% Bile Urine
Meglitinide Repaglinide D-phenylalanine Nateglinide
1.512b 180360b
0.75 0.51.9
1 1.25
aUsualmaximumeffectivedose.
Dividedintothreedoseseachgivenbeforethemeal.
DatafromLebovitzHE.Insulinsecretogogues:oldandnew.Diabetes Rev1999;7:139153;andLebovitzHE, MelanderA.Sulfonylureas:basicaspectsandclinicaluse.In:AlbertiKGMM,ZimmetP,DeFronzoRA,KeenH, eds.International textbook of diabetes,2nded.Chichester,UK:JohnWiley&Sons,1997:817.
K A T P ch an nelsare presen tinmanyoth ertissues, in clu din gbrain ,myocar diu m, andv ascular smoot h musclecells(38, 39, 40,51).The SURsub unitofthebr ainK A T P ch an nelist hesameasthatoft he pan creatic-cell(SUR -1),wh ileth eisoformsinmyocardiuman dvascu larsmoothmusclecellare differen t(SUR-2Aand SU R-2B). Theabilit ie sofvariousinsu linse cretogoguestointer actwitht he differen tisoformsofthe SURsub unitar enotth esame.Th isre sultsin pharmacologicdiffere ncesandhas bee npostulate dtoprodu ceclin icaldiffere ncesinside-effe ctprofiles. P. 694
SPECIFIC CLASSES OF INSULIN SECRETOGOGUES Sulfonylureas

Sulfon ylureadrug sh ave been usedinth etre atment oftyp e2diabe tessincet heearly1950s.Ext ensive lite rat ure, in clu din gmanyre vie warticles,isavailable(13, 45, 47).The majorne winformationcon cern in g th euseofsulfon ylureasin the treatme ntoftype2diabete shascomefromth eUKPDS(12,52, 53,54), th edeve lopme ntprogramsofthe newer sulfony lu reassu chasglime pir ide (55) ,an drecen tstud ies invest igatingth eeffectsofsulfon ylureason myocar dialandvascularre spon sestoisch emia (56,57,58, 59). The su lfony lu readr ugsdonotappe artocorrectt hede fe ctinearlyinsu linse cretioncharact eristic oftype 2diabetes(60, 61) .Theirprimaryactionistoin creasethe latestageofins ulin se cretion.Th isincre ases th elikelihoodoflatepostprandialan dfastingh ypoglyce mia. Th esulfonylure adru gsdon otincr ease insulinbiosyn the sisand,inde ed,se emt oinh ibitproin sulinbiosyn the sisin vitro.The reisnoe vidence th atth eyareeithe r-cytotropic orth att heyfacilitate -cellexh au stion(12, 47).Inth eUK PDS, patien ts tre ate dwith sulfon ylu reasshowedan in crease in -cellfun ction forth efirstyearbut ther eafte rshowed th esamerateoflossof-cellfunct ionastheconve ntionallytreatedgr oup (12). Quest ionsh avebe en raised con cerningt hepossibilit ythatsulfonylure as,be cause ofth eirprolonged e ffectsonth epan creatic -cellK A TP channe ls, cou ldlead tode sensitizat ion,with d imin utionoft heirpharmacologiceffects. Seve ralclinicalstu die sshowing t hathigher dosesofsulfon ylureasmaybelesseffect ive thanmodes t dosesinlowering h yper glyce miapr ovidesome supportforthishyp oth esis(62,63).Cont in uousin vitro incubation of-cellswith gly burideh asbeen showntole adtoan in creasein funct ionallydeficientK A TP chann els(64). Pr eviou sstudiesh avesh own thatsulfon ylu reascane xertavar iet yofex trap ancr eaticact ionsin laborat orymodelsin v ivoan din vit ro(47). Ithas b eendifficulttodemonst rate con clu sive lyanyofthe se effect sin human s.Somein vivostudiesinhu manshavesh own t hat sulfon ylu reascanlowe rplasma glucoselevelsun dercondition sin wh ich the peripher alplasmain sulin lev elsareu nchange d.These stu die shave notexclude dsmallchangesinth eportalvein insu linconce ntration s,whichinfluen ceth e live rbutaren otmeasurable inp eripher alb lood. Twoeffect sofsu lfonylure asth atoccurinh umanst hat mayre sultin extrapan creatice ffectsar ein teraction swith K A T P ch ann elsin oth ertissue s(39)anddirect effect son calciu mion -me diatedex ocyt osis(65). K A T P ch an nelsin cardiacmyocytesandvascularsmooth mu sclece llshaveSUR r egulat ory subun it s,which
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differsomewh atfromtheSU R-1su bunitin-ce lls(38,39,40).Th esedifferen tsubu nitschange t heir bindingch aracteristicssuch t hat the ymayhav ele ssaffinityfor someligandsth atcauseinsu linse cretion th anforother s.Brain- cellplasmamembr ane scon tainK A TP chan nelsth ath avet hesamer egulat ory subu nitaspancre atic-cells. Itisther efor epossibleth atsome sulfony lu reasmightinte ract with K A T P chann elsint issu esot hert han -cellsandcau seext rapancre aticeffect s.Another mech an ismbywhich specificsulfony lu reasmightcausee xtrapancr eaticeffect sisth roughdire ctenh an ceme ntofcalciu mmediatede xocy tosisofoth erhormon esth atarestoredinse cretorygranu les. Pre sent ly, ther eislittle eviden ceth atsu lfonylure asexe rtan yclin icallysignificante xtrap ancr eaticeffect sin human s.Theonly exce ption may beeffect sont hemyoc ardialan dvascu larsmoothmuscleresponse stoische miaand hy poxia.
Chlorpropamide
Ch lorpropamideisafir st-gen erationsu lfonylur eath ath asbee npre scribe dexte nsivelywor ldwidefor almost40ye ars. At dosagesrangingfrom100to500mgonce aday ,it ish igh lye ffe ctiveinredu cin g hy perglycemia,but becau seofitsve rylon gplasmahalf-life ,it hasbe enassociat edwit hasignificant incidence ofseve reandprotractedh ypoglyce mia,particular lyinth eelderly(47,66). Other sign ifican t sideeffect sarewaterre ten tionwith h yponat remiaand alcoh ol-in duced facialflush in g(45). Ch lorpropamideisunique amon gsulfon ylu reasint hat itst imulate ssecret ionofant idiur etichormone s an dpot ent iatesan an tidiur etichormone effectinth eren altubu le s.Thee ffectonwat erbalan ceis th ou ghttoexplaint heobserv ation in theU KPDSofanincreaseinsystolicanddiastolicbloodpre ssure as wellasagre ate rnee dforantihyp erten siv ethe rapyint he619patient streatedwithch lorpropamideth an inpat ie ntstre ate dwith in sulin ,glybur ide ,or conv ent ionalth erapy(2). In the UKPDS,ch lorpropamide tre atment redu cedHbA 1 c sign ifican tlymoreth an didglybu rid eorinsu lin;h owe ver, t hiswasnot accompaniedby any g reat erred uction in risk forpr ogre ssionofretinopat hy(2).Many p reviou sstudies haven ote dthathypoglycemiaisamajorriskofch lorpr opamidetr eatmen t.Major hypoglycemicev ents occurre dle ssfr eque ntlyinth eUKPDSinth echlor prop amide -treatedcohortth anint heglybur ide -treated cohort(2).
Glyburide
Glyb uride(glibe nclamide )iscu rren tly themos twide lypr escribedsulfonylure abu tnotbec ause itis more effectiveorsafe rthanother sulfon ylu reas.Itismarkete dasaformulationwit hpoorandvariable bioavailability(dosage 1.2520mgdaily)andasamicronizedformu lation with relativelygoodand consisten tbioav ailability(dosage1.512mg d aily)(45, 47, 67).Itsefficacy inr educingh yperg lyce mia app earst obee qualtothatofoth ersu lfonylure as,bu titisassociat edwithah igh rat eofse riousside effect s,includingitslong d urationofaction,witharat eofser iousandfat alhypoglycemiathatis significantlyhighe rthanth atwith oth ersulfonylure as,mod estweightgain,andar elativelackof specificity ont hediffere ntK A T P ch an nels(67,68,69). Care fulevaluation ofth e615patientswith t ype2 diabet estre ated with glyb urideforamean of11yearsinthe UKPDShascle arlydefine dthe charact eristicsofchr on icglybu ride ther apy(2).Itismosteffec tiv ein con trollinghyp erglycemiain pat ie ntswithn ewly diagnosedtype 2diabe tesforthefirsty earor2andt hen b eginstolose effect ive nesspr ogre ssive ly with time(second aryfailure orsu lfonylur eaine ffe ctivene ss)(52,53,54). Glyb uridetre atment alon ewasre lativ elyin effectiveincontr olling h yper glyce miaafter4or5years(54). The median decre aseinHbA 1 c in pat ien tstre ate dwith glyb urideascompare dwith patien tsrece iving conven tion al(die t)treatmentover 10y earswas0.7%(7.2%v s.7. 9%)(2). W eigh tgain occur red primarilyint hefirst3or4year softr eatmen tan dwasmain taine dthr ou ghoutth estu dy,sothatat10 yearsth egly buride-tr eat edpat ien tshadgaine d1.7kgmore thanthe con vent ionallytre ate dpatien ts (2). Seriou shypoglycemiaoccu rredprimarilyduringt hefirstfewye arsofglyb urideth erap y,whe nit had bee nmoste ffe ctivein redu cin ghype rglycemia.Majorh ypoglyce miceve ntswere notedinap prox imate ly 1. 4%ofpatient siny ear1,1.3%inyear2, and0.4%inye ar3(2).Th eseratesofseriou shypogly cemic eve ntsarecomparabletoth oser eportedinothe rlargese rie sandaregre ate rthanth ose with oth er sulfonylure as(Table41.5)(68,70,71, 72). TABLE 41.5. Serious Hypoglycemia Reported in Large Retrospective Studies
Study TennesseeMedicaid(13,963patients; 20,715person-years)(71)
Sulfonylurea Allsulfonylureas
Rates of serious hypoglycemiaa (per 100 person-years) 1.23
Glyburide Glipizide
1.66 0.88
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VAMP-ResearchDataBase(33,243 patients)(72)
Tolbutamide Allsulfonylureas
0.35 1.77
aSerioushypoglycemiawasdefinedintheTennesseeMedicaidStudyasadmissiontothehospitalemergency departmentordeath,withameasuredbloodglucoselevelof<2.8mmol/L;andintheVAMPDataBase,asa conditionrequiringtheassistanceofanotherperson.
Glipizide
Glipizide isasulfon ylu reat hatisavailablein bot hash ort -actingformulationan din ane xten ded-re lease formu lation (g lipizide -gastrointest in alther apeu ticsy stem,orglipizid e-GITS)(45).Th eshort-acting formisrap idlyabsorbe dandiscomplete lybioavailable. I tismetabolizedbyoxidativeh ydroxylation an d iselimin ate dwith ahalf-lifeof2to4hours(45). P. 695 Itseliminationisnotaffe ctedbymildtomoder ate renalinsu fficien cy(creatin in eclearance 30mL/min ) (45).Glipizideis admin iste redonceortwiceaday.It se fficacyise qualtothatofg lybu rideincon trolling hy perglycemia,but becau seofitsmetabolismandmore rapideliminat ion, t her apywithglipizideis associate dwith le sshypogly cemia(45). Theofficialmaximu mdosageofglipizideinth eUnite dSt ate sis 40mg p erday ,althoug havailab leclinicalstudiessh owlit tle orn obe nefitingivin gmoret han 15or20 mgperday.Glipizide shouldbeadministere dbefor eme als,asitsabsorp tionmaybe mild lyde layedby foodinge stion. The e xten ded-re leaseformu lation ofglipizideprovidesonce-a-daydosageof5to20mg(73,74).Plasma levelsofglipiz ide 24h ou rsafte rdose sof5mgand20mg ofglipizide-GITS(GlucotrolXL)are54ng /mL an d310n g/mL, respect ive ly. Thedecr ease sin Hb A 1 c inclin icalt rialswith glipizide -GITSwer e1. 50%an d 1. 84%comp ared with placebotreatme nt. Th edecr ease inHbA 1 c wasmax imalat5mgpe rday. FPGleve l wasre duced 57mg/dLto74mg/d Lcompare dwit hplacebotre atment .Thee xten ded-releasefor m app earst oh aveglucose-lowe ringeffect ssimilar tot hos eofimmediat e-releaseglipizide,asmeasure dby th eimprovement in Hb A 1 c . Inast udycomparingglipizide-GITStoimmediat e-act in gglipizid e,th e au thorsconcluded thatthe g lipizide -GITSformu lation atdosage sof5mgan d20mgh aveanimpr ove d metab olicpr ofile compare dwit hthatofimme diate-actin gglipizide;however ,th edesignofthest udy makessu chaconclusionten uous. Noin creaseinhyp oglycemiawasnote dwith the e xten ded-actin gfor m.
Glimepiride
Glime pir ide isth ene we stoft hesu lfonylure astobeapprovedfor use. Itissaidt obemoreselectivefor th e-cellK A TP chan nelth anforth ecard iovascu lartissueK A TP channe l(75).It appearstobin dtoa sligh tlydiffe rent p artofthe sulfon ylu rea-bin din gsit ethandoesglybur ide ,although the two sulfonylure asdisplaceeachother fromthe irr espective b in din gsit es.Glime pir ide associates2.5-t o3.0foldfasteranddissociat es8. 0-to9. 0-foldfasterth an glybu ridefromits-cellK A TP -bindingsite(75,76). Insu linr ele aseisth ereforemor erapidan dofsh or terdu rationth ant hat with glyb uride.Hype rglycemic an deug lyce mic-hype rin sulinemicclampstu die sinp atient swith type2diabete sdemon strat edthat glimepiridedoesnotrest ore first -phasein sulin secret ionandth atitincreasessecond- phase in sulin secre tion ,whole -body g lu coseu ptak e,andincreasesinsulinsen sit ivity(61). Somestudiesh ave sugg estedt hat g lime pir ide r educe shyper gly cemiawith lessinsu linse cretion thanth atre quiredby oth er sulfonylure as,andth ish asledtotheclaimthatglimepirid ehasaninsu lin-sparingact ion (57,77,78, 79,80).The dataare mar gin ally sign ifican t,an dadditionalstud iesarere quiredtosubst an tiate th isclaim. Forglimepiride,asforallother sulfony lu reas ,the rear eclaimsth atithasextr apan creatic effect s.Someofthee ffectsdescr ibe dareanincre aseinglucoseup take andu tilizat ionbyanincre asein th etranslocationofth eGLU T4transporte rproteininad iposean dmu scle cells, aneffe cton the reg ulation ofth eintracellu larroutingofthe in sulin recept orcomp lex estowardde gradativepat hway s, an dan in crease dassociation ofth ein sulinrece ptor with proteinkinaseCisozy mes(76, 79).These ext rapancre aticeffectsh ave beend emonst rate din in vit rosyst ems, an dtheirre lev ance toglime piride effect sin human sisde batable . Glime pir ide isadministere don cedailyatdosag esran gin gfrom1to8mg. Th erec ommen dedstarting dosageis1t o2mgdaily,andth eave rage main tenance d osageis1mgt o4mgdaily(57,77, 78, 79,80). Glime pir ide isabsorbe dquicklyan dachieve smaximalbloodglucoseloweringwith in 2to3hour s,but its blood-glucose-lower in geffectisstilleviden tat24h ou rs.Likemostsu lfony lu reas, glimepiride is metab oliz edbyth eliver anditsmetabolitesar eexcre tedviat hekidne y.Ina1-ye arcomparat ive clinical trial,glimep irideandglybur ide we reequ iv alentincont rollin ggly cemia;h owe ver,fastingplasmainsulin an dC-pe ptid evalue swe restatisticallysignific ant lylowe rin patien tstre ated with glime pir ide thanin
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pat ie ntstr eate dwit hglyburide(77). Glimepiridered ucedHbA 1 c 1. 2%to1.9%andmean FPG54mg/dL to76mg/dLcompare dwith placebotreatmentinst udiesofmon ot herapy(57,78). Glime pir ide treatme ntisassociatedwith lowerratesofdocu men tedh ypoglyce miath an isglybur ide tre atment (1.7%vs.2. 4%)an dwith rat esthatar eequivale nttothosewithglipiz ide(0.9%vs. 1.2%) (57,79,80).
Repaglinide
Rep aglin ide isanon-sulfon ylureain sulin secre togogu e.Itisamemberoft hemeglit in ide family(Fig. 41.9)(81,82,83).Th eme chan ismofaction ofinsu linre leaseforrepaglinideissligh tly differ entfr om th atofsulfon ylu reas(44).Repaglinideint eract swith aspec ificbin din gsit eonthe SUR-1subun it thatis distinctfromt heglybur ide sulfon ylu rea-bin din gsit ebutst illcause sclosure ofth eK A T P ch ann el. Rep aglin ide ,un likesu lfonylur eas, d oesn ot dire ctlystimulat eexocytosisofinsulingranules(65). Rep aglin ide israpidlyabsor bedorally ,wit hth eC m ax occur rin g45to50minut esafte rin gestionan d plasmalevelsret urn in gtobaselin ein3to4h ou rs(47,83).Th epharmacokin etican dK A T P channe l inter activepr ope rtiesofre paglinideresu ltint hemor erapidre leaseofin sulin andforash or terdu ration th anwithsu lfony lu reas. Theinsulin-re leasingact ionofrepaglinidecommen ceswit hin30minu tesand facilitatese arlyme al-relate dsecret ionofin sulin .Itsmajorin sulin secret ory e ffectsub sides in app rox imate ly4hours. Be cau serepaglinideisash ort -acting insulinsecre togogu e,itmustbet aken with in 30minu tesofeach meal. When amealissk ippe dor delay ed,th eadministrat ionofrepaglinidesh ou ldbe altere dsimilar ly(84). Th eabilit ytoalt erth etime an ddos eofre paglin id eadmin ist rat iontomatchmealingest ionmor ecloselyre ducesth elike lihood of postprandialorfastinghy poglycemia.Thisisanadvan tag eove rtradit ionalsu lfonylure atre atmen t, alth ou ghmultipledosesofrepaglinidepe rdayaren ecessary.Re paglin id eisadminister edas0.5mgto 4. 0mgbeforeeachmeal,andth edose canb eadjust edon the basisofth eestimated caloriesand conten toft hemeal(83,85). P. 696
FIG. 41.9.Structureofthenewrapidinsulinsecretogoguescomparedwithasulfonylureasuchasglyburide.
Mon oth erapywit hrep aglin ide in p atient swith type2diabete swasfoundt ore ducemean HbA 1 c by1.7% an dme anFPGby62mg/dLascomp aredwith placebotreatme nt. One-ye artr ialssh owedt hat the an tihyper gly cemiceffect sofrep aglin ide andg lybu rideare equivalen t(86).Although repaglinide-t reat ed pat ie ntsex perience hypogly cemiaandweigh tgain, t hemagn it udeissign ifican tlyle ssthanwith glybur ide. Rep aglin ide ismetabolizedbyth elive r,an d90%ofth edose isex crete din thebile.The refore, rep aglin ide isn otcontr aindicate din patien tswit htype 2diabet eswhohaveimpaire dren alfu nction.Th e doseofr epaglinideshouldbere duced inpatient swith clinicallysign ifican tlive rdise ase.
Nateglinide
Nate glinideisaD-phe nylalanine derivat ive (Fig.41.9)thatdoesnotcontain asulfonylure amoiety, is rapidlyabsorbe d,an dbindstothe SU R-1s ubun it ofth eK A T P ch ann elwith bin din gcharacte risticsqu it e differen tfromth ose ofsulfonylure as(43).Wh ennateglinideisadmin iste red10min ute sb efor ethe meal, itspeakplasmale velisachievedatamean timeof0. 92h ou rsan dit smeanh alf-timedisappe arance rateinplasmais2.14h ou rs(10,87).Oralbioavailabilit yisest imate dtobe72%. Thedru gis metab oliz edbyth emixed-fu nctionoxidasesyste mofthe liver(C YP3A4an dCYP2C9)b efor eexcre tion (87).The druganditsmetabolit esare elimin ate drapidlyand c omple tely.Ifnateglinideistake nafte rthe meal,itsrateofabsorption isdecr ease d,resu lt in gin a22%in crease in thet imetomaximalplasma levels.
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Bindingan ddisplacementst udieswit hnateglinidean dthe - cellK A T P ch an nelin dicatet hat itdissociates ver yrapidly.Inh ibitionoft heK A T P chan nelcur rent bythe patch -clampt echn iqu ean dit sr ever salcon firm th erapidandshortdu rat ionofnat eglin ide action on thech an nel.Nat eglin idese le ctiv ely bin dstot he K A T P ch an nelofth e-cellandbinds r elativelylitt let oth eK A T P ch an nelofvascularsmooth mu scle (relative bin din g,45-to311-fold r elativeselect ivity)(51). It hasa1. 6-foldselect ivityforinhibitionof th e-cellK A TP chan nelcur rent ascomparedwithth ecar diacK A T P chann elc urre nt.Th eseproper tie sof nateglinideare predictiveofarapidandsh ort d urationofstimu lationofin sulinsecre tionwith littleorno poten tialforeffect son cardiacorvasculartissue s. Clinicaldataare consiste ntwithwh atwouldbepred icte dfromth epharmacologicpr ope rties. Admin istr ation ofn ate glinidetofaste dpatien tswit htype 2diabe tescau sedasmallin creas ein plasma insulinlevels(45U/mL),whichpe ake dwith in anh ou ran dcau sedasmallde creasein plasmaglucose overth e4-h ou rperiodfollowingdosin g(10,88,89). In con trast,whe nnateglinidewasgiven tot hesame individ uals10minu tesbe fore ame al,th eplasmain sulin le velsin creasedby30minu tes, peake dat2 hour s,an ddeclin edat 3hourst oth ose lev elsse enfollowin gtreatmentwithplacebo(88). Nateglinide increasedmeal-mediated p lasmain sulin lev elsinadose -depen dent manne r,withamax imumeffective doseof120mg. Whe nadministere dasmon oth erapyfor 12we ekstopatien tswit htype 2diabet eswhoseglucoselevels were in adequ ate lycont rolledbydietandexe rcise(me anHbA 1 c 8.4%;mean FPG182mg/dL), adoseof 120mgadministere d10minut esbeforemealsresu lt edinade crease in HbA 1 c of0. 55%andina red uction in FPGof21mg/dL (10). Alargerandomizeddouble-blindstu dyinpat ien tswithtyp e2 diabet es,withwashoutofthe irpr eviou streatme ntfor4wee ks,compared24wee ksoftr eat men twit h 120mgofn ate glinidebe fore each mealt o500mgofmet forminthr eetime sadayand t oacombin ation ofmet formin an dnateglin ide (89).Place bot reat men tresu lt edina0.5%incre aseinHbA 1 c ,wh ereasmet formin tre atment resu lte din a0. 8%decre aseandnateglinidetre atment resulte din a0. 5%decre ase. Comb in ation nateglin ide -me tforminth erap yresulte din great erimpr ove men tinglycemiccontr ol(1. 4% decr easeinHbA 1 c and40mg/ dLdecreaseinFPG)thandideithe rdrugalone .Themajorbene fit of nateglinidetre atment isar educt ioninth epostprandialglu cose e xcurs ions. The p ote ntialsid eeffectofnateglin ide ish ypog lyce mia. In the clinicalstud iescomple tedtodate , hy poglycemiaappe are dtobe relativelyun common andmild. P. 697
INSULIN SECRETOGOGUES AND CARDIOVASCULAR EFFECTS

Startingwithth ereportofthe resultsofUnive rsit yGroup Diabet esProgramin1970,t here hasbe enan ongoin gcon cern aboutwhe the rsulfon ylu reashav eadet rimen taleffectont hecardiovascularsyst em (90).In thatstudy ,the aut horsnotedth atch ronictreatme ntofpatien tswit htype 2diabet eswit h tolb utamidefor8yearswasassociat edwithast atistically sign ifican t75%incr ease incardiovascular mort ality ascomparedwithth emort ality int heplace bo-t reat edcontrols.Thede sign and r esultsofthat stu dyweree xten sive lycr iticizedth roughout the1970s, andse veralsu bseque ntstu die sfaile dtoconfirm th eir fin din gs. Int he1980s,K A TP chan nelswere fou ndtobepre sentint heplasmamembran esofmyocardialan d vascularsmooth musclece llsan din pancr eatic-cells,an disch emicpre con dit ioningwasdiscovere d (91,92). Isc hemicpr econ ditioningisth ephen omen on where byash ort p eriodofisch emiafollowedby rep erfusiontransient lypr ote ctsthe myocar diu mfromasubseq uen tmorese vereandprolon gedischemia an dredu cesth eare aofinfarction in the isch emicreg ionbyasmu chas75%to80%.In for mationh as accu mu latedt hat ind icatesth atth emechanismre spon sibleforischemicpr econditioning inv olvesan openingofthe myocar dialandcoron ary arte ryK A T P ch ann elsbythe met abolicconsequ ence sofischemia (93).The effectsarean in creaseinK + efflu xan dare ductionin Ca 2 + influxint oth ecells. The consequ ence sareashorten in goft hedu rationoft hemyocardialactionpoten tial, are duction in contractility, ener gycon servation bythe myocard iu m,andvasodilatation bythe c oronaryar tery. Another consequ ence ofth eK + changes, however, isapossiblein creaseinven triculararrhy thmias. Whe nitwasre cogn ize dthatthe primaryactionofsu lfony lu reasistocloseth eK A T P ch an nelsin the pan creatic-cells,t hequ estion aroseas t oth epossiblee ffe ctsofsu lfonylur easoncardiovascularK A T P chann elsandwh ethe rsulfon ylureatreatmentmightinte rferewith thepr ote ctiveeffect saffor dedbyth e openingofK A T P ch ann elsbyisch emiain cardiov ascular tiss ues(94).Aser ie sofstu die swe recarriedou t, firstinan imalmodelsan dsubseq uen tly in h uman s,thathavedemonstratedt hat dose sofglyburidein th eran geofthemaximalprescribeddosescanblock isch emicprecond itioning,pr esumablybyclosing t he K A T P ch an nel(95,96). The clinicalsign ifican ceofthese obse rvat ionsisnotcle ar. Ar etrospectivest udyfromt heMayoClinic rep ort edthatpat ie ntswithdiabe tesu nderg oingangioplast yforacute myocar dialinfarction hadariskof early mortality2.77timesgr eat erth anpatientsr eceivingnothe rapy orre ceivin gin sulin (97).The BypassAn gioplast yRevascularizat ionIn vestigat ionre por tedth atpatientswithd iabetesh adgre ate r lon g-termmortalityfollowin gan gioplastyt han didpatient swith ou tdiabete s,but thet wogroupsh ad
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similarmort ality followin gbypasssurge ry.The sulfon ylu rea-treatedpatie ntsinparticularh adgre ate r mort ality 4to7ye arsaft erth ean gioplasty(98). Incontrast,Klaman net al.(99)havereporte dno increaseinmort ality orinfarctsizeinacohortof245patie ntswitht ype2d iabetest akingglybur ide wh o were admitt edwithan acu temyocardialin farctionan dfollowedforameanof6.5year sascompared withth ose not taking asulfon ylurea.Someinve stigatorshaveindicate dthatpat ie ntswithdiabe tes tre ate dwith gly buridemayh avealowerrateofven triculararrhyt hmias. Alloftheclinicalandanimalst udiesshowin geffect softh esulfon ylu reason isch emicpre con dit ioning haveu sedglyburideasthesu lfonylur ea. Th ebindingaffin itiesofgly burideforthe K A T P chann elsin car diovas culartissue sandforth ose ofth e-cellarealmoste qual(51).Tolbu tamidehasvir tuallyno bindingactiv ity tot heSUR -2subu nits(th ose inK A TP channe lsincardiovasculartissue s).Glime pir ide had noeffect onblockingischemicpr econditioninginh uman st udiesinwhichglybu ride abolishe dit(77). The non-su lfonylur eainsu linse cretogog uesh aveve rylitt le bin din gaffinityfor theSU R-2su bun itsandh avea ver yhighspecificit yfort heSUR -1(-cells ubun it )(51) .Summariz in gthedata, on ecan maketh e followingconclusions:(a)itislikelyth atinsu linsec retogog ueswithre lativelyequalspe cificityfor the SUR-1an dSUR-2subun itscou ldaffectcar diovascularre spon sesun derspec ificcon dit ions;(b)th eonly condition u nde rwhichadr ugth atclose sthe K A TP channe lmigh tinter ferewithn or malcardiovascular resp on sesisone in wh ich the reistran sie ntische miafollowe dshortlythe reaft erbymor eprolonge d ischemia;(c)the effectswouldbemanifestasagre ate rare aofinfarction ;(d)maximu mdosesof glybur idearemost likelytoin terfe rewithth ecard iovascu larresponse stoische mia;and(e)t hen ew non-su lfonylur eainsu linse cretogog uesaremuchlessornotat alllik ely topr odu cethosee ffe cts. De spit eallofth estudies, thequ estionofwh eth ersulfonylure atre atment hasde trimen talcar diovascular effect sin human sremainscontrover sial. Th erearecu rren tlynoclinicaldatathatun equivocally demon strateanadv erseeffe ctofglybu ride on ou tcomesre latedtocar diovascu lareve nts.
Insulin Sensitizers
The majorityofpatient swith type2diabete shave in sulin resistan cean dthe met abolicdisease syndrome asacomponen tofth eirdisorde r.The normalcompensator yresponse toinsu linre sist ance isasufficien t increaseininsulinsecre tion toovercomethe in sulin resistan cean dmain tainn or malglucosemetab olism. Glu cose int oleranceisan in dication thatthe in dividu al's-cells aren otse cretinge noughinsu lint o overcome theinsu linr esist ance adeq uat ely .Thee volutionofglu coseint oleranceinth eseindividuals progresse sfromnormalglu cose tolerancewith in sulin resistan cean dcompen satoryhy perinsu linemia,t o IGTwith in sulin resistan cean ddecre asingcompen sat oryh yperinsu line mia, tot ype2d iabeteswith insulinresistanceandfranklyinade quatesecre tion ofinsulin.Are duction in in sulin resistan ceat each an dever ystage ofth eevolution ofty pe2diabe tesinsu chin dividu alswillimproveglucoseme tabolism byallowingt heiren doge nousinsulintobemore effective(77,100). Additionalb enefitstobeaccrue dfr omredu cin gin sulin resistan cear eameliorationofsomecompone nts oft hemetabolicsyndrome(in sulin resistancesyn drome). Thesecompon entsincr ease macrovascular disease risk ,an dredu ctionofthe compon en tsofth emetabolicsyn drome areasimportan ttothe h ealth oft heindividualwitht ype2diab etesasisth etre atment ofth ehyp erglycemia(101,102,103).Treatme nt ofinsu lin r esistan ceatt hestageofIGTwithmetformincanslowt heprogre ssiontotype 2diabet esby 31%ove r3ye ars,alt hought hiseffectisnotasgr eatasthatwit hinten siv elifest yle modificat ion,wh ich slowsprogre ssionby58%ov er3y ears(104).Thiazolidine dione treatme ntmayalsobeh igh lye ffe ctive indelaying orpr even tin gthe developmen toft ype2diabetes ininsu lin-r esistan tin div idu als, ast roglitazone treatmentofwomen with previou sgestation aldiabete sdecreasedth edeve lopme ntof diabet esby56%ove r30month s(TRIPODstud y)(100).It h asbe enpostulat edth attr eatmen tofinsu lin resistanceitselfinthe absen ceofglu cose int olerancemay slowthede velopmen tofathe rosclerosisand macrovascu lardisease (36, 101, 103).C linicaltrialstoevaluateth ispossibilityar eun derway . The h ig hprev alenceofinsulinresistanceworldwide anditsimpactasacon tributortoth edevelopme ntof somanydisease shasmade thed iscovery ofdru gsfort hetr eatmen tofinsu linre sist ance aver yhigh prior it yfort heph armaceu ticalin dustr y.Cu rren tly ,twoclassesoforalagent s,the bigu an ides and th iazolidin edion es,areav ailable totr eat in sulin r esistan ce,andbothareimportantagent sforth e tre atment oftyp e2diabe tes.Met formin ist heonlywid ely availablebiguanide.Rosiglitazon ean d pioglitazone aret hecu rren tly availableth iazolidin edion es.Troglitazone, wh ich wasth efir st th iazolidin edion etobemarket ed,waswith drawn fromth emarket b ecau seit streatme ntwasassociated withrarecasesofidiosyn crat icliv ertoxicity with liverfailur ean ddeat h. P. 698
METFORMIN Mechanism of Action

Metformin, abiguanide,h asbee nuse din thet reat men toft ype2diabetessince the 1960s. Its mechanismofactionhasbeen s tudiedex tensively,andalt hou ghman yme taboliceffect shav ebeen descr ibe din in v itr osyst emsandanimalmode ls, t hemolecu laran dbioche micalsit esofaction hav e elude ddiscover y(105,106,107) .Me tfor minex ertssev eralph ysiologiceffectst hat con tribute t oitsab ilit y todecre aseh yperglycemiainpat ien tswithtyp e2diabe tes.Patien tstakin gme tfor minfrequ en tly
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complainofametallict asteandoften hav esomedeg reeofanore xia(108).Tre atment ofpatie ntswith type 2diabe tesisusuallyass ociate dwith amean weig htlossof2to3k g,whichisduepr imarilytoa decr easeinadip oset issu e(52,109).Thiseffecth asbee nob scuredinsomestudiesby confoun din g weightg ainassociated with improvedglycemiccont rolan dare duction in gly cosu ria.Though notwell documente d,th eweightlossusuallyisassociatedwithadecreaseinap petite. R ecen tstudiessh owth at th eperce ntre ductionin the visce raladiposetissuede pot issignificantlygre ate rthanth atinth e subcu tan eousortotaladiposetissuepool(110).Theabilityofmetformin toincr ease in sulin -med iated glucosedisposalinske le talmu scle appearstobeat bestqu ite modest. St udiesinth e1980susingth e eu glyc emichyp erinsulinemic-c lampte chnique demon strat edthatmetforminsignificant lyincr ease d insulin-mediated g lu coseu ptak ebymuscle.Thosestu dies,howeve r,didnotcontrolforweight lossor red uction in glu cose tox icityre sultin gfromimpr ove dglyce miccon trol. Severalsu bsequ ent st udiesin whichweigh tlosswasn otafactorfailedtoshowasignificanteffe ctofmetformin oninsu lin-mediat ed glucoseupt akeinpe rip heralt issu es.Twomorerec entst udies,whichwe respecificallyde sign edto eliminat echangesinwe igh tan ddiffer ence sin g lyce miccon trol, fou ndnoeffectandasmallin creasein insulin-mediated p eripher alglu cose u ptake,re spectively(9, 111). In con trast,allwell-des ign edstud ies havesh ownmar kedeffect sofmetformininde creasin gthee le vate dhepaticglu cosep rodu ction thatis associate dwith fastingh yperglyce mia(20,109,112). Thedecr ease in hepatic g lu cosepr odu ction b y metforminappearstob eduepr imarilytoadecre aseinglucone oge nesis,alth ou ghth ereissome contribut ionfromadecre aseinglycogenolysis(112).Admin istr ationofmetformin hasbe ensh own to lower plasmalev elsoffree fattyacid sandt oincre aselip idoxidation in some, b utnotall,stu die s.The effect son lipid met abolismaremode stan dnotlikelytoplayamajorrole in decreasin ghep aticglu cose product ion(20,109,112, 113). Met forminhasnodire cteffectsonpancre atic-cellsanddoesn ot influen cein sulin secre tiondirect lybu tonlythroug hit sin flu ence sonch an gin gplasmaglu cose le vels.
Pharmacokinetics and Metabolism

Metforminisincomplete lyandslowlyab sorbe dfromth esmallintest in e,withabioavailabilit yof50%to 60%fr oma500-mgtable ttakeninth efast in gstate (114).Absorptiondecr eases with in creasing d ose, an dadmin is trat ionwithfoodde creasesthe exte ntofandslightlydelay sabsorption .Pe akplasma concen trat ionsre ach 1g/mLto2g/mL1to2h ou rsafte ran oraldoseof500mgto1,000mg. Metforminisnotboun dtoplasmapr ote in s,hasaplasmah alf-lifeof1.5to4.9hours,isnotmetaboliz ed, an disr apidly clearedby t hekidne y(90%with in 12h ou rs).The sepropert iesofme tfor minarequite important, sin cethe drugdoesn otaccumulate in t hebody,andex cessiveplasmalevelsare unlikelyto occurinth eprese nceofnormalr enalfu nction .The sepropertiesareincontrasttothoseofphen for min, abigu anideth atisnolong erav ailable in mostcou ntr iesb ecau seofitsoccasion alassociation with the deve lopmentoflacticacidosis.Dos e-response studiesofthee ffe ctofmetformin on glyce miccontrolin pat ie ntswithty pe2diab etesindicat ethatmaximaleffe ctsoccu rat dosagesof1,750to2,000mgper day (115).Metformin isadminister edtwiceor thre etime sadaywith meals, becau seth atmin imizesth e gas troin testinalsideeffe cts. Metforminisnowalsomar keted asalon g-act in gpreparation(metforminh ydrochlor idee xten ded-re lease table ts).The peakplasmaleve lfollowin goraladministr ation ofth ispr epar ation occu rsat 4to8hour s an dis20%lower t hanthatfollowingacompar abledoseofth ere gularformu lation ofmetformin(114). The e xten ded-re leaseformu lation isadminister edatdosagesof500to2,000mggiven on cedaily with th eeven in gme al.Thep eakplasmaleve lattaine dwit h1, 000an d2, 000mg we re1.1g/mLand1.8 g/mL, respect ive ly.
Clinical Use
Admin istr ation ofmetformin topatientswith type2diabete sr esultsinad ecreaseinhep aticin sulin resistance. Theconsequ ence isanincreaseinth eeffective nessofendogen ou sport alveininsulinan da resu lt ant decreaseinhe paticglucoseproductionan dfastingh yperg lyce mia(9,109, 112).Fast in gplasma insulinlevelsare either unch ang edor modestlyred uced. Ar educt ionininsulinresistanceofmu scle isa lesscon sis tent andr elativelyminoreffec tofmetformin. Me tfor mintr eatmen tgen erallyredu ces hy perglycemiabyappr oximatelyth esamemagn itu deassulfony lu reat reatme nt,e vent hought heir mechanismsofactionare ent ire lydiffere nt(52,116). Whilemanyclinicalstudiesmeasu ringth eeffectsofme tfor mintr eatmen tin patien tswit htype 2 diabet eshavebee npublished, relativelyfewh avebe enr andomize d,bee nplacebo-controlled ,in clu ded large numbersofsubject s,hadtreatme ntpe riodsext endingformore thanafe wmonth s,an dhad ade quateasse ssme ntsofglyc emiccontrol.There gist rationstu die sdon efor met formin appr ovalinth e Un it edStat es(116)andth eUKPDSprovideth ebestdatar elativetothe clinicaleffect ive nessof metformin(3).Int here gist rationstu die s,me tfor minmon oth erapyin obe sesubject swith type2 diabet es(me an b aselin eHbA 1 c an dFPG8.3%and240mg/dL, r espective ly)for29weeksloweredmean HbA 1 c 1. 8%andmeanFPG58mg/dLcompared with placebo-treatedcontr ols.The glu cose -lowering effect wasgreatest insu bjectswithth ehighe stHbA 1 c and FPGvalu esan dthe leastinth osewith t he lowest HbA 1 c andFPGvalue s.Thee ffectofmet formin on gly cemiccontrolwasdue primar ilytoa decr easeinFPG,asthe rewas P. 699
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nosignificantre ductionin the post pran dialglucoseex cursion s.Fastingplasmainsu linandC -peptide levelswere u nch ange d.Bodyweightdidnotch ange sign ifican tly.Metformint reat men tresu lt edinsmall decr eases inse rumtotalchole sterol,low-den sit ylipoprot ein(LDL )cholest erol, andt rig lyce ride s. Int heUK PDS,342obesepatientswith newlydiagnosedt ype2diab eteswer eran domizedtome tfor min tre atment and followedforamediandu rat ionof10.7ye ars. Th emedianHbA 1 c forthe first 5yearsof metformintr eat men twas6.7%.Forthe sametimeint erval, t heconve ntion alcon trolg rou phad avalue of7.5%. Forth esecondandth ird5-yearperiods,the me dianHbA 1 c fort hemetformin -treatedgroupwas 7. 9%an d8.3%,respe ctiv ely.Through ou tth estudy ,the med iandiffe ren cebetwe enth eme tforminand conven tion allyt reat edgroupswas0.6%. Me tfor mintre atmen twasass ociate dwith noweig htgain ,wit ha decr easeinfastingplasmainsulinlevels,andwithnosignificantinciden ceofh ypoglyce mia. Stud iescomparingt heeffe ctsofmetformin andsu lfonylur easonglycemiccont rolinpat ie ntswithty pe2 diabet esconsistent lysh oweq uivalence ,eve nthoug hthe ir modesofaction aree ntirelydifferen t.The practicalcon seque nceofthisfin din gist hat replacemen tofsu lfonylur eatr eatmen tbymetforminor metforminby su lfony lu reasdoesn otimprov eglycemiccontr ol(116).Th ereare,h owe ver,differe ncesin effect son bodywe igh tan dtheinciden ceofh ypogly cemia. Ina1-yearstud yin wh ic hpat ien tsofn or mal weightwe rerandomizedt ometforminorchlorpropamid e,glycemiccont rolinthe twogr ou pswas remar kablyth esame,bu tthe chlor propamide-t reatedpat ie ntsgain edameanof4.6kgwhile t he metformin-t reat edpat ie ntslost ame anof1. 5kg(117).Hypogly cemiadoesn otoccur with met formin mon oth erapy(105,106,107).Combining t hetwooralagen ts,h owe ver,isadd itivebe cau sethe ylower glycemiaequallybu tbydifferen tme chan isms. Metformint reat me nthasben eficialeffect son man yaspe ctsoft heinsu linre sistance sy ndrome (metab olicdiseasesyn drome):itdecr easesobesityandparticularlycen tralobesity;hasasmall ben eficialeffe cton decreasingseru mtr iglycer ide sandLDLcholester ol;improvesfibrinolysisby decr easingplasminogenactiv atorinhibitor1(PAI1);an dfrequ entlydecr ease splasmain sulin lev els (105, 109,113).The met abolicdisease s yndrome isassociat edwit han in creasein clinicalmacrovascu lar disease .Adrugt hat improvessomeorallofth ecompone ntsofthemetabolicdise asesyn drome would bee xpecte dtode creasemacrovascu lardise ase. Oneofthe majorfin dingsoft heU KPDSwasthat tre atment ofth eoverweight patien tswit htype 2diabet eswit hme tfor minre ducedt heriskofmyocar dial infar ctionby 39%an dofdiab etes-r elatedde ath sby42%(3).Thosewer ehighlysignificantre ductions whe ncomparedwithconve ntion altreatment, butn ot wh encompared with theoth erinten siv e tre atment s,whichwer eassociated with smallbutst atistically insign ifican tredu ctionse vent hought hey red ucedHbA 1 c toadeg reeeq uivalent t oth atwith met formin . Whilethe datafromth eme tfor minprimarypre ven tionarmofthe UKPDSap pearv alid, asubst udyinth e UK PDScomparingth eeffect ofaddin gme tformintothe regime nofpatient sp oorlycon trolledwith sulfonylure asshowedas tatisticallysign ifican tin creaseincar diovascu larmort ality wh encompare dwith th oser andomize dtoaddedplace bo(3).Afurt heranalysisoft hedatacompared with ther esultsofthe en tir estud ysuggest edth atth eresu lt sweredu etoanu nex plain eddecre aseinmor talityin the sulfonylure a-plus-placeb ogroupr ath erth ananincre aseinmort alit yin thesu lfonylur ea-plus-met formin group. Tworece ntre trospectivestu dieshavereporte dthatdiabet icpatie ntst reat edwit hsulfonylure as plusmetforminh ave ahighe rmortalityth an thosetre ate dwith die tor sulfony lu reasalone .Astudy of 2, 275patie ntswithdiab etesandcoron ary dise aseinIsraelwhowe refollowe dforameanof7.7years foundanincre aseinmort alit yin patien tswhoreceivedmetformin in combin at ionwithglybur ide comparedwithth ose on die tary orglybu ride manage me ntalone(118).ASwedishstu dyreporte dan increaseinmort ality in 169pat ien tstakin gsulfon ylureasin combinat ionwithmetformin ascompared with741p atient stakingsu lfonylur easalone (119).The majorflawsinth esestu die saret helackof randomizedcohorts, wh ic hme anst hegroup saren ot comparable ,an dthe retrospect ive analy sis, wh ich impliesdissimilar caredu ringth efollow-up period. Th esub studyandtworetr ospe ctivestud iessu ggest th atadefin it ive long-t erms tudyofthe safety ande fficacyofcombination sulfony lu reaandmetformin th erap ywou ldbe u seful.
Side Effects
The majorcomplication sassociatedwithmetformin treatme ntaregastroin testinalsymptoms (105, 106,116).Ing ener al,the sympt omsare dose -relate dandt ran sie nt.Th eyhavebee nrep ort edto occurin5%to20%ofpat ie nts.Th emostcommongast roint estinalsymptomsaremetallict aste, an or exia,n ause a,abdominalpain ,an ddiarrh ea. Gastroin testinalsymptomscanbeminimizedbyst arting th erap ywith lowdosesofmetformin (500mg )andincr easingth edoseslowly.Tak in gthedr ugwith mealsdecre asesth esymptoms, anditisusefu ltoinitiatedr ugth erap ywith the even in gmeal. Lac ticacidosisisth emostfr equen tlydiscussedcomp lication,alth ou ghitisextre me lyrareandalmost alway soccu rsin clinicalsituationsinwh ich met formin iscont raindicat ed(105, 106,120).Ther eported incidence oflacticacidosisinpatientsr eceivin gme tfor minis3per 100,000patien tyears;the fatality rateis50%. Almostallcase soflacticacidosisdu ringmetforminth erapyhaveoccurre din patien tswit h impaire dren alfunct ionorthosewh ohaveillne ssesth atpre disposet oimpair edren alfunct ion.Met formin iscon traindicatedinth osepatient s(Table41.6).
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TABLE 41.6. Contraindications for Metformin Treatment
Decreasedrenalfunction:plasmacreatinine1.5mg/dLformenand1.4mg/dLforwomenoracreatinine clearance<60mL/min Patientswithcongestiveheartfailurerequiringpharmacologicmanagement Patients80yearsofageunlessacreatinineclearancedemonstratesadequaterenalfunction Liverdisease Chronicalcoholabuse Sepsisorotheracuteillnesswithdecreasedtissueperfusion Duringintravenousradiographiccontrastadministration FromGlucophage;GlucophageXRprescribinginformation.Bristol-MyersSquibbCo.RevisedOctober2000,with permission. Vitamin B 1 2 malabsor ption wasfou ndin30%ofpatie ntswithdiab etesdu ringlon g-termtre atment with metformin. Inth elargeU .S.reg istr ation studies, serumvitaminB 1 2 levelswere d ecreased29%during metformintr eat men t.Megaloblastican emiad uringmetformint reat me ntisveryr areandcanbetr eate d byadminister in gvit amin B 1 2 .Themech anismofth emalabsorption isu nknown.
P. 700
THIAZOLIDINEDIONES Mechanism of Action

The t hiazolidined ioneswe rediscove redinth elate1970sdu rin gscree ningforlipid-loweringagen ts. Ciglitazone, wh ic hwasth eoriginalcompou nd,wasnotedtoredu cehy perglycemia,hy perinsu linemia,and hy pertriglyceridemiainrodent modelsofinsu lin-re sistantd iabetes. Du rin gthe 1980s, manyder ivatives contain in gthe g litaz on estru cture we resyn the size dande valuated. Th eth reeth iazolidinedion es eve ntu allyapprovedforclin icalu seweret roglitazone ,rosiglitazone ,an dpioglit azone(Fig.41.10). Troglitazon ewasth efirsttobemarke tedandhadreason ableefficacyinre ducinginsu linre sistance and improvingh yperglycemiaintype 2diabet es(121). Itsuse, however, wasassociate dwith the r are deve lopmentofidiosyncr aticliver tox icity,wh ich cou ldpr ogr esstoh epaticfailur ean ddeat h,and troglit azonewasremove dfromthe marketinMar ch2000(122, 123).Rosiglitazon ean dpioglit azoneh ave bee nappr ove dfort hetr eatmen toft ype2diabetessince mid-1999.Noe vide nceofsign ifican tlive r toxicity hasbe enfoun dwith either rosiglitazoneorpioglitazone after almost2ye arsofuseandth e tre atment ofmore than2millionpatient s(124).
FIG. 41.10.Structureofcommonlystudiedandcurrentlyavailableglitazones.
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The mech anismofactionofthe thiazolidine dioneswasdiscover edaft erth eir clinicaleffectiven esshad bee nestablish ed.The thiazolidine dione swe refoundt obeligan dsforanorphanrece ptorknownasthe per oxisomepr olife rator-activate drecept or(PPAR)(125,126,127). Th isr eceptorisamemb eroft he nu cle arre ceptorsupe rfamilyofligan d-act ivatedtr anscr ipt ionfact ors. Itisahet erodimerconsistingof twosubu nits:on eth atbindsth iazolidinedion esandoneth atbindsr etinoids(Fig.41.11).Th ereareth ree subt ypesofPPAR s:PPAR-,PPAR-,andPPAR-. Th eth reesu btypesh ave d istinct action s.Allth reeb in d tospecificre spon seelement sofgen esth ath avece ntralr olesinthe storageandcatabolismoffatty acids.PPAR- ispre sent athigh conce ntr ation sin theliverandisactivat edbyfibrat es,whichare pharmacologicligan dsfort here ceptor.PPAR-isubiquitous,anditsactivationby specificph armacologic ligandsh asapr ofound influe nceonlip oproteinmetabolism. PPAR -ist here ceptortowhich th iazolidin edion esbind.Th enaturalligand sforeachofthePPAR sareu nkn own ,an dtheph ysiolog yof eachisbeingstu die dactively.Th ethre e-dime nsion alstruct uresofthe PPARclassofre ceptors,aswell ast hesitesinvolvedth atch aracterizee achofthe subtyp es,havebe endefine d,an dit isn owpossibleto designmolecu le sthatactivateasing lespe cificsubt ypeorsever alsubtyp essimultaneously.
FIG. 41.11.Mechanismofactionofthiazolidinediones.ThiazolidinedionesbindtothePPARreceptorofa heterodimericintranucleartranscriptionfactor.TheactivatedtranscriptionfactorbindstogeneswithaPPAR responseelementand,afterinteractionswithappropriatecoactivatorsandcoinhibitors,eitheractivatesorinhibits transcriptionofthegenes.(AdaptedfromFormanBM,TontonozP,ChenJ,etal.15-Deoxy-delta12,14prostaglandin J2isaligandfortheadipocytedeterminationfactorPPAR.Cell1995;83:803812.)
Whe nth iazolidin edion esbindtothe PPAR -het erodimer, theh ete rodimerbecomesactivatedan d at tach estothePPAR -responsee le men tsofge nest hat c ont ainsuch an ele men t(Fig. 41.11).Bindingto th eresponse ele me ntisfollowedbyincorporationofactivator andinh ibitormolecules, andg ene transcriptionise it heractivate dorinh ib ite d.Thespe cificgen esthatar ePPARresp on sive aren umerous (e. g.,lip oproteinlipase, fatty acid-bin dingproteins, PEPCK)andinvolvethe regu lationoflipid metab olism,insu linaction, and adipose tissu edifferen tiation . The majorpharmacologicaction softh iazolidin edion esin vivoaretoincreaseinsulin-mediated g lu cose upt ake(d ecreaseinin sulin resistance)inmusclean dtoinc rease adipoge nesis(37,128,129, 130,131). Considerablecon troversy existscon cern in gthemech anismofbothofthe seactions.PPAR recept orsare P. 701 expr essedpr imarilyin adipose tiss ue(>10-foldh igh erth aninmuscle), y etth emajorqu ant it ativeeffe ct inimprovingtotalbodyinsulinsen sit ivityoccursinmuscle. On estrain ofge neticallyen gin eere dmice th atlackadip oset issu e(A-ZIP/F-1ph enotype )failtorespond t otr oglitazone orrosiglitazon eth erap yby ar eductionininsulinresistanceandhy perglycemia(132). Incon trast,another gene ticallyalte redmou se (aP2/DTA)thathaslittleornowhiteorbrownadiposetissuer espondstotroglitazon ewithth eexpe cted improvemen tin in sulin resistan cean dhyp erglycemia(133).Th elatter dataplu smu scle cellcultu re stu die sshowing t hattroglitazon eincreasesglucoseupt akesu ggestt hepossibilitythatth esmallnu mbe r ofPPAR -recept or sinmuscleandlive rmight med iateth ein sulin -sens itizingeffe ctsof th iazolidin edion es.Re cent s tudies,h owe ver,h ave emph asizedth atp rodu ctsreleasedfromadiposetissu e such asfree fatty acidsand t heirmetabolicd erivativesr ath erth anadiposet issu eit selfmediat ethe insulinresistanceinmuscle(7,134), andt hesepr odu ctsar eelevat edinthe micewithoutpe ripheral adiposetissue (132).Oth erstu die sshowthatthiaz olidine dione sactonadiposetissue tode creasenot onlythe c ircu latinglevelsoffre efat tyacidsbut alsoproteinfactorssuch astumornecr osisfactor-,
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resistin, andlept in thatare r elease dfr omadiposetissueandth atcancau seinsulinresistanceinmuscle (135, 136).Th iazolidin edion esalsostimulat ethe release ofan adiposetissueh ormone, adipon ectin, whichisassociated with in crease dhepaticin sulin sensitivity(137). Th us, wh eth erth eimprovement in insulinact ionissecondarytoaprimaryact iononadiposetissue ,isaspecifice ffectonfree fattyacid metab olism,orisadirecteffe cton mu scle hasn oty etbee nresolved(125, 126,127,129).These con d majoru nre solvedissue ish owadr ugth atincre asest hequ ant ity ofadiposetissue cande crease in sulin resistance. Inrodent s,th iazolidin edion esin creaseth enu mber ofsmalladipocyte sandd ecreasethe nu mbe roflar geadipocytes(138).Thesmallercells aremor esensitivet oinsulinan dhavealowerrate oflipolysis.Inh uman s,thiaz olid in edione sin creaseadipogene sisinsu bcutaneousadiposetissue buth ave noeffect onv iscer aladipose tissue(139,140). Th us,t hiazolidinedionesappeartofacilitat eadipogene sis but in awayt hat improvesinsulinsen sitivity. PPAR-re ceptorsar eprese ntinmode rate con centr ationsin macrophag es,colonicepithe lium,and en dot helialandvascularsmooth mu scle ce lls.Th eir fu nctionsinth esetissue sarebe in gin vestigat ed act ive ly, asisthet herapeu ticp ote ntialofth esedr ugsforthe treatme ntofin flammatoryboweldise ase an dthe earlylesion sofather osclerosis.

Rosig litaz on ean dpioglitazonearerapidlyandwellabsor bedorally (141,142).Bot har eexte nsively metab oliz edin the liverby theC YP450isoenzymes rosiglit azone b yCYP2C8andC YP2C 9and pioglitazone byCYP2C8,CYP3A4, and severaloth erCYPisoenz yme s.Approximat elytwot hirdsofth e rosig litaz on edose isex crete din theu rineandappr oximate lyonet hirdin the bile,wh ereastwothirdsof th epioglit azonedoseisexcre tedinth efecesandonet hirdin the urine. Theplasmah alf-lifeof rosig litaz on eis3to4hoursandth atofpioglit azone anditsact ive me tabolite sis16to24hours.Both dru gscan b eadmin ist eredsafelytoind ividualswith impairedr enalfun ction .
Clinical Use
Rosig litaz on eisadministe redindosesof4to8mg give nonceortwicedaily(130,141).Pioglitazoneis givenindosesof15to P. 702 45mg admin iste redoncedaily(131,142). Th esediffere ncesineffe ctiv edose sreflecttosomede greet he differen cesinbindingaffinitiesofthese twodr ugsforthe h uman PPAR -recep tor .When admin is tered t o pat ie ntswithty pe2diab eteswh oar ein ade quat elycon trolledwithdiet andincre ased p hysicalactivity, rosig litaz on eat4and 8mg dailyde creasedHbA 1 c and FPG1.2%an d58mg/dL and1.5%and76mg/ dL, resp ectively.Pioglitazon eat 15and45mgdailydecreasedHbA 1 c an dFPG1.0%and39mg/dLan d1.6% an d65mg/dL ,respe ctiv ely .These datareflectcomparison stoplace bot reat men tinth esamestu die s.Of th epat ien tstre ated with rosiglit azoneat4mgtwiceaday,59%ach iev edaHbA 1 c leveloflessth an 8% an d30%achieved ale velle ssthan7%.Th edataon gly cemiccontrolwith monothe rapyind icateth atth e twothiazolidine dione saresimilarine fficacy.Becauseth epat ie ntpopulat ionsstu die dhad s omewhat differen tclinicalcharacteristics(patien tstreatedwith pioglitazonehadpoore rbase lineglyce miccon trol, were moreobese, andwe rehy pertriglyceridemicthanthoset reat edwit hrosiglitaz one ),an ysubt le differen cesnotedint here spon sestothe t wodru gsmayhavebee ndue todiffere ncesinth e resp on sive nessofthe d iffer entpopulat ionsrathe rthananytru edifferen cesoft hee ffe ctsoft hedru gs. Anypr esumeddifferen cesne edtobesubs tan tiatedby acompar isonofcompar ablyeffectivedosesofthe twodrugsint hesamer andomize dcon trolledstu dy. Inadditiont oimpr ovingglycemiccon trol, b oth pioglit azoneandrosiglitaz on eimproveman yofth e componen tsoftheinsu linre sist ance syndrome(29,127, 128,129).Bothimp rove in sulin sensitivityan d decr easep lasmains ulin leve ls. Both improveth edyslip idemiacharact eristicofinsulinresistance, thatis, th eybothconsisten tlyin creas eplasmaHDLch oleste rolan dhavesomee ffe ctson lowering p lasma triglycerides. Differen cesinthe effectsofpioglit azoneandrosiglitazon eon dyslipidemiahavebee n rep ort ed(143). Rosiglit azonepr odu cedasmallincr ease in plasmacon centr ation sofLDLcholesteroland red ucedplasmatr iglycer ide son lyifthe yweree lev ated .Pre limin arydataindicat ethatth esechange s maybedu etoash iftinth echaract eristicsofth eLDL p articlesfromsmall, dense ,very ath erogenic par ticlest olarge ,buoyant,lessathe roge nicon esan dnottoanincr easeint hen umb erofp articles. Pioglitazon etre atment hasbe enassociat edwit hage ner alreduct ioninplasmatr iglycer ide sandn o increaseinplasmalevelsofL DLcholester ol.Asnoted p reviou sly ,acomparison ofth eeffectsofth etwo dru gson dyslipidemiain thesame ran domiz edstu dyisn ecessarytoclarifywheth erth esedr ugsdo indee dhav esomewh atdifferen teffect son se rumlipidsan dlipoprot eins. The t hiazolidined ionesde creaseplasmale velsofPAI-1,wh ich reduc esthe in hibitionoffibrinolysist hat is charact eristicofinsulinresistance(144).One ofth emorest rik in geffectsoftreatmentofpat ien tswith type 2diabe teswithth iazolidin edion esisa20%t o25%redu ctioninplasmaleve lsoffreefattyacids (130). Severalst udieshaveshownt hat thiazolidined ionesr educe rate sofur in arye xcretionofalb umin indepe nden toft heireffect son improvin ggly cemia(145).The thiazolidine dione scause anincre asein subcu tan eousad iposetissue (~5%8%)bu teithe rhav enoeffectorsligh tlyredu cevisceraladipose tissue (128,146).Pr elimin arydataindicat eth atth iazolidin edion esimprovet heen dot helialdysfun ction
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th atischaracte rist icofin sulin resistan ce(16). The d ecline in -cellfun ction char acter isticoftype2diabete shasbe enpostulatedtobere latedinpar t todetr iment aleffectsofin sulin resistan ce(147). Insulinresistanceincr eases-ce llsecre tor yfunct ion an dassu chincreasesth eme tabolicactiv ity ofth e-cellandalsoin creasesthe secret ionofamylin. Incr ease dsecret ionofamylincanresu lt in in crease damyloiddeposit swith in the isletsandindest ruction of-c ells.In creasedme tabolicactiv ity ofgen eticallyprog ramme d-cellscouldle adtoin creasedratesof apoptosis.Ithasbeen post ulate dthatthiaz olidine dione s,byre ducinginsulinresistance, might d ecrease th erat eof-ce lllossinpat ie ntswithty pe2diabe tes.C on trolledst udiescompar in ggly buridetr eatmen t withrosiglitaz on efor 1yearshowbett erprese rvat ionofglu cose con trolwithr osiglitazon e.On e-year stu die sareinadequ atet oprove-ce llprese rvat ionandne edtobefollowe dupby3-to5-yearstudies. Stud iesint woroden tmodelsofinsu lin-r esist ant diabete shave shownth atrosiglitaz on etreatment d oes pre serve-ce llsin thatsett in g(148).R ecen tly r eportedst udies(TRIPODstu dy)haveshownth att he administrationoftroglitazon etowomen wh oh adpre viouslyh adgest ation aldiabete sdecre asesth erate of-c elllossandcan preve ntth edeve lopmentorprogre ssionoftype2diabete s(100).Th iseffe ctis like lydu etoit sreduc tionininsu linre sist ance ,an effectsh aredb ythet woavailable thiazolidine dione s, rosig litaz on ean dpioglitazone.
Side Effects
The majorsideeffectsobser vedwithrosiglitaz on ean dpioglitazoneh avebe enfluidret entionwith per iph eralede maand, in unu sualcircumstances, con gestivehe art failur e,andweightgain (37,128,141, 142).Idiosyncraticlivert oxicitywithlive rfailu rede velope din afewpeopletreatedwith troglit azonewh oth endied. Th eclin icalt rialswith t rog litaz on eshowedsomech an gesin liver funct ion th atinre trospectwere probablysignalsofp ote ntialhep atotoxicity(130).Seru malanine aminotran sferase(ALT)le velsgreat erth ant hree timest heup perlimit ofth erefe rence ran ge(ULR R) were recordedin1.9%oft hepatients with type2diabete st reatedwithtr oglitazone compare dwith 0. 6% oft hosewhoreceive dplacebo(Fig.41.12). As man yas0.68%ofth etroglitazone-tr eat edpat ien tshad seru mALTvalu es10timesorgre ate rthanth eULR R,an djaun dice developedintwopatien tsthat rev ersedondr ugwithdrawal.Incont rast, neith errosiglitazone norpioglit azonesh owe dany sign alof he patotoxicity d uringth eirclinicaltrials,andafterapproximate ly 2yearson the market, nosign ifican t seve rehe patotoxicity hasbe enassociat edwit heithe rdrug .
FIG. 41.12.Theresultsofmonitoringalanineaminotransferase(ALT)levelsinthephasethreeclinicaltrialsof troglitazone,rosiglitazone,andpioglitazone.ThepercentageofsubjectswithanyALTthatisgreaterthanthree timestheupperlimitofthereferencerange(ULRR)isreported.Troglitazonetreatmentwasassociatedwitha significantlyhigherrateofabnormalvaluesthanwastheplacebocontrol.Neitherrosiglitazonenorpioglitazone treatmentshowedanydifferencesinabnormalvaluesfromtheirplacebocontrols.
Asmallincreaseinplasmavolu me appearstobere latedtoactivationofthe PPAR-rece ptor,asjud ged byasmalldecre aseinhe moglobinandhe matocr it v alues(0.6g /dLand 2.8%, respect ive ly) (130,131). Thischangewasnotaccompaniedbyanyalte rat ioninred bloodce llmassin an ypatien tswit hdiabet es tre ate dwith any ofth ethiaz olid in edione s.Mild-to-moder atepe ripherale demaisobse rvedin3%to5% ofp atient streatedwithathiazolidine dione asmonoth erap y(37,128, 130,131).Thisin creasesto app rox imate ly15%in pat ien tstre ate dwith thecombin ationofpioglitazon ean din sulin (128).Th e mechanismforthe developme ntofedemaispresen tlyun known.The edemare spon dspoorlytoloop diure ticsandinh ibitorsofangiot ensin-conve rtingen zymes.Rarely,se veree demacan developthatis rev ersedwith d iscontinu ationoft hedru g.Itisun cle artowhatexte ntth iazolidinedionetr eatmen tmight pre cipitatehe artfailur ein asusce ptible patient ,ast here aren ocont rolleddat a.Itmightbe anticipate d th atanindividu alin bor derlin econgest ive heartfailurewoulddeve lopclin icalfailure ifth eplasma volu me we reex pande dsign ifican tly.The reisnoe vidence in1-an d2-ye arstu die sofcardiovascular fun ction t hat thet hiazolidinedionesh ave anyde trime ntaleffe cton myocar dialfu nction (149). The we igh tgainassociat edwit hth iazolidin edion etre atment isdu etoacombinationofflu idr eten tion an dan in crease in adipose tissu e.Aprimaryaction ofth iazolidin edion esisthediffere ntiationofst em
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cellsint oadipocyte s(126,127).Inh umans ,PPAR-agonistsdiffere ntiate subcut ane ou sadipose tissue stemcellsint osmalladipocyt esbutappeartohav enoeffectonth e differen tiation ofvisceraladiposet issu estemcells(140).Seve ralstudiesh ave e xamin edth eeffect of eithe rtroglitazoneorrosiglitazone on we igh tgainandadiposetissu edist rib ution .Allstu die sshowa significantincre aseint otalbodyfatand s ubcut ane ou sadipose tissu emass.Massofvisceraladipose tissue isusu ally notchanged(128,146, 150). The e ffectsonexpansion ofplasmavolumeusu allyaresee ninth efir st12weeksoftreatmentand probablystabilizeby6month s.The fe wlong-t ermstudiesonweightgainshowin creasesthatten dto slowdownan dstabiliz eafte r12month softr eat men t.C arefu llong-ter mstu die sofbothe demaan d weightg ainare nee dedtoclarifythese issu es. P. 703
Potential Cardiovascular Benefits

Thiazolidine dione sameliorate manyofthecompon entsofthe in sulin resistan cesyn drome, andone might an ticipateth atsu chac tionswoulddecre aset hecardiovascularcomplicationsoft ype2d iabetes (128, 151).Att hepr esent time, c linicalou tcomest udiesare limite dtoafewpreliminaryob servations th atth iazolidin edion etre atmen tpreser vesth epat encyofcor on aryarter ysten tsbyslowingth e prolifer ation ofth ecells ofth ein timaandmedia. Th ereareman yobse rvat ionsofimprovement of en dot helialfu nctionin vivo. Th eimprovemen toft hedyslipide miabyincr easingplasmah igh -den sity lipoproteinch oleste rol,lowe rin gelevatedplasmatr iglycer ides, an dshiftin gLDLparticlesfromsmallden setolarge-bu oyantp articlesare sign ifican tan dcon sist ente ffectsoft hiazolidined iones, asisthe improvemen tin the procoag ulant state .Alt hought hecu rren tdataare in sufficien ttorecommen d th iazolidin edion esaspr imaryt reat me ntforimprovingmacrovascu laroutcome sin p atient swith type2 diabet es,onen eedst obeaware ofth epot ent ialofthes eagen ts.Ou tcomest udiesare unde rwayt o det ermin ethe effectsofthes eagen tsonclin icalcardiovasculare vent s.
-GLUCOSIDASE INHIBITORS
The r ecognitionofthe importan ceofcont rollin gpost pran dialh yperg lyce miabeg anwh enph armacologic age ntsspe cificallytarg etedatpostpran dialplasmaglu cose lev elsbe cameavailable .Thefirstgroup of th eseag entswe reoralagen tsspecificallyde sign edtodelaypostpr andialcar boh ydratedigestion an d lower postp ran dialplasmaglucoseex cursion s.The -glu cosidase in hibit oracarboseisa pseu dot etrasacch arideofmicrobialorigin thatwasisolat edan dpurifiedinthe late1970san dapprove d forthe t reatme ntoftype2diabete sin thee arly1990s(152).It actsex clu sive lyont hegastroin testinal tractan dspecificallylowe rspost pran dialglucosee xcursions.
Mechanism of Action
The d iges tionofcomplexcar boh ydratesinvolve sin it ialcleav ageby amy lasesin the smallin test in ein to oligosaccharides(11,153).Oligosacch aridesarepoorlyabsorb edan dhav etobecle ave din to mon osacchar ide sbefor eabsorptionth rou ghth eintest in almu cosa.Thecleavage ofoligosaccharidesin to mon osacchar ide soccu rsin theb rushborde rofth een terocyte sandiscar rie dou tbyavarietyofglucosidaseen zymes(glu coamy lase,su crase, malt ase, d extrinase,andisomaltase).The mon osacchar ide sgener ate dareabsorbedrapidly. Th edigestion ofcomp lex c arbohydr ates n or mally occursinth edistalduoden umandpr oximaljeju num. The cleavage ofth eoligosaccharid esbyth e-glucosidaseen zyme in volvesbind in gofth e oligosaccharidestoabindingsiteonth een zyme ,followe dbyhydr olyticcle avage.The -glu cosidase inhibitorscompete with the oligosacc haridesforth ebindingsite. Th eybindtoth esit ebutcann otbe hy drolyze d.They areclassiccompe tit ive in hibitors. Th emechanismsofactionoft hedifferen tglucosidaseinhibitorsare similar though not ide ntical.Acar bose bin dstog lu coamylase ,malt ase, sucr ase, andde xtrinase.Itbind st ointe stinalsucr asewithabin din gaffinity10 4 to10 5 greatert han that tosucrose. Acarbosehasminimale ffectsonisomaltase andn oe ffe ctonlactase,whichisa-glucosidase en zyme .Acar boseisalsoaninh ibitorofp ancr eaticamylase. Voglibose inh ib itsmos t-glu cosidase en zyme sbutisweakerth anacarb oseatinhibitin gsucraseandhaslittleeffe cton pan creat icamylase . Neithe racarbose norvog libosein terfe reswithglucoseab sorpt ionth rought heinte stin alsod iu mdepe nden tglucosetransporter .Miglit olisaneffe ctiv e-glucosidaseinhibitor and h asgre ate ractivity th anacarboseonisomaltase.Mig litolh asnoeffectonpancre aticamylasebu tdoesmildlyint erfere with glucoseabsorpt ionbyinte ract in gwith the int estinalsodiu m-d epen dentgluc oset ran sport er. P. 704 The conse quen ceofadmin iste ringan -glu cosidasein hibitor with themealisthatoligosaccharide cleavageison lyp artiallyaccomplishedinth eup persmallinte stine.Th erest ofth eoligosaccharide sgo intothe middlean ddistalsmallin testine ,wher ethe yare cleavedifthe ente rocytescontain sufficie nt en zyme .Ifen zyme isinsu fficient ,the olig osacchar ide sgointoth elargeinte stine, wh eret hebacteria fermen tthe carbohydr ate andpr odu ceshort-ch ainfat tyacids,h ydrogengas,meth ane ,an dcarbon dioxide. Sincecarboh ydratedigestionan dabsorptionnormallyarecomplet ein the u pperjejun um,th eamou ntof
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-glucosid aseen zymein the middlean ddist alsmallin testine islowandinsu fficient t odigestt he car boh ydrateloadpresen tedt oitduring theinitiationof -glu cosidase treatme ntu nlessthe the rapyis initiatedwith avery lowdose andt hedoseisin creasedvery s lowlyover time.

Thre e-glucosidaseinhibitorsare available:acarbose,voglib ose, and miglitol(Fig.41.13).Acarboseisa pseu dot etrasacch arideth atcontain san itr oge nin placeofanoxyge n.Vogliboseisavaliolamine der ivative,andmiglitolisasynt heticdeoxyn ojirimycinanalogue(11).Th eprimarysiteofaction ofboth acarbosean dvog liboseisatthe ent erocytes, s in ceneith erissign ifican tlyabsorbed(acarbose<2%; voglibose3%5%).Miglitolisabsorbedrapidlyandex crete dunch an gedbyth ekidney. Alth ou gh acarboseisnot absorbed, itismetab oliz edin the colon bybact eriatosever alin termediate sand 4methy lpyr ogallol,wh ich are absorbed, c onju gate d,an dexcre tedas su lfatesorglucur on idates. Be cau se th e-glucosidaseinhibitor sarecompetitiveinhibitorsofth ebindingofolig osacchar ide s,the ymu stbe administere datth estartofe ach meal.
FIG. 41.13.Structureof-glucosidaseinhibitors.
Clinical Use
-Glu cosidasein hibit orsmust begivenatthe start ofeachmeal.The yare effectiveonlyift hediet contain satleast 40%andpre fe rably50%carbohy drate .Asnotedpr eviou sly, ther apymustbe in itiat ed withve rylowdosesan dthed osest itr ated upquiteslowly. Foracarbosean dmiglitol,th erapy shouldbe startedwith25mgwit hth eeven in gme al(153).Afte r2wee ksor soth edosecan bein creasedto25mg withth estartofbr eakfastan d25mgwitht hestartofthe e ven in gmeal. Aft eran ot her se veralwe eks, th edose canb ein creasedto25mgatthe start ofeachoft heth ree majormeals.Incr easingt hedoseto 50mg with each mealsh ou ldalsobedone in incr ementalst eps.Ifatany stage ,gast roint estinalside effect sbecomeasign ifican tproblem, thedosesh ou ldbe reduc edfor se veralwe eksan dthe nthe titrationcont in ued. Mostpatie ntswillinitiallyobtainamaximaleffect on glyce miaat50mgwithe ach meal.Some, however, maynee dtoh ave thedoseincre ased slowlyt o100mgwitheachmeal.Th e primaryclin icale ffectoft he-glucosidaseinh ib itorsistod ecreasethe post pran dialglucosee xcursionin pat ie ntswithe ith ertyp e1ortype 2diabet es.The meande crease in thepe akpostprandialrisein plasmaglucoselevelduring acar bose monother apyindiet-t reat edpat ie ntswithty pe2diabe tesis app rox imate ly54mg/dLan disassociat edwitha mean decreaseinHbA 1 c of0.9%(11,154).Themeandecr easeinFPGisapproximately24mg/ dL,an d th atisprobablydue toaredu ctioninglucosetoxicit yasaresultofimprovedpostprandial hy perglycemia.Vogliboseisgiven atadose of0.1to0. 2mgwit heachmajormeal. Th erearen o comparative d ataforvogliboseandacarbose,bu tthe fewreporte dstudiessu ggestth atvogliboselowe rs mean Hb A 1 c be tween 0.3%and0.7% P. 705
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-Glu cosidasein hibit orsareex tremelyeffectiveforth etre atment ofseve reh ypoglycemiafollowing gas troin testinalsu rgeryandothe rfor msofreact ive hypoglycemia.Sever alstudieshavesh own thatglucosidaseinhibitorsgiv enwithth eeve ningmealcan redu cethe in cide nceandseve rityofn oct urnal hy poglycemiainpat ien tswithinsulin-tr eate dtype1diabete s. Oth ereffect sof-glucosidaseinh ibitorsar easligh tredu ction in meanweight (<1.0kg),adecreasein postprandialplasmain sulin le vels,asmallde creasein post pran dialp lasmatriglyce rid es,andamod est increaseinplasmalevelsofg lu cagon-like peptide-1(11).
Side Effects
The majorsideeffectsof-glucosidaseinhibitorthe rapyaregastroin testinalandinclude abdominal discomfor t,flatu s,an ddiarrh ea, wh ic hare duet oan excess ive amoun tofcarbohydr ater each in gthe colonandun dergoingfermen tation(11,155).Rarecase sofjau ndicewit hcholestasish avebe enre por ted inpat ie ntsinJap ant reat edwit hacarbosean dvog libos e.Howe ver, studiesofacar bose admin istr ationto individ ualswit hlive rdiseaseh ave notshownan ysig nificantworsen in gofth ehep aticproble ms. Hypogly cemiad oesn ot occur with monothe rapy with these agen ts.Th eaddition ofan-glucosidase inhibitortoasulfon ylu rea,an ot herinsu linse cretogogue, orinsu lin, mayimproveglycemiccont rolsuch th ath ypoglyce miamayoccur. Insuch cases, theh ypoglyce miamustbe treatedwithglucosebe cause the digestion ofsu crosean dcomple xcarbohy drat eswillb edelaye d.
COMBINATION THERAPY WITH ORAL AGENTS AND ORAL AGENTS AND INSULIN
Although alloftheoralantidiabeticag entsarere asonab lyeffe ctiv easmon ot herapyinimproving glycemiccontr olan dredu cin gHbA 1 c , the yare r are lyable tore storeglycemiaton ear normalandHbA 1 c levelstole sst han 6. 5%in patien tswit htype 2diabet eswhopresen twithfast in ghype rglycemiaand HbA 1 c le velsof7%orgreater ( 13). Thisisprobab lybe cause the h yper glyce miaiscau sedbyth e combinationofme tabolicde fectsth ath avecausedt hediabe tesandth emarkedde ficien cyof-cell fun ction t hat hasoccur redbyth etime anindividualh asdev elopedsy mptomatichype rglycemia(12) . Oralmedicationssuch assulfonylure asan dme tfor minth atpre dominat ely lowerFPGwilldecreaseHbA 1 c valu es2. 0%to3.0%inpatientswitht ype2d iabeteswh oh aveHbA 1 c valu es10%orgre ate rbya combinationofth eir specificph armacologicaction san dther esultantdecr ease in g lu coset oxicity (13,14,128).The sameage ntswilllowerHbA 1 c only0. 5%to1.0%wh enth ebaseline HbA 1 c isbet we en 6. 0%an d8.0%.Thesame t ypesofresultsareobtaine dwith or alagen tsthatlower both fastingand postprandialplasmaglu cose s,such asre paglin ide and t hiazolidined iones. Oralage ntsth atpr imarily decr easep ostpr and ialplasmaglucoselevelswillhav ealesser absolu teeffect on Hb A 1 c leve ls(de crease of0.5%1. 0%atabaselineHbA 1 c of8.0%9. 0%),but again theireffe ctsdecre aseasthebaselin eHbA 1 c leveldecre ases(13). Itappear sthatthe reisalimit edben efit toimprov in gglyce miccon trolby ameliorating anyone specific mechanismth ataccou ntsforth ehype rglycemiain p atient swith type2diabete s.Gene rally ,replacingan oralage ntwithonemech anismofact ionbyanothe rwit hadifferen tmechanismofactiondoesnotresu lt inbett erglycemiccont rol(116, 156).C ombiningage ntswithdiffere ntmode sofaction, asdepicte din Figu re41.5,produce sadditiveeffect son glyce miccon trol;allowstheu seofsu bmaximaldosesofthe age nts, ther ebydecr easingu nwan tedsidee ffe cts;an dprovide sforcomplemen tary bene fitson car diovas cularriskfact ors(13, 14).Tables41.7and 8,wh ich arefromone ofth eau thor'srecen t rev iews, illustrateth eseadvan tage s(13).Table41.9summariz esthe resultsofmostofthepu blish ed U. S.Foodand Dru gAd ministrationr egis trat ionstu die sthathaveexamine dthee ffectsofcombin ation oralan tih yperg lyce micagen tth erap yon glyce miccon trolinpatient swith type2diabete s(13). TABLE 41.7. Direct Effects of Oral Antihyperglycemic Agents on Cardiovascular Risk Factors in Patients with Type 2 Diabetes
Cardiovascular risk factor Insulin resistance Hyperinsulinemia LDLcholesterol levels LDLparticle
Sulfonylurea 0
Rapid-acting insulin secretogogues 0
Metformin
Thiazolidinediones
Glucosidase inhibitors 0
0 0
0 0
or0
Largebuoyant
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pattern HDLcholesterol levels Triglycerides Lp(a) PAI-1 Endothelial function Bodyweight Visceraladiposity HDL,high-densitylipoprotein;LDL,low-densitylipoprotein;Lp(a),lipoproteinlittleAantigen;PAI,plasminogen activatorinhibitor-1. ,markedincrease;,moderateincrease;,smallincrease;0,noincrease. ,markeddecrease;,moderatedecrease;,smalldecrease. ModifiedfromLebovitzHE.Oraltherapiesfordiabetichyperglycemia.Endocrinol Metab Clin North Am 2001;30:909933. 0 0 0 0
0 0 0 0
0 0 0 0
0 0 0 0
0or
TABLE 41.8. Side Effects of Oral Antihyperglycemic Agents
Drug
Hypoglycemia
Weight gain 1+ 2+ 1+ 1+ ? 0 0 3+ 3+
Edema
GI effects 0 0 2+ 3+ 3+ 0 0
Lactic acidosis 0 0 0 0 0 1+ 0 0 0 0
Liver toxicity 0 0 0 0 0a 0a
Glipizide-GITS Gliburide Glimepiride Repaglinide Nateglinide Metformin Acarbose Miglitol Rosiglitazone Pioglitazone
1+ 4+ 2+ 1+ 1+ 0 0 0 0 0
0 0 0 0 0 0 0 0 2+ 2+
0,none;,veryinfrequent;1+,infrequentproblem;2+,occasionalproblem;3+,moderateproblem;4+, significantproblem;,decrease.
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a Noevidenceoflivertoxicitybutmonitoringofliverfunctionevery2monthsforthefirstyearoftreatmentstill recommended.
DatafromLebovitzHE.Oraltherapiesfordiabetichyperglycemia.Endocrinol Metab Clin North Am2001;30:909 933.
The mainpr in ciplesth atu nder liecombination ther apy(Table41. 10)start with theassessment ofa pat ie nt'sspecificpathophysiologyat thet imeofin itiat ionofther apy. Th easse ssme ntsh ou lddet ermin e (a)t hepre sence orabsence ofsignificantinsu linr esistan ce;(b)the compon en ts,ifany, ofth einsulin resistancesyn drome thatare p resen t;(c)the stage of -celld ysfunct ion;(d)th emagn itu deofb oth fastingandpostprandialhype rglycemia;(e)the presen ce ofsu bclin icaland/orclinicalcomplication sofdiab etes;and(f)th elikelylife expect ancyofthe patien t. Aftert heassessment, theg oalsforthe planne dthe rape uticin terv entionshouldbede fin ed.The choiceof an in sulin sensitizern eedst obemade .Metforminandth eth iazolidin edion eshavemajordiffere ncesin th eir effects. Rath erth an r egar din gthe mascompetingagent s,on emigh tcon sid erth emas complement aryagent s.Freque ntly,t here isar ationaleforprescr ibingt hemin combinat ion.Th enex t choiceist ode cidewh eth er-cellfu nctionissufficien ttowarrantt heu seofaninsulinsecre tog ogu eor whe ther in sulin oraninsulinan alogu eshouldbeu sed.Ifaninsulinsecre togogu eis ch ose n,itis ne cessar ytode cide whichonetouse .Sulfon ylu reasareine xpen sive andcanbegiven on ceaday.Rapidact in gin sulin secret ogogue saree xpens ive andmustb eadmin ist eredwith e ach meal. Weightgain and hy poglycemiaare le sswith ther apid-act in gin sulin s ecretogogues. Theyalsopar tiallyre stor eearly postprandialin sulin secret ionandprovideamuch moreflexible lifestyle. Ifinsu liniselecte d,ach oiceof abasal,bed time, ormeal-re latedinsulinoracombination ofth emmust bemade(see Chapter39). If postprandialhype rgly cemiaisth emajoru nresolvedissue, theu seofan-glucosidaseinh ib itoras p art oft heth erapeut icpr ogrammightbede sir able.C ombin ationsoft woandsomet imesth reeoral an tihyper gly cemicage ntsmaybe nece ssarytoreachth etargetglycemicgoal. TABLE 41.10. Guidelines for Developing Combination Therapy Strategy for Patients with Type 2 Diabetes P. 706 P. 707
Assesspatient'sspecificpathophysiology Isinsulinresistancepresent? Arethereanycomponentsoftheinsulinresistancesyndrome? Whatisthestageof-cellfunction? Howabnormalarethefastingplasmaglucoselevels? Whatisthemagnitudeofpostprandialhyperglycemia? Evaluatethepatientforsubclinicalorclinicaldiabeticcomplications Estimatethepatient'slifeexpectancy Definethegoalsoftreatment Selecttheappropriateinsulinsensitizers Selectamethodofincreasinginsulinavailability Insulinsecretogogue Insulinpreparation Decideifan-glucosidaseinhibitorhasanyadvantage Inpatientsinwhomglycemiccontrolhasbeenelusive,consider48-to72-hrcontinuousbloodglucose
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monitoringorpatterntestingwithhomeglucosemonitoring MonitorHbA1cevery3mo
The availabilityofdevicesth atallowforcontinu ou sbloodglu cose monitorin gfor48t o72hours h as rev olutionizedouru nderst an din gofth eindividu alvar iabilitythatoccursinglucosere gulation in patien ts withdiabe tes.Th esedev icesmayassistin plann in gandmodifyingcombin ation the rapyinpatient swh o ar enotach ie vin gtar getgoalswit hth eir curre ntre gimen, although the advantageoft hesed evicesov er traditionalh omebloodglucosemonitoringfourtoseve ntime saday h asn otbe ende termined. Among t heu nan swered q uestionsconcern in gcombinationt herapyiswh eth eritshouldbestarte datth e time ofclin icaldiag nosisoron ly after atrialofmonother apyh asfailedtoachieve thet arge tgly cemic goal.Ther ecen tclinicaltrialcomparin gthe efficacyofg lybu ridealon e,metformin alon e,anda combinationofsubmax imaldose sofglybur ide andmetformin on glyce miccon trolinpatient swith type2 diabet esinade quatelycon trolledbyd iet ande xerciseshowedbe tter g lyce miccon trolwithinitial combinationt herapyth anwith monother apywithe ith eragent alon e(157).It wasun cle arfromt hat stu dywhet hert heimpr ove dbene fitr esultedfromsomepotent iatingofe ffectsorfromalimitat ionofthe doseoft hemon ot herapybecauseofsid eeffects. The combin ationofone ormor ein sulin sensitizer swith aninsu linse cretogoguewillresu lt in targe t glycemicgoalsonlyifth ereissufficient-ce llfun ctionre main in gtoallowendogen ou sin sulin secret ion inth eprese nceofimprovedinsu linsen sit ivityt ore gulateg lu coseandlip idmetabolismap prop riately.In manyinst ance s,an dpar ticu larlyafte rsever alyear sofclin icaldiabe tes,-ce llfun ctionissoreduce d th atinsu linsecr etogogu eseith erne edtobereplace dbyorsupplement edwit hexogen ou sin sulin pre parations. Aneffect ive strat egyistoadministe reither in termediate -actinginsu linorglargine at 10:00p.m.toregu lateovern igh the paticglucoseproduction,re sultinginan FPGlessth an 110mg /dL,or eithe ran oralinsu linse nsitiz erorash ort -actinginsu linsecr etogog ue,oracombin ationofboth ,to reg ulatepr and ialglucosecontrol(158,159).Thistype ofprogramwilldecre aseHbA 1 c bet we en1.8%and 2. 5%when the baselineHbA 1 c wit htwooralagen tsisapproximat ely9.5%(Table41.11).In the instanceswh ere-ce llin sufficie ncyissoadvan cedthatth epat ien twithtyp e2diabe tesreq uiresfull insulinreplaceme ntth erapy,itisalsoimportantt otre att heinsulinre sistance(e it here ffe ctivelifest yle modification orinsu linse nsitiz ers),asit willde crease the q uan tityofinsu lin(160,161, 162)th ath asto beadminister edan dwillimproveth ecomponen tsofth einsulinresistancesy ndrome ,mostofwhichar e kn owncardiovascular r iskfactors(3, 128,147,163). TABLE 41.11. Effects of Bedtime NPH Insulin and Daytime Oral Agents or Morning NPH Insulin on Glycemic Control in Patients with Type 2 Diabetes with Previous Poor Control with Oral Agents (Treatment Duration 1 yr)
Parameter Numberofpatients HbA1c(%) Bodyweight(lb) Triglyceride(% change) Insulindose(U/day) Bedtime Morning Hypoglycemia(%)
Glyburide 22 -1.9a +8.6a -30
Metformin 19 -2.5 +2.0 -29
Glyburide + metformin 23 -2.1a +7.9a -17
Morning NPH insulin 24 -1.9a +10.1b -35
24b 2.2b 1.1 36
20b 1.8a
24b 29 1.2
Hypoglycemiadefinedasfastingbloodglucoselevel<63mg/dL(3.5mmol/L).
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P<.05comparedwithbedtimeNPHinsulin+metformin.
bP<.01comparedwithbedtimeNPHinsulin+metformin.
DatafromYki-JarvinenH,RyysyL,NikkilaK,etal.Comparisonofbedtimeinsulinregimensinpatientswithtype 2diabetesmellitus:arandomized,controlledtrial.Ann Intern Med1999;130:389396.
The rapyfortype 2diabet eswit horalme dication shasbe comemore complicat edbecauseofthe av ailabilityofse veraln ewclassesofdrugs, particularlyt heinsu linsen sit ize rs.The sedru gsappeartobe increasingth enumber ofpat ie ntswhocan ach iev etar getglucosevalu eswit horalthe rapy. Inadd ition, th esene wdrugs, usedsinglyorin combinat ion, may prolongth eresponse sofimpr ove dglyce miccontrol byimpr oving-ce llfun ctiondire ctly orindirect ly. Th elon g-termresu lt softh esecombination son clinical diabet esou tcome sr emaintobeestablish edbylon g-termin ter vent iontrials.
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dep ende ntdiabe tesmellitus. N E ngl J Me d1995;333:550554. 110.Kur ukulasu riyaR, Bane rjiMA,Ch aidenR ,etal. Se le ctiv edecre aseinvisceralfatisassociated withweigh tlossdur in gmet formintreatment inAfricanAme ricanswithty pe2diab etes. D iabete s 1999;489[Su ppl1]:A315(abst). 111.YuJG,Kru szynskaYT,Mu lfordMI,et al.Acompar isonoftroglitazon ean dme tfor minoninsulin re quirement sine uglycemicint ensivelyinsulin-tre ate dtype2diabeticpat ie nts.D iabete s 1999;48:24142421. 112.Hund alRS,KrssakM, Du fou rS,etal. Mech an ismbywhichmetformin reduce sglu cose product ioninty pe2diabe tes.D iabete s2000;49:20632069. 113.Chu NV,KongAPS, K imDD,et al. Differen tialeffectsofme tforminan dtroglitazoneon cardiovascularriskfact or sinpatient swith type2diabete s.Diabe tes Care2002;25:542549. 114.Glucoph age;Glu cop hage XRprescr ibinginformation .Bristol-Myer sSq uibbCo.RevisedOct obe r 2000. 115.Garber AJ, Du ncan TG, Goodman AM, etal.E fficacyofmetforminint ype2diab etes:re sultsofa double-blin d,place bo-cont rolled,dose-re spon setrial.Am J Med 1997;103:491497. 116.De FronzoRA,Goodman AM:E fficacy ofmetformininpatientswith non-insulin-depe nden t diabe tesmellitus. N E ngl J Me d1995;333:541549. 117.Clarke BF, CampbellIW .Comparison ofmetforminandchlorpropamid ein non-obese, maturityonset diabeticsun con trolledbydiet. BMJ1977;2:15761578. 118.FismanE Z,Tene nbaumA, BoykoV,et al.Oralan tidiabetictre atment in p atient swith cor on ary disease:time-r elatedincr ease dmortalityoncombine dglyb uride/metformint herapyovera7.7year follow-u p.C lin Cardiol2001;24:151158. 119.OlssonJ, Lin dbergG,Gottsat erM,etal. Increasedmor talit yin type2diabeticpat ie ntsu sin g su lph on ylu reaandmetformin in combin ation:apopu lation-basedobserv ation alstudy .Diabe tologia 2000;43:558560. 120.Emslie-Smit hAM, BoyleDI,EvansJM,et al.Contr aindicationstome tforminth erap yin patien ts withty pe2diabe tesapopulation-bas edstudy ofad here ncetopre scribing g uidelin es.Diab et Med 2001;18:483488. 121.SalehYM,MudaliarSR ,Henr yRP. Me tabolican dvascu lareffect softh ethiazolidin edion e tr oglit azone. Diabet es Rev 1999;7:5576. 122.Watk in sPB,Wh it combRW.Hep aticdysfun ction associatedwithtr oglitazone .N Engl J Med 1998;338:916917. 123.GitlinN,JulieNL,Spurr CL,e tal.Twocasesofs evere clinicalan dhistologich epatot oxicity associate dwith troglitazone.An n Int ern Med1998;129:3637. 124.LebovitzHE,K reiderM,FreedMI.E valuation oflive rfunct ioninty pe2diabe ticp atient sduring clin icalt rials:e vid encet hat rosiglit azonedoesn otcauseh epat icdy sfu nction.D iabete s C are 2002;25:815823. 125.Willson TM,Br ownPJ,Ste rnbachDD,et al.ThePPARs:fr omorp han recept ors t odru gdiscove ry. J Med Ch em2000;43:527550. 126.Willson TM,L amb ertMH,Klie werSA.Peroxisomeproliferator-activatedre ceptoran dme tabolic disease.Ann u Rev Biochem2001;70:341367. 127.Kliewe rSA,XuHE, LambertMH,et al.Pe rox isome proliferator -activat edrece ptors:fromgen es
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tophys iology.R ecen t Prog Horm Re s2001;56:239264. 128.LebovitzHE,Baner jiMA. Insu linre sistanceanditstre atmen tbythiazolidin edion es.Re cent Prog Horm R es2001;56:265294. 129.Ole fskyJM.Treatme ntofin sulin resistan cewit hper oxisomepr olife rator-activate drecept or agon ists. J Clin Invest 2000;106:467472. 130.LebovitzHE,DoleJF,PatwardhanR, etal.R osiglitazon emon oth erapyise ffectiveinpat ie nts withty pe2diabe tes. J C lin E ndocrinol Metab2001;86:280288. 131.Aran offS,Mat hisenAL,R osen blattS, e tal.Pioglitazoneh ydrochloridemon ot herapyimpr ove s glycemiccont rolinth etreatmentofpat ien tswithtyp e2diabe tes.D iabete s Care 2000;23: 1605 1611. 132.ChaoL ,Marcus-Samu elsB,Mason MM,e tal.Adipose tissu eisrequ ire dfort heantidiabetic,bu t notth ehy polipide miceffectofthiaz olidine dione s.J Clin Inve st2000;106:12211228. 133.BurantC F, Sr eenanS,Hiran oK ,etal. Tr oglitazone action isinde pende ntofadipos etissue. J Clin Inv est1997;100:29002908. 134.Dre sner A, Lau rent D,Mar cucciM, e tal.E ffe ctsoffre efat tyacidsonglucosetransportan dIRS1-associatedph osph atidylin ositol3-kinaseactivity.J C lin In vest1999;103:253259. 135.Kat sukiA,Murat aK, Fu rutaM, etal.Troglitazonere ducesplas maleve lsoftumourne crosis fact orin obese patien tswit htype 2diabet es.D iabetes Obe s Me tab2000;2:189191. 136.Steppe nCM,BaileyST,BhatS,et al.Theh or monere sist in linksobesitytodiabet es.Nat ure 2001;409:307312. 137.YangW-S, JengC -Y,WuT-J,e tal.Synt het icper oxisomepr olife rat or-activate drecept or- agon ists, rosiglit azone, in creasesplasmalevelsofadipone ctinintype 2diabet icpatie nts. Diabet es Care2002;25:376380. 138.Okun oA,TamemotoH, TobeK ,etal. Tr oglit azoneincr ease sthen umberofsmalladipocytes withoutt hech ange ofwhite adipose tissu emassinob eseZuck errats.J Clin Inve st1998;101:1354 1361. 139.Mont agu eCT,O'Rah illyS.Thepe rilsofp ort liness. Cau sesan dcon sequ ence sofvisceral adiposity.D iabetes2000;49:883888. 140.AdamsM, Montague CT,Pr in sJB,etal. Act ivatorsofPPAR have depot-specific e ffectson hu manpre -adipocytedifferen tiation .J Clin Inv est1997;100:31493153. 141.Balfou rJA,PloskerGL.Rosiglitazon e.D rugs1999;57:921930. 142.GilliesPS,Du nnC J.Pioglitazon e.D rugs2000;60:333343. 143.KhanMA,StPe terJV, Xu eJl.Aprospective, r and omize dcompar isonofthe metaboliceffectsof piog litaz on eor r osiglitazoneinpatie ntswitht ype2d iabeteswh ower epreviouslytreatedwith tr oglit azone. Diabet es Care2002;25:708711. 144.Fr eedM,FuellD,Men ciL, e tal.E ffe ctofcombin ation the rapywith rosiglit azoneand glib enclamide on PAI-1antigen ,PAI-1activity, andt PAin pat ien tswithtype 2diabe tes.D iabetologia 2000;43[Suppl1]:A267(abst ). 145.ImanoE,KandaT,Nakatan iY,e tal.Effec toftr oglit azone onmicroalbu minu riainpat ie ntswith incipie ntdiabe ticneph rop ath y.Diabe tes Care1998;21:21352139. 146.MayersonAB, Hu ndalRS, Du four S, etal.Th eeffects ofrosiglitazone on in sulin sensitivit y, P. 710
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lipolysis, an dhepaticandske le talmu scle triglyc eridecon ten tin pat ien tswithtyp e2diabe tes. Diabetes2002;51:797802. 147.LebovitzHE.R ationaleforan droleofthiaz olidine dione sin type2diabete s.Am J C ardiol2002 (in pre ss). 148.Fine goodDT, McArt hur MD,KojwangD,etal. -Cellmassdy namicsin Zu ckerdiab eticfatty rats. Rosiglitazon eprev entst heriseinn etcelld eath .Diab etes2001;50:10211029. 149.Gh azz iM,Pe rezJ, An tonucciT,et al.Cardiacan dgly cemicben efit softr oglit azonet reatme ntin NIDDM.TheTroglit azoneStu dyGrou p.Diabetes1997;46:433439. 150.AkazawaS,Sun F, ItoM,e tal.Efficacy oftroglit azoneonbodyfat dist ribu tion in t ype2 diabe tes.D iabete s C are 2000; 23:10671071. 151.Hsueh WA,JacksonS, LawRE .Contr olofvascularce llproliferation andmig rationbyPPAR. Diabetes C are2001;24:392397. 152.LebovitzHE.Or alant idiabe ticagen ts.The eme rgen ceof-glucosidaseinh ibitors.D rugs1992;44 [Supp l3]:2128. 153.LebovitzHE.Alpha-glucosidaseinhibitor s.En docr in ol Me tab C lin North Am1997;26:539551. 154.Chiasson J L,Joss eR,Hu ntJ,e tal.The e fficacyofacarboseinth etre atment ofpatie ntswith non-ins ulin d epen dentdiabetesmellitu s.Ann In tern Me d1994;121:928935. 155.HolmanRR ,Cu llCA,Tu rner RC.Arandomized dou ble -blindt rialofacarbosein type2diabete s sh owsimproved glyce miccon trolover 3years.D iabetes C are 1999;22:960964. 156.Rask in P,Jovan ov icL, Be rgerS, etal.Re paglinide/troglitazonecombination the rapy:improv ed glycemiccont rolintype 2diabet es.D iabetes C are 2000;23:979983. 157.Garber A, DavidsonJ, Moor adian A, etal.E ffectofmet formin/glyburidet abletsonHbA1cin first-lin etre atment oftyp e2diabe tes.D iabete s49[Su ppl1]:432-P,2000(abst ). 158.Yki-Jarvinen H,Ryys yL,Nik kilaK, etal.C ompar isonofbedtime in sulin regime nsinpat ie nts withty pe2diabe tesmellitus:aran domized,cont rolledtrial.Ann Inte rn Med1999;130:389396. 159.Yki-Jarvinen H,Dr esslerA,ZiemanM.Les sn oct urn alhypoglycemiaandbe tter p ostdinn er glucosecontrolwith bedtimein sulin glarginecomp ared with bedtime NPHin sulin duringcombin ation th erapyin type2diabete s.HOE901/3002St udyGroup.D iabetes C are 2001;23:11301136. 160.Rask in P,R endellM, Rid dle MC, etal.forth eRosiglitazone Clin icalTrialsStud yGroup .A randomizedt rialofrosiglitazone ther apyinpatientswith inadequ ate lycontr olledin sulin -tre atedt ype 2diabetes. Diabet es Care2001;24:12261232. 161.Schwar tzS,RaskinP, FonsecaV,etal. Effectoftroglitazoneininsulin-tr eate dpatien tswit h typ eIIdiabete smellit us.N En gl J Med1998;338:861866. 162.Aviles-SantaL,Sin dingJ,RaskinP. Effectsofme tfor mininpatie ntswithpoorly con trolled, insu lin-tr eate dtype2diabete sme llit us.Arandomized, dou ble -blind ,placebo-con trolledt rial. Ann In tern Med 1999;131:182188. 163.KoshiyamaH,Shimon oD,Ku wamu raN,e tal.In hibitorye ffe ctofpioglitazon eoncar otidar terial wallthickne ssin type2diabete s.J Clin End ocrinol Met ab2001;86:34523456.
Chapter42
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Treatment of the Child and Adolescent with Diabetes

Lor i Laffel Cindy P asq uare llo Mar gar et Lawlor Diabetesinch ildhoodisachronicmet abolicdisor derth atre sultsin hype rglycemia.Inch ildren ,asin adu lt s,en ergymetabolismisaltere dasar esulteith erofinadequ ate insu lin se cretionorofinadequate insulinact ion, causingaberrantfu elhomeostasis, wh ich affect scarbohydr ate ,protein,andfat metab olism.Diabete sisclassifie din tofour t ypes:ty pe1, type2,gestation al,an dot hert ypes,including secondarydiabe tes.The approac hestotype 1an dtype2diabete sin childr enandadolescen tswillbe rev iewe d.Gestationaldiab etesdoesn otge nerallyoccurint heped iatricpopu lation .Manyformsofothe r type sofdiabe tes,du etocau sessuch aspan creatich ypoplasiaor pancr eat ectomy(se con daryt o hy perinsulinemiaor chronicpan creatit is), b ehavelike andaretr eate dsimilarly tot ype1diab etes. Anothe rcommon formofse con darydiab etes, c ysticfibrosis-relate ddiabete s,appe arsclin icallylik e eithe rtype 1ortype2diabete s;read ersar erefer redtorece ntre vie wson t hissubject(1,2,3, 4,5).
DIABETES IN CHILDREN AND ADOLESCENTS: INCIDENCE AND PREVALENCE

Although d etailedinformation ont heep idemiologyofdiabe tesap pears inC hapter20,we willsu mmarize fun dament alstatisticsabout theoccur rence ofdiabe tesinyouth ,becausesu chinformation ishe lpfu lto practicin gcliniciansinth eirwor kwith familiesan dthecommun it y.Int heU nitedStates,t heincidenc e rateoft ype1diabetes isap prox imate ly18pe r100,000(6, 7).Th eageofpeakin cide nceoftype 1 diabet esisg ende r-specificandcoin cide swith the in crease din sulin demands ofpube rty(8).Inge neral, th ehighe stin cide nceisin the 10-t o14-ye ar-old g rou pan dthelowestisin the0-to5-year-oldgr ou p forbot hgen ders(8,9). Type1diab etesismostlik ely tode velopingirlsbetwee nth eage sof10an d12, an dboy sbetwee nth eages of12an d14.Thepr evalen ceoft ype1diab etesisestimated t obe 1.7cases per 1,000childr enan dadolescen tsyou nge rthan20yearsold. P. 712 Whilethe prevale nceislowerwith 1in2, 500children u pto5years,itisabout1in 400children b y5to 18yearsofage.Th istr anslat estoapproximately123, 000children andadolesce ntsinth eUn ite dState s whohavetype 1diabe tes(6, 7). In child renofallagegroups, the over alloccur rence oftype 1diabe tes hasbeen in creasin gove rthe pastfewde cades(9).Est imat esofth enu mbe rsofyout hwithtyp e2 diabet esare le ssclear.Ofth eapp rox imate ly18, 000childrenint heUn it edStatesdiagn osedwith diabet eseachyear,8%to45%appeartohav etype 2diabet esin reportsfromu rbancen tersinth e Un it edStat esduring t helast d ecade (10,11,12,13). Th eDiab etesSE AR CHStudy ,curr entlysu ppor tedby th eCen tersforDiseaseCont rolan dPre ven tion(C DC)andth eNat ionalInst it uteofDiabe tesand Digest ive and K idn eyDiseases(NIDDK)aimstop roviden ationaldat aonbothty pe1andtyp e2diabe tes inchildrenandadolesce nts(7;http://www. search for diabete s.or g).
Type 1 Diabetes
Type1diabete sisamultifact orialimmune -me diateddiseasecharacte rizedbydest ructionofthe pan creatic-cellsbyT-cells,leadingt oast ate ofinsulindeficie ncy. Ty pe1diabe tesh aslong been ident ifiedbyitspre viousn ame,juv enile diabete s,implyingitscommon ,although notexclusive, occurre ncedu ringchildhood. Curr ent u nde rstan din gofitset iologyinclude sanint eract ionbe tween a gen eticpredisposit iontoau toimmu nitycoupledwit han exte rnal, e nvironmentalt rig gerleading t o au toimmu nede struct ionofthe in sulin -prod ucing-cells ,resu lting int otalorn ear-t otald eficien cyof insulinproduct ion(see Chapter23). Environment alfactors,including foods(14,15,16,17), tox in s,an d viruse s,havebee nsugg estedastriggersofthe aut oimmun eprocessingen etically suscept ibleper son s (18,19). Markersofau toimmu nityin clu deth eprese nceofcir culatingautoan tibodiestoth e-cells, such ascy toplasmicisletce llan tibodies(ICAs), in sulin aut oantibod ies(IAAs), g lu tamicacidd ecarboxylase (GAD)an tibodies, and64-kilodalt on (IA-2)au toant ibodiestotyrosin ephosphatases(IS-2andIA-2) (20,21,22, 23,24,25,26, 27,28).Withimprov eme ntsinth ean tibodyassays, it h asbe enpossib let o ident ifyantibodies int heser aofmoreth an90%ofp atient swith newlydiagn osedt ype1d iabetes. Howe ver, these ant ibodiesare neith erne cessary norsufficie ntforthe diagnosisoftype1diabet es. Iden tifyin gthe p resen ceoft hese autoan tibodiesmaybe helpfulinclinicalsituation sin wh ich it is un cle arwh ethe rthe childh astype 1ortype2diabet es,particularlywit hth ecurr ente pide micof childhoodobesityandtype 2diabe tesinyouth .Scree ningfor pancr eat icautoan tibodiesinfamily membe rsofpatient swith type1diabete salsoisusedasare search toolin studiesofthe preve ntion of type 1diabe tes(seeC hapter23). Se veralh umanleu kocyt ean tig en(HLA)classIIgen eshavebee n lin kedtosusce ptib ilit ytot ype1diabetes, and somehavebee nlin kedtoare ducedr iskofdiabete s (29,30,31, 32).Itiscle arth atge neticfact ors, likee nvironme ntalfactor s,donotexclusivelyaccoun tfor th epat hog enesisoftype1diabete s.Infac t,80%offamiliesofc hildre nwithne wlydiagnosedtype 1 diabet esdonot reportanyfamilyh ist oryofthe dise ase, andt heconcordancerateinident icaltwinsis
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only30%to50%.Thecomp lex in terplayofgen etics,en vir on men t,andau toimmu nityasitre latestoth e etiology,pathogen esis,an dposs iblepre vent ionoftype1diabete sisth esubject ofongoin gresearch. Withth edest ructionoft hemajorit yof-cells,insulindeficie ncyre sultsin the on setoft heclassic symptomsoftype1diabete s:polyur ia,polydipsia, andpolyphagiawith accompanyingwe igh tloss.Th e stagesar eou tlin edbelow. Onset:Sympt omssuchasin creasedth irst ,in creasedur in ation ,weight lossdespiteincre ased app etite.
Hone ym oon:Onceinsu lint herapyisin itiat ed,th eresidu al-cellsreg ainfun ctionalcapacity, producingsomein sulin forashorttime. Intensif ication:Dest ructionof-ce llscon tinue s,an dcon trolofbloodglu cose becomesmore difficu lt. Total diabe tes:Allofth einsulin-producing -c ellsar edestr oye d,resu lt in gin tot alin sulin deficiency.
Treatmentoftype1diabet esbeginsatdiagnosisandinclude sin sulin ther apy, thede velopmen tofameal plan, an activity/exe rcise plan,t raininginth euse ofabloodglucosemon it or, and familysupport. Initial self-managementt rainingaimstop rov idet hech ildor adole scentwh oh asdiabe tesan dhisor h erfamily withth eknowledge, skills,an dproblem-solving abilitiestomanag ediabete son adailybasis.Thisinitial edu cationisfollowedup byon goinge ducatione volvingwithdu rationofd iabetesandth egrowthand deve lopmentofthe childandadolescen t(33,34,35).
Type 2 Diabetes
Type2diabete sin childre nan dadolescen tswasident ifiedinth elate1970san dhasbecomeagrowin g medicalandpu bliche althpr oblemasar esultoft hebu rgeoninge pide micofch ildhoodobes ity (10,11,12, 13,36,37).Like t ype2diabetesinadults,t heincre aseinyout his t hedirect resultofgreater caloricint akewith decreasedcalorice xpen dit ure. Yout hcommon lyh ave pooreatin ghabit s,eatin ghighcalorie ,high-fat,su per-sized fastfoods;spe ndanin creasedamount oftime watch in gtelevisionor usingcompute rsorp layin gvid eogame s;and arevictims ofare duced emph asison physicaledu cationin schoolsandphy sicalactivit yin gene ral(38).Almostally ou thswithty pe2diabe tesareoverweight and haveap ositivefamilyh istoryoftype 2diabet es(10,12,37, 39) .Theincre asingpre valenc eofty pe2 diabet eshasbeen mostmarked in e thn icmin or ity grou ps,includingAfrican Amer icans,Mexican Ame ricans, As ians,Hispan ics, andNativ eAme ricans(10,12, 13)( seeCh apte r29). The firstdataont ype2d iabetesinyout har efromth ePimaIndian s,th egroupwithth ewor ld'shighe st pre valence oftyp e2diabe tes(6) .In1979,th epre valence oftyp e2diabe teswas1in 1,000child ren5 to14year sofag ean d9in1, 000youth s15to24ye arsofage(40). By1996,the prevale nceh ad increasedto22.3per1,000inth e10-to14-year -oldage grou pan d50.9pe r1,000in the 15-t o19year-oldgr ou p(13).InNorthwe stOntario,be tween 1978and1984, t hepr evalen ceoft ype2diab etesin Native- American child renu nder theageof16y earswas2.5per1,000, apre valence higher thanthatfor type 1diabe tesinthe whitepopulation(11,13,41). InManitoba, the p revalen ceoftype2diabete s amongNative-American childr enst udiedbetwe en1984an d1990was0. 53per1,000ch ildren 7to14 yearsofage(11,13, 42).InJapane sejunior-high-sch oolchildre n,t heinciden ceofty pe2diabe teswas rece ntlyfoundt obese vent imeshighe rthanth eincidence oftyp e1diabe tes(13.9/100,000vs. 2. 07/100,000)an din creas edmoret han 30-foldov erth epast20ye ars(43, 44). Astud yfromCincinn ati,Ohio,wasth efirsttodocu me ntinciden cerat esoft ype2diab etesinth e pediat ric p opu lationover ane xten dedtime ( 45). One-t hirdofallne wcasesofdiabete sd iagnosed bet we en1982and1995in the 10-t o19-ye ar-oldagegroupwe reclassified astype 2,givinganage specificin cide nceof7.2per100,000pe ryear.In1992, t ype2diabetesaccou nte dforonly2%to4%of allnewlyidentifiedcase sofdiabe tesinpat ie ntsyoun gerth an19ye arsofage, butby 1994, 16%ofall ne wcasesinch ildren werety pe2diabe tes. In the Cincinnatireport,70%oft hech ildren with type2 diabet eswere Afr icanAme rican, wh ere ason ly 10%ofthech ildre nwit htype 1diabetesand14.5%ofth egene ralpopulation wereAfrican Ame rican(45). Incont rastt oth esimilargen derratioforchildr enwitht ype1diabetes, moregirlsthanboysare rep ort edtohav etype2diabete sin studiesoftype2diabete sin childre n.Th erat iooffemalest omales inth ePimaIndian popu lation is2:1;inOnt arioIn dians, 6:1;inMan it obaIndian s,4:1;an din the pre domin an tly Afr ican-Ame ricanpopulat ioninCinc in nat i,2:1(11). Fu rthe rmore, diabete sisconsisten tly relat edtotwoimport an tvariab les, obe sity andpu bert y:bot hstatesar eassociatedwith in sulin resistance. Indee d,marke rsofinsu linre sistance h ave recen tlybeen ide ntifie din 5-to10-year-old overweight Afr ican-Americanch ildre n(46). Seve ralriskfactorsar eassociatedwith thede velopmen tofty pe2diabe tes:et hnicback ground, family historyoftype2diabete s,in creasedbloodpre ssure, in creasedlipidle vels,an dobe sit y P. 713
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(10,12,20, 37,45,47,48)(Table 42. 1). Inaddition,acant hosisn igrican s,th ou ghtt obeacutaneous manifestation ofhy perinsu linism, ispre sent in 60%to70%(v s.the 7%normallysee ninth ispopulat ion) ofch ildre nwithtyp e2diabe tes.Th esefact orsarequ it esimilartot heriskfactor sforty pe2diabe tesin adu lt s(10). TABLE 42.1. Risk Factors Associated with the Development of Type 2 Diabetes in Children and Adolescents
Familyhistoryofdiabetes Bodymassindex27kg/m2;weightforheight>85thpercentile;>120%idealbodyweight 10yofage(inmidorlatepuberty) African-American,Hispanic,Asian,andAmericanIndiandescent Acanthosisnigricansin41%92% Signsofinsulinresistancesuchashypertension,hyperlipidemia,andpolycysticovariansyndrome(PCOS)
FromtheAmericanDiabetesAssociationType2diabetesinchildrenandadolescents.Diabetes Care 2000;23:381389.
Arece ntlycon ven edtaskforce fromthe NI DDK,CDC,American Diabe tesAssoc iation(ADA),an dthe Ame ricanAcademyofPediatricsrecommen dtest in gfordiabe tesinyouth beginn in gat10yearsofageor at theonse tofpu berty ifearlier .Thisrecommen dation in clu deste stin gfor type2diabete sin ch ildre n an dadolescent sifth eyareov erweight (defin edaswe igh t>120%ofidealbodyweight ,bodymassin dex [BMI]>85t hper centilefor ageandgen der, orweigh tforh eight>85th percen tile ),an dhav ean ytwoof th efollowing: Familyhistoryoftype2diabete sinfirst-orsecond-d egree relative Race/eth nicit y:African, Hispanic,Asian/South Pacific,an dNative-American descen t Signsofinsu linr esist anc esuch ashype rten sion, hyper lipidemia,or polycysticovarysy ndrome (PC OS)(10).
De terminat ionofthefastingplasmaglucoseisthepr eferr edme ansoftest in g,wit hapositivediagnosis whe nfasting plasmaglu cose is126mg/dLorhighe r.Testing s hou ld berepe ated every 2years(20).The initialt reatme ntoftype2diabete sin y ou thisdict ate dbyclinicalpre sentation .Diab eticketoacidosis (DKA)orse vereh yperg lyce miawithn on ketotichyper osmolar hyper gly cemicsynd rome(NKHHS)requ ir es emerge ncymanagement peraDKAprotocol.Ins ulin willlik ely bene ededasther apyinth esepatie nts eve naft erth eir recoveryfromtheacute con dit ion.Ot herswh oarenotillat diagnosiscaninitiallybe tre ate dwith med icaln utrition the rapyandph ysicalactivit y(seese ctionsbe low).Un le ssthe reis succe ssfulweig htloss, mostpat ien tswillrequ ir esomeformofdrug ther apy. Prev iously,insu linwas t he onlydrugapprovedbyt heU. S.Foodan dDru gAdministration (FDA)foru sein childr enandad olescen ts. Rec ently,metformin hasb eenapprovedforuseinadolesce nts12yearsofageandolde r.Non eth eless, mostpe diatricend ocrinologistsuse someoftheanti-diabet esor alagen tstotreatchildrenwith type2 diabet es(10,12).Th estudy ofmetformininch ildren an dadole scentsh asre cent lybe enpu blishe d,while invest igation sofother oralh ypoglyce micage ntsinyouth are curre ntlyun derway(10,49).Mark ersth at aidinth ediffe rent ialdiagn osisoftype1andt ype2d iabetesinch ildre nan dadole scent sareoutlinedin Table42.2. TABLE 42.2. Differential Diagnosis of Type 1 and Type 2 Diabetes in Children and Adolescents
Type 1: immune-mediated diabetes Notgenerallyoverweight(althoughasmanyas onefourthmaybeoverweight) Lowendogenousinsulin LowC-peptide Positiveinsulinandpancreaticautoantibodies Highketonelevels(30%40%haveketoacidosis)
Type 2: non-immune-mediated diabetes Overweight/obese(85%) Signsofinsulinresistance Highendogenousinsulina HighC-peptidelevelsa Lowketonelevels(<33%haveketonuria;5% 25%haveketoacidosis)
Canbesuppressedfor2to3monthsafterdiagnosis.
Whileit isappare ntth att ype2d iabetesisdeve lopinginan in creasin gnumberofchildren, asinad ults,
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th eprevalenceofthisdisor derislikelyun dere stimat ed,given thet ypicallackofsymptomse arlyin the courseofthe dise ase. Th us, t hee mer gin gepidemicoftype2diabete sin childre nan dadolescent s pre sentsachallenge noton ly toth ediabe tesspecialistbutalsotothe primar ycare prov ide r,whoplays apivotalrole in screen in gforr iskfactorsforde velopmen tofth isdiseaseinth egene ralpediat ric population(10,50).Th erearecu rren tly NIH-fu ndedmulticent erclin icaltr ialsu nder waytoexamine tre atment and p reven tion strat egiesofty pe2diab etesinyout h.
Maturity-Onset Diabetes of the Young

Animportantcategoryofot herformsofdiabe tesismaturity-onse tdiabete softh eyoung ( MODY).MODY isamonogen ic(51, 52),au tosomaldomin an t,he terogen eousfor mofdiabete s.Itisrelate dtoadefectin insulinsecre tion b ythe-ce llsinthe pan creasr ath erth ant oan impairmen tofinsu linsen sit ivity (52,53). It isest imat edthatabout 1%to3%ofpeoplewit hdiabet eshaveMODY.MODYischaracte rized byearlyage ofonset(1030year sofage,alth ou ghitcan bease arlyas2to3yearsof age ),tre atmen twith or alant i-diabe tesmedication sversu streatmentwith in sulin ,usu allyanan tibody ne gativest atu s,an dadiagn osisofdiabe tesinth reeormore familygen erat ions, ofte nwit hmultiple individ ualswit hinth ose g ener ation s.The majorityofind ividualswith MODYaren otover weig ht.Th is diagn osisshouldbeen tert ainedinch ildren an dadole scentswith astrongfamily histor yofdiabe tesin multiplege neration s(54).MODYis r eviewedex tensivelyinCh apt er26. P. 714
THE TEAM APPROACH

Int hiscurre nter aofint ensivediabe tescontr olfollowingth ereleaseoft heDiabetesC on troland Comp licationsTrial(DC CT),th eteamapproacht odiabe tescar eremainscen traltoth esucces sfu l tre atment ofch ildren and adolesce ntswithdiab etes(55, 56, 57).Careofyou thwithe ith erty pe1ortype 2diabetesiscomplexandtime -con sumin g.Inth isageofmanage dcare andcost-contain me nt, fe w primarycarephy sician s,includingpediatricians,possessth etime tocareforthe sepat ie ntsandkee pup withev olvin gthe rapiesorne wtechn ologie s. The e xpert ise r equired t ode livert hen ume rouscomponen tsoft hediabe testr eatmen tprogramresides withinamultidisciplinar yteamth atworkswithth echild'sfamily, primar ycare physician, andsch ool (55,58). Th ephy sician -led pediatricdiabet esteamsh ou ldbe traine din allaspectsofpediatr icdiabe tes management andinclude sadiabet esnu rseedu cator,adie titian, andamen talhe althpr ofessional eithe rasocialworke ror aclinicalpsych ologist. Inad dition,t hete ammayin clu dean exer cise phy siologistan dsubspe cialistssuc hasophth almologists, p odiat rist s,nep hrologists,gastroent erologists, an dot hersasnee ded(55).E acht eamme mber shouldappre ciateth egoalsofth erapy,th ecomplexities ofp ediatricdiabet escare ,th enee dforindividualization, thecomplicat ionsofdiabete s,preve ntionof an dear lyint erven tion forde terioratingglyce miccon trol, andt heimpactoft hediseaseon normal childhoodandadolescen ce,aswellas onfamilydynamics. The p roce ssofedu cating p aren tsan dchild renindiabe tescareshouldbeginatth etimeofdiagnosis. Initially,manyparen tsan dchildr enoradolescen tsare ove rwhelmedan dunable toassimilateth e ext ensivebodyofin format ionofdiabetesse lf-man agemen ttrain in g.Ther efor e,itisr ecommende dthat self-managementt rainingandedu cationbecarriedoutinstages(33,34,35, 59,60).
PATIENT AND PARENT EDUCATION

Tod ay,t hech ildwit hne wlydiagn ose ddiabete sisu suallytreatedasanout patien tor d uringav erybrief inpat ie ntadmission. There fore ,edu cation goalsn eedt obe t ailoredt oth ene edsoft heindividualchildor adolescen t,th efamily, andth ere sou rcesoft heh ealth caret eam.The sein it ialgoalsbecome an importantpartoftheongoingprocessofdiabete sfollow-upcare.C ent raltosuccessfu lman agement and at tainment oftr eatmen tgoalsareth echildoradolesce ntwithdiab etesandhisorher family,whose ne edsshouldrece ive priorityinplan ningandimplement in gthet reat men tprogram.Th echild 'sprimary car eprovid ermustbeinclude dasamemberofthe diabete shealth -care team.In addition ,car egivers such asday-care prov ide rs,te ache rs,schooln urses, coaches, gran dpar ents, andb abysitter sare int egral tosuccessfu lout comes(Fig. 42. 1). Th iscollabor ativeapproachh elpsthepatient r eceiveoptimal diabet escar e,takin gin toaccount hisorh erag e,day-care orsch oolsch edu le, eat in gpatt erns, per son ality ,temperame nt, familystru cture ,cultur albackgr ou nd,andothe rmed icalcondition s.
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FIG. 42.1.Thediabeteshealthcareteamforthechildoradolescentwithdiabetes.
Initialgoalsarelimitedtoimpartinganun derstandingofthe fundame ntaln atu reofd iabetesandh owit istreated. Ne xt,diabe testre atmen troutinesn eedtobeint egrat edintoschool,sportsactivit ies, day car e,andfamilyactiv ities. Th isoccur sthrough pract icale xperien ceath omean dbyfreq uen tcon tact withth ediabet eshealt hcar eteam. Ast imepasses,mostfamiliesarere adytolear nthe in tricate details ofd iabetesse lf-man agemen tnece ssaryformaintain in gopt imalgly cemiccontrol,while copingwith t he challen gesimposedbysu chth in gsasph ysicalactivit y,pickyorselectivee atingh abits,inte rcur rent illne sses,an dot her n or malvariation sin achildor adolesce nt'sdaily rou tine. In addition toimpart in g fact sandt each in gpract ical skills,diabe tesself-management traininganded ucat ionshouldattempttopromotede sirablehealt h beliefsan dattitu desinthe you ngpe rson whohastolive with achr on icandincur abledisease (33,34,35). Fort hech ild,th isisoft enbe staccomplishedinanedu cationalsett in gsuch asage -appropriat epeer edu cation/supp ort g rou psor summer camp sforch ildren with diabete s.Thee ducationalpr ogr ammust match thech ild's leve lofcogn it ive developme ntandbeadapte dtot helearningsty leandinte llectu al abilit yofth eindivid ualchild,adolescent ,an dfamily(35,61, 62, 63).Weu rgeth atparen tsbefully involv ed,andween cou rage thediabetesh ealth caret eamtosuperv ise ,when appropriat e,agr adu aland flexible t ran sferofresponsibilityfromparen tstot headolesce nt,facilitating t hen ormalprocessof separat ionandat tainment ofindepe nden ceth atoccursdu ringth etee nage years(64,65,66,67). Ideally, ween cou rage cooperation aroun ddiabete st asksbe tween thet eenandparen twith the goalof deve lopinginte rdepen den ce,becausep aren tinvolve me nthasbeen con sist entlyassociate dwit hbett er medicalandbe hav ioraloutcome sforyout hswithdiabe tes(64,65,66, 68). Cont in ueded ucat ionisnece ssarydu ringtransition sbetwee ndeve lopmentalst agesofchild hood, s uchas at schoolent ry,be tween thesch ool-ageye arsandad olescen ce,wh enth eadolescen tle avesh omefor collegeorforin depen den tliving, aswellasthrough ou tth elifespan.Some familie sbene fitfrom reinforcemen toft each in gskillsath omewit hth ehelpofvisitingn ursese rvices,eith ershortlyafter diagn osisor duringch alle ngingfamilytimes.Weh ave estab lished adeve lopme ntalmod elofcare , edu cation,andpsych osocialsupportth rou ghourage-basedmu lt idisciplinaryclin ics. Beginn in gwith the mostvulne rablegr ou pofyouth and t heirfamilies,t hePediatrican dAdolesce ntU nit oft heJoslin Diabet esCen terh asimplement edacomprehe nsive,family-focu sedoutpatie ntpr ogramof car efor c hildre nwithtyp e1diabe tesyoun gerth an8yearsofagecalledthe You ngCh ildren 'sProg ram (69,70). It isofferedonce each month ,an dappr oximately400familie swith you ngch ildren hav e par ticipatedtodat e.Thr ou ghasys tematicassessmen tofinitialnee ds,wedocument edth atparent sof pre schooland earlysch ool-agechildren with diabete sareconce rned aboutth efollowing:collisions bet we endiab etestr eat men tan dnormalch ildh oodbehavior;differe ntiat in gsympt omsofh ypog lyce mia fromn ormalbeh avior andmoodswings;andth eimpactofdiabe tesonfamilyre lation ships(69,70).Fear ofh ypogly cemiasu rface dasapr imary c onc ern. Oneofseven ofth eseve ryyoungch ildre nexpe rienced seve rehy poglycemia(70).Thu s,familiesofyou ngchildren becomee xtraordinarilyr elian tuponblood glucosemonitoringinth eseyoun gpatien tswhoare u nable toiden tify andcommun icateh ypoglyce mic symptoms. Weh aveimple men tedasimilar compreh ensivepr ogramforschool-agechildren ,8to13yearsofage, an dthe irfamilies. Thisgrou palsomee tsmonth ly ,wit hth eprovisionofind ividualized medicalcar e followe dbysimultaneoussep aratesupp ort g rou psfor p aren tsan dfor t heyout h.Similartothe You ng Ch ildren 'sProgram,th epar entgr ou pisfacilit ate dbyme mber softh eme ntalh ealth team,eith erach ild psych olog istorsocialworker ,an dbyme mbe rsofth emedicalteam,includingaphysician, apediatric P. 715
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diabet esspecialtyn urse, or r egistere ddie tit ian.Majortopicsofdis cussion inc lu detransitiont omidd le school, impactofpube rtyonglycemiccont rol,andrev iewofne wt echn olog iesalongwith research upd ates. Anearly c hildh oodedu cator,wh ocoord in atesd evelopmen tallyappropriat eactivitiestoin sure posit ive clinicencoun terst hat encourageroutine follow-up, super vise sthe g rou pofyout h.Diabete sspecificeducationalcu rriculaarenotrout in ely discu ssed. The secompreh ensive p rogr amsencourageposit ive in teractions b etween the diabete sh ealth care team an dthe patien tsalon gwit hthe ir familie s.Thepositiv eresu ltofthe seinter actionsise vid entinour asse ssme ntoftheYoun gChildren'sPr ogram(70). Th eprogramev aluat ionyieldedimpr ove dfollow-up at tend ance atdiabe tescar evisits forfamilieswhopar ticipatedinth ecompre hen sive Youn gCh ildren 's Pr ogr amcompare dwith in frequ entpr ogr amatte ndee s( 70). Inad dition,t hegroupofpat ien tswith improved follow-upcarehadsignificantlyfewer ch ildre nwithpoor cont rol(glycosylatedh emoglobinA 1 c [HbA 1 c ]>9. 9%)thanth egroupwithinfre quen tprogramatt endanceandfollow-upcar e(P<.05)(70). Adolesce ntswithdiabetesandth eirfamiliesreceivemultidisciplinar ydiabete scareaswellasmedical car ean dpsychosoc ialsu pport .Thepr ogr amforte ensatthe Joslin Clin ich elpsteen san dtheirfamilies deviseindividualizedman agemen tprogramsth atfitthe irlifestyles.Familiesarehe lpe din t he ne got iationofacce ptableparent alin volvemen tin the tasksofdiabete smanag eme nttosust ain adh ere ncetoinsulininjection rou tinesandbloodglucosemonitoring(66,71). Toprovideadd itional supp ort forth epar ent sasthe ytryt ohe lpt heiradolescen ts,weinitiate dabimonth ly even in gpare nt supp ort grou pfacilitatedbyt hemultidisciplin arype diatricteam. In an in itialne edsasse ssmen t,fe arof complication ssurfacedasacon cern in50%offamilies ,while fe arofhypoglycemiawasnotedb y19%. Westr essth eimportan ceofcont in uedmedicalfollow-u pand fr eque ntbloodglucosemonitoringforthe se familiestohelpth emover cometh eseconcer ns. Weh aver ecent lylau nch edapr ofessionallymonitoredDiscu ssionBoard forTee nson the Joslinwebsite. Paren tsofadolesce ntsalsocan participate in aDiscuss ionBoardspe cifically forth em,aswellin the bimonth ly discu ssiongr ou p.Paren tsofadolescen tsreq uireongoin ghelpindeve lopingrealistic expe ctat ionsforadolescent bloodglu cose lev elsandmon it oringbe havior,aswellasinn egotiatingan acce ptableleve lofin volvemen tin the diabetesman age men ttasksofth eirteen .Adole scentswith diabet esalsor equireh elpin developin grealisticexpect ation sfor blood g lu cosemonitor in gandin ne got iatin gwit hth eir paren tsab ou taccept ablelevelsofinvolvement inmonitor in gand insu linr ou tin es. The t eamappr oachtopediatr icdiabe tescarepromotest hese g oalsandremainst heacceptedst and ardof car ethr ou ghoutch ildhood andadolesce nce(55).
GOALS OF THERAPY
In1993, t here sultsoft heDCCTh eraldedint ensiveman agemen tor so-calledtight con trolas t he standardofcareformostpatie ntswitht ype1diab etes(56). W ith scie ntifice vide ncesh owingamarked decr easeint heriskofmicrovascu larcomplications ofth eeyes, kid neys, andn erve swith in ten sive management ,the post-DCC Te rae mer ged(56).Although the st udydidnoten rollpatien tsyounge rthan 13yearsofage,t here were195you th, b etween the agesof13and 17y earsold,at e ntr yin thest udy sample.Asar esult,diab etescaretoday u tilizesint ensiveman agement in thediab etestr eat men tplans forthe majorityofch ildre nan dadole scent swith diabete s(72). Theth eoreticalgoaloftre atmen tist o rest ore met abolicfun ction t oasnearnormalaspossiblewhileavoidin gseriou scomplication softh erapy, espe ciallysymptomatich yper-andh ypog lyce mia.Howeve r,th eappr oachtocare alsoincorporate smore globalgoals,su chas t hen ormalizationofch ildh oodan dadole scentde velopmen tan dthemaint enanceof succe ssfulfamilyfun ctioning(34, 55,59)(Table42.3). TABLE 42.3. Goals of Therapy of the Pediatric and Adolescent Unit of the Joslin Diabetes Center
Avoidanceofsymptomatichyperglycemiaandhypoglycemia EarlyinterventionforincreasinghemoglobinA1clevels Preventionofparent/childburnoutandisolation Preventionofmetabolicdeteriorationofadolescence Identificationandtreatmentofbehavioral/adjustmentdilemmas Provisionofpositivemedicalexperiences Provisionofrealisticexpectationsfordiabetesmanagement Integrationofdiabetesroutinesintoschool,daycare,andfamilyactivities Maintenanceofnormalgrowthanddevelopment
Glyce micgoalsvaryforchildren andadolesce ntsandreflect d evelop men taldiffe ren ces.Since hy poglycemiacan hav emoreofan impactont hen eurocognitiv efun ctionofyoungch ildren (73,74,75, 76,77,78,79, 80),the ADApositiondoesnotsup port tigh tglycemiccontr olfor childre nun der th eage of2y earsandadvise scaut ionforchildren8yearsoldan dyounge r(55).Table42. 4showsthe glycemiccontr olgoalsforyout hwit hdiabet es.
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TABLE 42.4. Goals for Glycemic Control for Children, Adolescents, and Young Adults with Diabetes
Blood glucose goal range (mg/dL)
Values by age Toddlersandpreschoolers Wholeblood Plasma Schoolage Wholeblood Plasma Adolescentsandyoungadults Wholeblood Plasma
Before meals 90180 100200 70180 80200 70150 80170
Bedtime/overnight 100200 110220 90180 100200 80160 90180
HbA1ca 7%9% 8% 7%
aReferencerange,4%6%,astheDCCTstandard.
Seve ralstudiesindicat ethatchildren wh ode velopdiab etesdu ringinfan cyan dearlych ildhood may beat increasedriskforthe subsequ ent developmen tofc ogn itiveimpairme nt(75, 81, 82,83,84).Su ch impairmen tisp resumedtobeth ere sultofmultiple e pisodesofseve rehyp oglycemia,whichmay b e more fr eque ntinve ryyoungch ildre nbecauseofthe irh ypoglyce micun awar eness(85, 86,87).The refore, maintain in gveryt igh tcon trolofglucosele velsin childr enwithve ry-early -on setdiabet esmaybe harmfu l, giv enth eriskofcausingre curre nt, severe ,an dpot ent iallydebilitatingepisodesof hy poglycemiathathaveth epoten tialforne urocog nitiv eseque lae(78,88,89, 90).Caremustalsobe takent oavoidpoorglycemiccon trol, ason ewan tstolimitt hehy perglycemice xposuret hat isass ociate d withfut urecomplicat ions(91).On ereportr aisesthe quest ionofacorrelat ionbet weenh igh long -term HbA 1 c value sandint ellect ualimpairmen tin boy sdiagnosedbelowt heageof6years(92).Furth ermor e, fearofh ypog lyce miaamongparent swhoh ave witn essedse vereh ypoglyce miainth eiryoungch ildre n becomesamajor deter rent both toachievingoptimalcont rolinth esechildren asthe ymatur ean din allowingth emtoe xperien cemanyn ormalact ivitiesofchildh oodthatreq uireseparat ionfromparen ts (93,94,95). Arecen tpublication reportsincre ased p aren tingstre ss,ingen eralandinrelat ionto mealtime s,in familieswit hyoungch ildre nwit hdiabet es,which u nde rscor espare ntalfe arsof hy poglycemia(96). The p repub ertalch ildmaybere lativelyprotected fr ommicrovascu larcomplication s,alth ou ghth isisstill controver sial. Sign sofeye orkidn eydisease aree xtremelyrareinthe prepu bertalch ild(97).Diabetic ne phropat hy,forexamp le, with microalbumin uriau sedasanindex ofre nalglomeru lardamage ,is significantlylessprev alentinch ildre nyounge rthan12yearsofageth an in t hoseolder than12yearsof age matche dfordu rat ionofdiabetes (98). Indee d,itise xtremelyraretounc ove rclinicallysign ifican t microvascularcomplicationsin child renyoun gert han theageof10y ears (97, 98,99).However, debate continu esaboutt hecontr ibu tion ofglycemiccontr olduring thepr epube rtalyearstothe developmen tof fut urecomp lications(100). Thus, curre ntclin icalcaresh ou ldapproacht hisdilemmabyaiming forsafe an drealisticgly cemictargetst hat limitth eoccurre nceofsign ifican thyp erglycemiaand h ypogly cemia an dthatmatch thepatientandfamily 'spar ticularne eds. Inch ildre nan dadole scent s,asinadults,individualizationoft het reat men tprogramisimpor tan t.In highlymot ivatedfamilies, closemon itoringofbloodglu cose andadministe rin gmu lt ipleinsulininjection s orutilizinginsu linpu mpt herapyusing d osageadjust me ntalgorithmsare fair lyr ou tin e.In oth erfamilies, simplificationofthe regime nmaybeth eonlykeytosucce ssfulmanage me nt.Th us,wh ilekee pin gthe gen eralth erapeut icprinciplesinmind ,the diabete shealth care teammusttailorthe goalsoftreatment tothe need sandcapabilitiesofeach in div idu alchildorad olescen twit hdiabet esan dhisorh erfamily
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(33,34,35, 59,60).
TYPE 1 DIABETES: GLYCEMIC CONTROL IN THE PEDIATRIC POPULATION AND THE DCCT/EDIC STUDY
De spit emu lt idisciplinaryspecialtycare, glyce miccon trolr emain ssuboptimalinman ypediatr icdiabe tes cen tersworldwide ,in cludingourowncen ter. Inare cent sampleof300ch ildren wit htype 1diabet es,th e mean Hb A 1 c was8.7%1.2%, with 33%achievingan HbA 1 c lev elbe low8. 1%(101).Glycemiccontr olin ourpopulat ionap pears q uitesimilartothatreporte din oth erlarg e,cross-sectionalstu die sofpediat ric populations(Table42.5).Amultice nte rcross- section alstudyinv olving22pediatr icde part men tsin18 count rie sin Europe, Japan,andNor thAmericaen rollin g2, 873children with type1diabete s,reporte da mean baselineHbA 1 c of8.61.7%, with 34%ofpatien tsach ie vin gan Hb A 1 c <8.0%(105). Three year s late r,th eme anHbA 1 c fromt hesece nte rsremained8.7%1.7%(111). Similar ly, arece ntcrosssect ionalnation wide studyof2, 579 French child renwitht ype1d iabetesr epor tedanoverallme anHbA 1 c of8.97%1.98%,with 33%of pat ie ntsachievingan HbA 1 c lesst han 8.0%(105).In theDCC T, 83%ofthe int ensivelytr eate dpatien ts ach ie vedHbA 1 c value sof8%orless,comparedwithonly20%ofth epat ien tsre ceiv in gstan dardcare. Fewerth an 5%ofth einten siv ely treatedpatie ntsachievedHbA 1 c valu es<6. 05%(56). TABLE 42.5. Average Glycemic Control in Children and Adolescents Around the World P. 717
Study (year) (ref)
Country (city)
Mean HbA1cSD 12.0%2.1%(HbA1)= 9.68%(HbA1c) 11.3%2.9%(GHb)=9.08 (HbA1c) 8.3%1.6%
Jacobsonetal.,1994 (102)
USA(Boston)
61
Paltaetal.,1996(103)
USA(Madison,WI)
507
Tubiana-Rufietal.,1995 (104) DCCT,1994(112)a Rosilioetal.,1998(105) Mortensenetal.,1997 (106) Dorchyetal.,1997 (107) Nordfeldtetal.,1997 (108) Vanellietal.,1999 (109) DIABAUD2,2001(110) Danneetal.,2001(111)
France
165
USAandCanada France 18countriesinEurope,Japan,and NorthAmerica Belgium
92/103 2,579 2,873
8.06%1.25/9.76%1.22% 8.97%1.98% 8.6%1.7%
144
6.6%1.2%
Sweden
146
6.9%1.3%
Italy
201
7.8%1.4%
Scotland 21internationalpediatriccentersin 17countries USA(Boston)
1,755 2,101
9.1%1.5% 8.74%1.66%
Levineetal.,2001(101)
300
8.7%1.2%
aDCCT,N=92,intensivecohort;N=103,conventionalcohort.
Int ensiveinsu linth erapy,comparedwithconv entionalth erap y,inthe DCC Tdelayed t heonse tand slowed t hepr ogre ssionoflong-t ermcomplicationsinboth t headolesce ntandadu lt coh ort s.Thesu bset oft he195adole scentp atient s,age s13t o17ye arsat studye ntry ,ran domizedtointen siv ethe rapy expe rienced asimilarredu ction in r iskforcomplication stotheiradultcou nte rpar ts(112).In con trastto
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th eadolescent coh ort sfromthe DCC T,the adu ltsinboth con vent ionallyan din ten sive lyt reat edgroups ach ie vedlowe rHbA 1 c v aluesbothd uringth eDC CTan dduringt hefollow-upEpidemiology ofDiabetes Int erven tion sandC omplication s(E DIC )study (56, 112,113,114).Du rin gthe DC CT,inten siv elytreated adu lt sachiev edHbA 1 c valuesof7. 1%compar edwit hvalue sof8.9%inconven tion allyt reat edadu lt s (Fig. 42.2). Amongth e195adolescen ts,both in tensivelyandconven tion allyt reat edadolescen tpatien ts hadHbA 1 c valuesabou t1%high erth anth ose ofth eirolder coun ter parts. Atthe endofthe DCC T,all stu dypatien tswere encouragedtouse int ensiveinsu lint herapy.Duringt heEDICfollow-up,both grou ps ofadultpatie ntse xperienc edach ange in theirglycemic cont rol,withHbA 1 c valu esininten siv ely treated adu lt patien tsin creasin gto7.9%andHbA 1 c value sin the conv entionallytreatedadultsdecr easingt o 8. 1%.Noneth eless,th einte nsivelytreatedadultpat ien tsben efitedfromt heirinitiale xposu reto inten siv ein sulin the rapy ,wit hasu staine drisk r educt ioninth eoc curre nceofretinopat hyand ne phropat hydu rin gthe first 4yearsoffollow-upinth eEDICstu dy(114). Th isriskre ductionhasbeen confirme dafter 7yearsoffollow-upinEDIC(115).
FIG. 42.2.Levelsofglycosylatedhemoglobin(HbA1c)achievedintheDiabetesControlandComplicationsTrial.The conventionallyandintensivelytreated(firstandthirdcurvesfromtop,respectively)adolescentshadhigherHbA1c valuesandmoreoverlapthandidtheiradultcounterparts(secondandfourthcurves,respectively).
Thissig nificantre duction in riskformicrovascular complicat ionswassustain edin the in tensivelytr eat ed adolescen tswhen the ywerefollowed4ye arsafterth een dofth eDC CT(113). Oneh undr edseve nty-five oft he195adole scents initiallyenrolle din theDCC Tparticipated in t hefollow-upEDICStu dy(115). Aftert here le aseofthe r esultsoftheDCC T, the c onv entionallytre atedp atient swereinvited t ore ceive inten siv ein sulin the rapy .Du rin gthe first 4yearsoffollow-up, 50%ofcon vent ionallytre ated adolescen tsselected multipledailyin je ctions, appr oximately17%sele ctedinsu linpu mpth erapy,wh ile th eremainde rcon tinue dtor eceiveconven tion alin sulin ther apy(113).Amongt heinte nsivelytreated youth duringt heDCCT,90%electe dtocont in ueinte nsiveinsulinth erap yduringt he4year soffollowup. Desp ite thediffere nceindiabe tesmanagement betwee nth etwog rou ps,glycemiccont rolwas ident ical4year safter thee ndoft heDCCT, with the g rou passigne dtoint ensiveinsu linth erapyin the DC CTmaintain in gamean Hb A 1 c of8. 4%whilet hosewhoreceived conv entionalinsulinth erap yachieving ameanHbA 1 c of8.5%.Despiteth ise quivalen ceofglycemiccon trolbet ween t hetwogroups, the pre viousex posu retointen siv ein sulin the rapywasassociatedwithasustain edriskredu ction fort he occurre nceofretinopathyanddiabet icn ephr opathy(113,114). The sediffe rence sin glyce miccon trolb etween adu ltandadolesce ntpatie ntsdu rin gthe DC CTand E DIC stu die sunde rscor ethe challenge sassociatedwitht heman agement oftyp e1diabe tesinadolescen ts. Thissugge ststhatad olescen tsan dyou ngadultsmayhaveparticularlychallen gin gme tabolican d beh avior alfactorsth atwarran tadditionalstud yin orde rtodevisesucce ssful tre atment programsthatcan opt imiz ethe irglycemiccon trol. I ssuesre latedtopube rtalgrowthand deve lopment, aswellasbeh avior s,likelycontr ibu tetothe sechallen ges. Furth ermor e,achievement ofoptimalglycemiccont rolremainsch alle ngingformostcen ter scaringfor youth with type1diabete s.Arece ntfollow-u ptoalarge multination als tudye xamin in ggly cemiccontrol rep ort edwide diffe rence sin meanglycemiccont rolamongspecialtyce nter sandv aluessignificantly highe rthantarget sachieve din adultpopulat ion(111).Inaddit iontoth elong-t ermrisk soflate complication sthatfollowlon gperiodsofun con trolleddiab etes, you thwithpoorly con trolleddiabe tes expe rienced s ign ifican tly morehospitalizationsan demergen cyroomvisitscompare dwith you thwh o ach ie veHbA 1 c value sof8%orless(101).For2ye ars, we pros pectivelyob served300youth, ages 8to 16years,withty pe1diab etes. Th erewasath reefoldin crease in ther ate ofhospitalizationsan d emerge ncyroomvisit samon gthosewithav erageHbA 1 c valuesofgreatert han 9%compar edwithth ose withHbA 1 c value sof8%orless.In addition, the fr eque ncyofhypoglycemiawasequ allyh igh amon g th osewith poorlycon trolleddiabe tesandth osewith lowerHbA 1 c value s.De spit ethe lackofoptimal P. 718
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control,the occu rren ceofh ypoglyce miainth egroupwithpoorcon trolmostlikelyre sultsfromth elack ofatte ntion tod iabetesman agemen ttask s(71).Repe ate dly, achieve me ntofoptimalgly cemiccontrol hasbeen fou ndtobesignificantlyre latedtothe freque ncyofbloodglu cose monitorin g(65,66,71,101). (Seese ctiononbe hav ioralfact ors).
Puberty
Pu bert yisachallengingp eriodfordiabet esmanageme ntfromboth physiologicandbe hav ioral standpoin ts.Th ehormonalmilieuofpube rtyset sthe st ageforsignificantinsu linre sist ance duet o increasesinth eproductionofg rowth hormon ean dsexster oidhormon es(115). Amielandcolleagues per formedelegantst udiesofglucosedisposalusingah yperinsu lin emicclampin p repub ertal, puber tal, an dpos tpube rtalindividu als(116)(Fig.42.3).Theirinves tigation con firmedth at, despitesimilarlevels ofcircu latinginsulin,individualsinth emidstofpube rtydisplayed sign ifican tly lower(by30%)glucose disposalt han did p repub ertalandpostpube rtalindividuals(116). Thediminu tion in glu cose d isposalwas eviden tinpube rtalyouth with type 1diabet esaswellasinpube rtalnormoglycemiccon trolindividuals match edfor ageandgen derwitht heyouth wit hdiabet es.Thu s,itisqu it ecommon forinsu lin req uirementst oincre aseby50%dur in gpuber talgrowthanddeve lopment(116).
FIG. 42.3.Effectofpubertyoninsulin-stimulatedglucosemetabolisminnondiabeticanddiabeticsubjects.Tanner 1,prepubertal;Tanner24,pubertal;Tanner5,postpubertal.(AdaptedfromAmielSA,SherwinRS,SimonsonD,et al.Impairedinsulinactioninpuberty.Acontributingfactortopoorglycemiccontrolinadolescentswithdiabetes.N Engl J Med1986;315:215219.Copyright1986MassachusettsMedicalSociety.Allrightsreserved.)
Anobserv ation alstudy ofmore than900pe rson satource nte rwhowe re15to45year sofag e,allof whomwe rediagn osed with type1diabete sbefor ethe ageof40year s,fou ndsignificant relation ships bet we enHbA 1 c andage ofdiabe tesonsetandattaine dage (Fig.42.4).The p atient swhowe reth e young estat on setofd iabetesh adth epoore stglycemiccontr ol,ase xpecte dbythe greaterse verityof th eir deficitininsu lin-pr odu cin g-cellcapacity(au thors'unpu blish eddat a).On theoth erhand, HbA 1 c wast hehigh estdur in gthe lateadolescen tyears,ag es16to20, likelyreflecting t hepe riodofgreat est beh avior aladjust men tan dthe t imewhe npat ie ntsex perience difficultieswit hadh ere ncetothe diabete s tre atment program.The sefin din gssugge stthatpar ticularatten tionn eedstobefocuse don older adolescen tsan dyou ngadults,astheirglycemiccont rolapp earst obed eteriorating .Fu rth ermore , pat ie ntsofthisage may bechangingth eircare frompediat rict oad ultprovide rsan d,asaresu lt, maybe at greatris kforbe in glosttofollow-u p.Thecomb in ation ofde terior atingglycemiccon trolandlossto follow-u pcare placesth esepat ie ntsathighriskforthe start ofmicrovascularcomplications(117, 118). Tog ethe rphysiologicdemandsofpube rtyan dbeh avior alissu esaddt oth echallen gesofdiab etesdu ring th isde velopment alstage (65,66,110, 111).Th eperiodofadolescen ceisnotableforthe need forth e rapidlygrowingan ddeve lopin gyouth toe xperime ntandpush the limitsofhisorh eren viron me nt.Th ese youth are often encour agedt otakeovermuch ,ifn ot all,ofth eir diabetest asks. Howeve r,withth e recogn itionth atpu bertyisach alle ngingper iodfor glyce miccon trol, addition alpare ntalsu ppor tan d guidanceareimpe rativet opre vent excessiveglycemicdeter iorat ionatthisstage.Furt hermore,n ewer stu die shave con firmedth eimportanceofcon tinue dpare ntalgu idancet oh elp adolesce ntsavoid det erioration ofth eirschoolwor k,toredu ceth euseofdrug sandalcohol,an dtor educe theoccur rence oft een pregn ancy(110).Thu s,wepromote in terde pende ncebe tween familyme mbe rsan dthet eenwith diabet esthaten cou rage steamworktosupportth erigor sofdiabe tesmanagement. Thisisparticularly importantinligh toftheph ysiologicdeman dsofpu berty occu rringat atime wh ent heyout hiss trivin g formoreinde pende nce. Tohe lpmaintain adh eren cetodiabete stasks, especiallytob loodglucose mon itoring, caregiver smu strewardthe actofmonitorin g rather thanpun ish unfavorablebloodglucoseresu lt s(121).(See section on behavioralissue sandfamily stu die s.) P. 719
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FIG. 42.4.RelationshipofHbA1ctoageatonset(A)andattainedage(B)among900personsatJoslinDiabetes Centerwithattainedageof15to45years,allofwhomwerediagnosedwithtype1diabetesbeforeage40years (authors'unpublisheddata).
INSULIN THERAPY
Onlyth enu mbe rofinsu linscu rren tly availablean dthe toolswith whichtodeliv erth emlimitinsulin reg imensu tilizedinth emanagementofdiabet esin childr enandad olescen ts.The seregimenscanrange fromth euse ofasing leint ermediate- orlon g-act in gin sulin (NPH[neu tralprotamineHagedorn], le nte, ultrale nte ,or glargine)toan in ten sive p rogr amofmultip let ypesofin sulin sadmin iste redth rought hree orfou rdailyin je ctionsoraspart/lispro/regu larin sulin throug hcon tinuoussu bcut ane ou sins ulin infu sion (CSII)(Table 42. 6).Th eselection ofaninsulinreg imende pendsu pon manyfactor s,such astype of diabet es,age,glycemicg oals, andpe rson alchoice .Theu seofinsu linint ype1d iabetesisth emain focusoft hissection . Availableinsulinsar eliste dbythe ironse t,peak,anddu rationofaction in Table 42.6. TABLE 42.6. Insulin Actions by Type of Human Insulins P. 720
Insulin type Insulinaspart Insulinlispro Regular NPH Lente Glargine Ultralente
Onset 510min <15min 3060min 24hr 34hr 1.1hr 46hr 13hr
Peak 35hr 24hr 36hr
Duration
3090min 23hr 410hr 412hr Nopeak 820hr
1016hr 1218hr 24hr 2024hr
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70/30a 50/50 75/25
30min 30min 15min
212hr 23hr 1.53hr
1424hr 1024hr 1624hr
a70/30(70%NPH/30%regular),70/30(NovologMix)(70%insulinaspartprotaminesuspension/30%insulin aspart);50/50(50%NPH/50%regular);75/25(75%insulinlisproprotaminesuspension/25%insulinlispro.
FromAmericanDiabetesAssociation.HealthCareProducts.DiabetesForecast.Availableat: http://www.diabetes.org/main/community/forecast/jan_2002_insulin.jsp#relativeinsulins,withpermission.
Although t her eisn oonee stablishedformulafordeter miningachild'sin sulin requ ire me nt,e xperien ce hasshownth atch ildren with newlydiagn ose dtype1diabete sr equireapproximately0. 5to0.75U /kg per d ay.Forchildr endiagn ose dbeforeth edeve lopme ntofketonu ria,th einitialinsu lindosesmaybe lower thanthe 0.5U/kgpe rday .Wit hdiminishe din sulin sensitivit yassociatedwithDKA,ste roidu se, pub erty, orinfe ction, theinitialdosesmaybeashighas1.0U /kgper d ayormoret oachievere asonab le glycemiccontr ol.Us ualsubcu tan eousdailyin sulin dose calculationsar esummariz edinTable42.7. Ch ildren younge rthan8year sold,oftenindire ctcon tras ttoadolesce nts, aree xquisitelysensitiveto insulin.Th esmallinsulinne edsofinfantsandtoddlersmayre quireinsulindilu tedtoU10, U25,orU50 asopposedtothe stan dardU 100pre parations(100U/mL)toallowformoreprecisedosingan d measu rementofinsulininle ssthan1- unitincre men ts.Dilue ntsareav ailable forspe cifictypesof insulinsfromth einsulinmanu factu rers. Insulincan bedilu tedeith erinaph armacy orathome after par ent saret augh ttodilut ethe U100insu linu sin gthe d iluen tspecifiedbyth emanu factu rerforthe insulintype . TABLE 42.7. Usual Subcutaneous Daily Dosages of Insulin in Children and Adolescents with Diabetes
Type Type1diabetes Child,prepubertal Adolescent,pubertal Type2diabetes Adolescent DKA,diabeticketoacidosis.
Non-DKA presentation 0.250.5U/kgperday 0.50.75U/kgperday 2040U/daya
DKA presentation
0.50.75U/kgperday 0.751.0U/kgperday
a Oftenadministeredasintermediate-actinginsulinasstartingdosage.Dependingonlevelofhyperglycemiaat presentation,insulinneedscanbesignificantlyhigher.
Although t het heoreticalgoalistonormaliz ethe premealbloodglucosele velstov aluesbe tween 80and 120mg/dLandtomain tainth emiddle-of-the -nightbloodglucoselevelat 80mg/dLorab ove ,an umb er ofv ariablesmustbe con side redwhe nestablish in gin dividu altarge tbloodglu cos egoals. Thesev ariables include, butarenotlimitedto,th estageofdiab etes, issu esofgr owth and d evelop men t(e.g ., chr on ologicag eor Tann erstage),activ ity lev el, childt empe ramen t,familyinfrastru cture ,school supp ort ,an dfamilyfear ofhy poglycemiaorlong-t ermcomplications. Adju stmentsininsu lindosesare bas edon the evaluation ofpat tern sofbloodsu garsattaine dove ra3-daype riod,t akingintoaccoun tthe effect ofth ele velofactiv ity aswellasthe fr eque ncyan damou ntofcarb oh ydrat ein tak e.Ifth ereisan emergingpatte rnofou t-of-t arge tbloodglu cose lev elsataconsisten ttime ofday,th ein sulin most resp on sibleforin sulin actionat t hat timesh ou ldbe adjuste dby10%. Oncet hat adjustmen thasbe en made, ide allyitshouldre main fixed for2to3dayst osee theimpactofthe ch an gebeforefu rthe r
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adju stme ntsaremade. Itisnotun usualwith in aperiodofsev eralweek safter theinitiationofinsu lint herapyforachild's diabet estoent erthe honeymoon phase with residualinsu linpr odu ction. Du rin gthisphaseofdiabetes, insulinrequ irementsmayfallwellbe lowthe 0.5U/kgpe rdayge ner allyre quiredt omaintain blood glucosetargetsinth esett in gof-ce llfailu re.C hildr enmayre quireonlyminimalamou ntsof inter med iate-orlong-actinginsu lin,p ossibly combin edwithsmallamoun tsofaspar t,lispr o,orre gular insulin.Giventh eau toimmu nityoftype1diabete s,-cellde struc tioncontinu esinspiteofthis hone ymoonphase.With t hepr ogre ssive lossof-ce llfun ction, then eedforincreasedex oge nousin sulin willbecome r eadilyapparen tin the formofincre asedbloodglucoseleve ls.Th eseinsu linne edsmay continu etorise ove rthe ensu in gweeks, month s,an dyear sasar esultofd eclining - cellfun ction b ut alsowith growthofthech ildinboth height andweigh t.Insu linr equiremen tsmayrisetoasmuchas 1. 5U /kgperdayduring p ubert y.Asdiabet esin ten sifies,t heabilitytomanage gly cemiawith asin gle doseofinsu linorwithlessth an0.5U/kgbecomesvirtuallyimpossible .Inadequateover nightdosin gof insulinwillresu ltinanoverpr odu ctionofhep aticglu cose ,resu lt in gin fastingh yperglycemia, occasion allywith ketonur ia.Mostch ildre nwit hdiabet eswillrequ ire ,at minimu m,amixtu reofrapid-an d inter med iate-orlong-actinginsu linadministere dtwot oth ree t imesad ayb efor ebreakfast, beforeth e eve ningmeal,and/oratbe dtimetoremainfree frompersisten thy perglycemiaan dtoachieve reason able24-h our glu cose con trol.In the adole scentpopu latione specially, itisnotu ncommon forth e aft ernoonsnacktocon sistofmore t han 15to30gofcarb ohy drat e.Thatsnackmaycoincidewith t he wan in gofth emorn in gNPH.Th euseofaspartorlisprotocove rthe added c aloriesofamid-aftern oon snackmayben eeded toimp rove the p re-sup perbloodglucosele vel. The n ewest insu lins arecalledinsu linanalogues. Th esed esig ner ins ulin sarisefromth ebioch emical alte rationoft heh umaninsu linmolecu le .Modification stoth einsulinmoleculealt eritson set, p eak, and dur ationofaction ,wit hthe goalofcreatinginsulinprep arationst hat mimicin sulinactionproduce dby th ehu man-cellswithin t hepancre aticislet s.Clin icalt rialsh ave shown thatth esean alog uesaresafe an deffective;t heirad vant agesinclud emoreoptimalman agemen tofbloodglucoselevelsbyth eclose mimick in gofnormalphysiologicfu nction(123). The FDAapprovedth efirstinsulinan alogu e,lispro(Hu malog),in1996.Lisprohasarapidonse twithin 15minu tesofadmin ist rationb utad urationofactionshorte nedto2t o4hours.Th eon set, peak, an d dur ationofaction oflispr owere designedt omatch the p ostpr and ialincre aseinbloodglucoseth at followsth eintakeoffood.Itsrapidon setmakesitidealforadmin ist rationjustbe fore eating .Studies havedemonstratedt hefeasibilit yofadminister in glisproafter mealsinv eryyoun gchildr en(124). Dosingwithlis proaftermealsallowsacarep rovider tomor eaccu rat ely tit rate theinsu lindosesforan err aticeater,with thegoalofmat chingfoodintakeandinsulinmore closelyan dminimizingth epoten tial forhypoglycemia.Adilue ntforlisproisavailable,allowin gforaccuratelispr oadministration in ,for example, 0.1-or 0.25-U in crements, makin gthispre paratione xtremelyuse fulin veryyoun gchildr en. Clinicalstudieshavesh own that,comparedwithre gular insulin,lisproimprov esHbA 1 c values, improvespostprandialbloodglu cose lev els ,resu ltsinfe we r episodesofh ypoglyce mia, ande nhancesh ypoglyce miaaware ness(123,125). Asecondrapid -actinginsu lin, aspar t(NovoLog),wasr ecent lyapprovedbyt heFDAandisavailablefor use .Alt hought heonset ofac tionve rycloselymimicsthatoflisp ro, itsdu rat ionisbetwe en4to6hours. Rapid-actinginsu linssu chasaspart andlisproallowformaximalflexibilityofin jection satmealsver sus th atofregu larin sulin ,whichformaximale ffe ctivene ssmust beinjected30t o45min utesbe fore eating . Inaclinicaltrialcomparin gthe frequ encyofnoctur nalhypoglycemiain an insu linp rogr amofreg ular insulinoraprogramofaspart,th easpartgr ou phadfe we repisod esoflowbloodglucoseleve lsatnight, aswe llaslowe rHbA 1 c v alues(126).Cu rren tly ,insulinaspartisnotappr ove dbythe FDAforu sein per son sy ou nger t han 18year sofage.In sulin aspar trece ntlyrece ive dFDAapprovalforuseininsu lin pumps(127). Addit ionalpe diatricstudiesev aluat in gthe e ffectiven essofaspart areongoing(126, 128). The t hirdFDAappr ove din sulin analogu eisglar gin e(Lan tus). Glar gin eist hefirstlon g-act in gin sulin an alog uetohaveach ie vedFDAap prov al.Itap pears t obe analmost peak lessinsu lin, with adu rationof 24hoursorlon ger. Itspharmacologicactionmostcloselymimicst hebasalin sulin prod ucedbyt hecellswh ent hebodyisin thefastingstate,t hat is,du ringth eov ernigh thours. Glargine ,aclearU100 insulinprep aration, mu stbeinjecte dalon ewhichisunliketh eot herint ermediate-orlon g-act in g insulins,wh ich canbe mixedwithr apid-actinginsu lins. TheacidicpHofglar gin eprev entsitfromb ein g mixe dwith ot herinsu linpr eparation s.Clinicalstudiesofpremeallisproorregu larcomparin gglargine administere datbe dtimewithNPHadmin iste redeith eronceortwicedailydemon stratedth atth eglargine groupe xperience dlowerfastingbloodglucosele velswith le ssnocturn alhypoglycemiathanth eNPH group(129).Glargineh asnotbee napp rove dforu seinpediat ricpatient syou nger than6ye arsofage. Ongoingclin icalst udiesinthe pediatr icpopulationwilldefineth elevelofe fficacyofth isinsu lin pre paration. Anothe rcat egor yofinsu linpre paration sisth egroupofpremix edinsulins.On emixtu reofin sulin s contain sananalogueoflisprowithan in termediat e-act in gin sulin called NPL.NPL isalisproprot amin e insulinsuspe nsion creatin gamon omericinsulinwit han activityprofilelikethatofNPHin sulin .The P. 721
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mixt ureconsistsof75%NPL and25%lispro.Th eremaysoon beav ailable a70/30,aswe llasa30/70, pre parationofin ter mediat e-act in gNPHan din sulin aspart. The u seofpremixe din sulin s,i.e., 70/30(70%NPH/30%regu lar),50/50(50%NPH/50%regular ),an d 75/25(75%NPLan d25%lispr o), prov ides e aseofadministrat ion,b utth esemixt ures aren otcommonly use din thepe diatricpopulation .Premixe din sulin sare n ot recommend edin the pediatricpopulation un le ssallothe rin sulin programshavefailed.The premix edin sulin sdon ot allowfort heinde pende nt adju stme ntofeither ther apid-orint ermediate -actinginsu lin, asthe yare in fixe d,pre-se trat iosthat can notbealte redinde pende ntlyofone anoth er.Th isdoesnotallowaresponset oincre asedblood glucoselevelsor activitywit houtalte rin gthe ent ire in sulin progr am.Pr emixed insu linmay be adv ant ageousforad olescen tswhosepsych osocialn eedsimpairthe ir abilitytohandleyet on emore diabet esrelat edtask,th atis,th emixingofin sulin s.Familie sin wh ic hthe primaryin sulin -giverhasa learn in gdisabilityorcan notmaster these quen cin gofst epsnee dedtomixinsu linsoraddt oge ther t he clearandclou dydosesmayben efitfromth euseofpremixedinsulins. Amixed d oseofrap id-actingan din termediat e-acting in sulin sadmin iste redbe foreb reak fastwillprovid e insulincoveragefor breakfastandth emiddaymeal,aswellasprovideear lyaftern ooninsu line ffe ct. Becauseth epre breakfastinte rme diateinsu lineffe ctwillhave sufficien tlywan edbylateaftern oon, the ne edfor aseconddoseofin sulin topr ovidecover ageforthe even in gme alandover nighth ou rswill becomeobv ious.Th epeakactionofpr esuppe rinter mediat einsulinwilloccu rbetwe enmidn igh tan d3 a. m. ,in creasin gthe risk forn octu rnalh ypoglyce mia. Fastin gbloodglu cose le velsmay bein creasedasa resu lt ofincre asingovern igh the paticproductionofgluc oseandovern igh treleaseofgr owth hormone . Incr easingt helevelofp resupp erinter med iate-act in gin sulin tocompensateforthe fasting hy perglycemiawit hou tmon itoringth einsulineffect betwee nmidn igh tan d3a. m. maytriggersev ere noctu rnalh ypoglycemia.Ifth emiddle-of-the -nightbloodglucoseis100mg/dLor le ss,it isu nwise to raiset hesu pperinte rme diate-actinginsulintocor rectth efast in ghyper glyce mia, asth eriskfor noctu rnalh ypoglycemiaincreases. In such in stan ces,asaferapproacht omanagingth efasting hy perglycemiaist oad ministert herapid -actinginsu linalone atdinne ran dthe in termediate -orlongact in gin sulin atbe dtime(approximat ely 9p.m.), t husp rovidingmor ein sulin cove rage in theh ou rsjust beforedawnwhe nitisn eede d.Theu seofu lt ralent einsulinbeforesu pperasasubst itu teforabe dtime injection in the p repub escen tchild, main tainingatwice -daily in je ctionpr ogram, canoccasionallybe quite s uccessfu l(130).Thesu ccessoft hisin sulin regime nfade srath erdramaticallywith t hee xuber ant hormon alchan gesinth eadolescen t,ne cessitating amu lt ipledailyinjection program. Inacommoninsu linr egimen ,twothirdsofthet otaldailyinsu lindoseisgiv enbeforebr eakfastan dthe remaining one third,be fore din ner and/orbed time. R apid-act in gin sulin usuallymakes u pon eth ird of th emorn in gdose ,wit hthe remainingtwothirdscomp osedofth ein termediat e-acting ins ulin .Onet hird toon ehalfofthe even in gdose isdev ote dtot herapid-actinginsu lin, andt here main derisadmin ist ered ase ith erth esup perorbedtimein termediat e-act in gin sulin .Fine -tun in gofdosesisaccomplished th rou ghth euse ofbloodglucosemonitoringtodete rmine thee ffectivene ssofth einsulinprogram. Familie sshouldbeen cou rage dtobe comeac tiv epart icipan tsinevalu atingandself-ad ju stin ginsulin dosesbase don bloodglu cose lev els, ant icipat edcar boh ydrat ein tak e,andplann ed-foract ivityleve ls. Over thepast10years,sincet here le aseofthe DCC Tr esults,pr actition ersworldwide h ave recognized an dacce ptedth evalue ofaimin gtonormalizeglycemia(56).Toachieve thisgoal,regime nsshould at tempttomimicth efunc tionofthe -cells,u sin gabasal-bolusapproach t odiabe tesmanagement .To dat e,th isisaccomplishe dthrough eithe rmu ltipledailyin jection s(usingeithe rultrale nteorglarg in eas th ebasalinsu linandlispr o, aspar t,orregu larin sulinasth ebolu sin sulin )ort hrough CSIIusingan insulinpump.Bothofthe seprogramshavede monstr atedadvan tag esov erth emoreconve ntionalin sulin programsbu tare not with ou tdistinctdisadvantagesaswe ll(56).Advantagesincludegr eate rfle xib ilit y ar ou ndfood, with respect toboth thet imin gan damou nts;lowe rrisk ofhy poglycemia,asthev ariable peakingofint ermediate- actinginsu linsiselimin ate d;the abilitytosleepinwith ou tthe risk of significantwaningofins ulin e ffectbymor ningwithhy perglycemiaor ther iskofhypoglycemiafromlack ofcalories;andth eability t oimpr ove bloodglu cose lev elsandglycemiccont rol.C le arly,disadv ant ages includet hene edtoin creasethe frequ encyofbloodglu cose monitorin gtofour ormoretime sperday, th erequ ir edatt ent iontothe carbohyd rate con tent ofmeals/snacks,andth epot ent ialforweightgain . The DCC Te xperien ceshowedth atth ose part icipan tsin the in tensive lyman agedgr ou pwere, on average, 10poundsh eav ier thanthose inth econ ven tionallytre ate dgroup(56).Succe ssfulmanag eme ntofdiabete swith anint ensiveinsu lin programre quiresade monstr ate dcomfor tle velwith bloodglu cose monitor in gtoolsaswellaswit h insulindeliverysyst ems, in creasedfamilyandschoolsu ppor t,proficien cywit hcar boh ydrat ecou nting , record-k eeping,andmor efrequ ent cont actwithadiabete shealt hcar eteamth atcanprovide24-hour supp ort .Ithasbeen demon strat edthatth esucce ssofsuch an insu linp rogr amrequire st hat bot hthe child/adole scent andfamilywant thisapproach an dcommu nicate wellwitheachothe r.Familie swith majorst ress,su chasconflictualch ild-parent relation ships,major men talillne ss,or pooradh ere ncetoa more con vent ionaltr eatmen tprogram,sh ou ldde fe rin ten siv ein sulin the rapypr ogramsu ntilther ehas bee nsomere solut iontothe psychosocialorme dicalt ensions. 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INSULIN DELIVERY SYSTEMS

Optionsfor thede liver yofinsulinar emanyandvaried.The yin clu desyringe s,pen s,pumps,andair injectors. Trad itionally,mostpe diatricpat ien tsrece ive the irinsu linby inject ionwithsyr in gestoprovide mixingof insulinsan dfle xibilit yin dosingofbot hshort-andlon g-act in gin sulin preparations.Syr in gesare calibrat edto3/10cc,1/2cc,or1ccandh ave eit her29-gauge ,1/2-in chne edlesor30-gau ge,5/16-in ch ne edles. The u seofin sulin p enswithdisposablene edletipshas longbee nth edeliv erysyste mofchoice in Eu rope.The advantageoft heinsu linpe nsist hat they offeradisc rete, rapidway ofadministeringinsu lin accu rat elyfort hos echildr enwh oobje cttoorwh ofee lu nsafe carry in gavialofinsu linandasy rin ge. Pe nsar eavailableasdis posable deviceshold in g300Uofaspecifiedtype ofinsulinorasmore -durable equ ipmen tthatrequ ir esreplace ablecar tridgesofeit her 150or 300Uofvarioustype sofinsu lins. Cu rren tly,itispossible topu rchaseinsulinpen sorcartridges ofaspart, lispro,NPH,75/25, or70/30. The d isadvan tage ofth epen sy stemisth atitisnotpossibletomixinsu linstoget herforasingle injection wit hthe except ionofthe abovepremixedinsulinpre parations . Health care provide rsappr eciateth echallen gesas sociate dwith in ten sive in sulin ther apy. Th e pharmacokin eticsofinject edin sulinhampe rspon tan eityoflifestylean dincreaseth eriskof hy poglycemiaor hyper gly cemia. Sin cethe 1970s, physiciansandscient ist sh ave in vestigat edalter nat ive insulindeliverysyst emsinanattempttoimproveglycemiccont rolan dquality-of-lifeforpat ie nts.Th e use ofinsulinpu mpsorCSIIth erapyprovide son eappr oachtoin ten sive in sulin ther apyth atcan optimizeglycemiccont rol,re duceh ypoglyce mia, andmaint ainqualityoflife(131).Pu mpu seisgrowing rapidlyinth epediat ricpopulat ion. Insu linpu mpsofferacon tin uousinfu sionofin sulin ove rthe cour seoft hedayin ane ffort tore plicat e bas alins ulin p rodu ction bythe pancr eas. Bolusesofin sulin are admin ist eredatthe timeofme alsor snackstomimicth enormalphysiologicpe aksofin sulin release in r esponsetofoodintake. Four companiescurr ent lymake in sulin in fu sionp ump s:MiniMe d(htt p://www.minimed.com), Disetr onic (ht tp://www.disetronic.com/),Animas(htt p://www. an imascorp.com/),an dDelte c (ht tp://www.delte ccozmo. com).Although each hasind ividualized fe atu resdesign edtosetitapartfrom itscompet itors,t heyh ave man ysimilaritie s.SeeC hap ter39foraddition alin format iononinsu linpu mp th erap y. Eachofthese batt ery-ru n,compute rize din sulin pumpsisabou tth esiz eofabeepe r.The yholda rese rvoirofinsulinan dare worn exter nally,eith eronawaistb andorinapocket .Thepu mps are conne ctedbyaninfusionsetofthinplastict ubingth atcontain smostcommon ly anint rodu cern eedle withinaTe floncat het erat itse nd.Th ecath ete r,withth eaidoft heintr odu cerne edle,isin serte din to th esubcu tan eoustissueofthe abdome n,th ig h,orbut tock sandisleftinplaceafterre movaloft he introduce rne edle .Insu linisdeliveredt hrough thet ubingth rou ghout t hecourse ofth eday andn igh t. The ch ildoradolescen twith diabete sorapare ntmustr eplaceth emanu allyinse rtedinfu sionse tan dthe insulinsupp lyev ery2to3days. The ADA'sPosition State men tonCSIIprovidesre comme ndat ionsonprovideraspects, p atient selection , insulinpumpchoice,andsafe ty(132). Issuesre latedtoth euseofin sulinpumpsinthe pediatr icand adolescen tpop ulation sare notaddre ssedspecificallyint heposit ionstatemen t;however, the recommen dat ionshavebe enh elp fu lint hedev elopment ofcen ter-orpractice-specificp ump p rot ocols an dedu cation programssupportingassessment ,in it iation ,an dcon tin ued u seofCSIIin the p ediatric population.Table42. 8pre sents t headvan tage sandd isadvan tage sofinsulinpumpth erap y.Thesu ccess oft hese curre ntinsu lindeliverysy stemsrevolv esaroun dthe followin gfactors: TABLE 42.8. Advantages and Disadvantages of Insulin Pump Therapy
Advantages Greaterflexibilityaround timingofmeals Greaterflexibilitywith portionsizeof food Abilitytointensifyglycemic control Fewerseverehypoglycemic episodes Fewerinjections Immediateaccesstoinsulin
Disadvantages Increasedfrequencyofbloodglucoseandketonemonitoring IncreasedchanceofhyperglycemiaandDKAduetocrimpedinfusion sets,airbubbles,anddislodgedcannula Potentialforskinabscess Changeinhypoglycemicsymptoms Constantattachmenttothepump
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Int ensivebloodglucosemon itoringmin imallyfou rtosixt imesaday:none ofth eavailableinsu lin pumpsar eclosed-loopsys temsabletomonitorbloodglu cose lev elsandde liverinsu lin au tomatically;allpumpsmu stbeman uallyprogramme d.
Comfortwith andu tilizat ionofcarbohydr ate cou nting:match in gin sulin an dactivitywit h car boh ydrateintake. Adultsu pport bot hath omeandinschool. Accesstoadiabe teste amoffering 24-h ou r/7-day-a-weekproblemsolvingan dsupport. Th enu mbe r ofd ecision-makingpointsth rou ghth ecourse ofth edayaroundfluct uat ionsinbloodglucoselevels, car boh ydrateintake,activ ity variables, illn ess,andth epre sence/absen ceofke tonesmake sit impe rativet hat t her ebead ultsupportindet ermin in gin sulin dose s.
The reisn obe st,pr edete rmine daget oinitiateinsu linpu mpt herapy.Aswithalldiabet esmanageme nt issues, in dividualize dtreatme ntplan s,aft erconsideringth ene edsoft hepatient, aswellasthoseofthe family, arebe st.Presen tly,th erearefewer you ngch ildren thanpre- adoles centsandadolescen tsusing insulinpumps.U seofinsu linpu mpt herapyat nightt imefor you ngchildren alon gwith dayt imeinsulin injection shasbeen sh own toimproveglycemia,cou nte rregu latoryhormon eresponse ,an dawar ene ssof hy poglycemiaincert ainpediat ricpopulations(133,134). Wehaveevaluat edpumpuse in170you thwith type 1diabe tes.Wh ileglycemiccont rolimprovesafter3mont hsofpu mpu se,HbA 1 c valu esappe arto
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ret urn tobaselin eby1y ear (135).The worse ningofg lyce miccon trolaftert heinitialimprovementst ems fromdimin ish edbloodglu cose monitorin gan dmissedinsu linbolu ses. Atpre sent, the rear enoclinicallyapproved implantablepumpsfor c hildre n.Allofthe curre ntpu mpsare open-loopsyst ems, meaningt hat t hepu mpsaren otable todiscer nbloodglucosele velsand au tomaticallyde liverinsu lin. Clearly,t hegoalofallpumpmanu factu rersistodevelopaclose d-loop syste manartificialpan creas. Inh aledinsulinth erapymaysoonbe available.R ecen treportsde scrib eshort-te rmsafetyandefficacyof inhale din sulin useinpatientswith t ype1orty pe2diab etesdu rin ga12-wee ktrial(136,137,138).In add itiontoreceivinginh aledinsulinbeforemeals,t heex perime ntalgroupr eceivedinjecte dultralen te insulinat bedtime .Additionalpe diatricstudies, aswellaslong-t ermtrials,ar enee dedtocon fir mth e safe tyan defficacyofin haledinsu lin. Ch ildren shouldnev erbeforcedt oself-draworse lf-administerinsu linbe fore the yaree it here motion ally orphysicallyreadyfor t hisresponsibility.Althoug hthe reisnoon eright ageatwhichallchildr en shouldbet augh ttoprepareandinjectinsulinorin sertp ump se ts,th ere aregoodstudiestosupportt he th eor ythat,de velopment ally, manych ildren mayexpre ssin tere stan ddesiretopart icipat ein this resp on sibilityaroundt heageof10to12(63).Un tilth att ime,insu linadministration isth eresp ons ibility ofanadultcare provide r.Allinsu lindrawn-u pandse lf-administer edbyach ildsh ou ldbe su perv ised b y an adu ltforacc urac yofdosage andt echn iqu eofinject ion.
THERAPY FOR TYPE 2 DIABETES IN YOUTH

The t reatme ntgoalfor y ou thwithty pe2diabe tes, similar t oth atfortyp e1diabe tes,isnormalization of bloodglucosevalue sand HbA 1 c , with amajore mph asison lifestylech ang earoun dnut ritionandph ysical act ivity. Manageme ntofrelate dcon dit ionssu chash ypert ension an dhyper lipidemiainp ediatricpat ien ts withtyp e2diabe tesalsoisindicat ed.The ove rallg oaloftreatme ntistoreduc ethe r iskofacu teand chr on iccomplicationsofdiab etes. Tr eat men tis aimedatlower in gblood g lu coseleve lstone ar-n ormal valu esin allpatient swith diabete st oavoid(a)acute met abolicdecompensationd uetoDK AorNKHHS; (b)symptomsofpolyu ria,polyd ipsia, fatigue, weightlosswith p olyphagia,blurr edvision, recur rent vagin itis/balanitis;( c)t hede velopmen torp rogr essionofcomplication sin volvingth eeye s,kidney s,an d ne rves;and(d)failure t omaintain normalg rowt han ddevelopme ntan dan earn or mallife style. The initialtre atment oftype 2diabe tesinyouth depen dson theclinicalpresen tation(10). Se vere hy perglycemiawit hNKHHSsyndromerequ ire seme rgen cymanageme ntsimilartoth atforDK A. Insulin willlikelyben eede dasth erap yin these patien tseve nafte rrecovery fr omthe acut econ dition. Other s whoare notillatdiagn osiscan betre ate din itiallywit hme dicaln utr itionth erap yandp hysicalactivity (see s ection sbelow).U nlessth ereissuccessfu lwe igh tloss,most patien tswillrequire somefor mofdrug th erap y.Insu linwaspreviouslytheonlydru gappr ove dbythe FDAforu sein childr en. Met forminhas rece ntlybee napp rove dfort hetr eat men toft ype2d iabetesinyout hage 12year sandolder(139). Non eth eless,mostpe diatricen docrinologistsu sesomeoftheoralanti-diabete sagen tstotreatchildren withtyp e2diabe tes,e venwh ileth ereareongoin gstud iesofmanyofthe seage nts(46,49). Aswit htype 1diabet es,th egoaloftr eatmen tfor y ou thwithty pe2diab etesisnormalization ofblood glucosevalue sand Hb A 1 c . Manag eme ntofcomor bidcondition ssuch ashyp erten sionanddyslipid emia shouldbeinitiate d.Macrovascu larriskfact orssu chash ypert ensionan ddyslipidemia,whe nfoundina young erindivid ual,h avepote ntialforsignificant lysh or tening lifeifdiabetescomp licationsbeginine arly adu lt hood(140).
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Patient swh opr esen twit hDK AorNKHHSshouldbetr eate dperprotocol(see Chapter53). Indicationsfor initialt reatme ntwithinsu lininclude d ehydr ation ,ke tosis,andacidosis. Afterstabilizat ionan dfollow-u p, re-e valuation isne cessar y,asinsu linmaybe tape redandan oralanti-diabe tesage ntint rodu ced followingimprov eme ntinmetaboliccont rol.Ot herpatient smay beginoralant i-diab etesagent salon g withdietth erapyan dexer ciseatdiagn osiswhen thep resen tationsugg eststype 2diabe tesan dthe pat ie ntisstable. Th econsen susstatement ofth eADApub lished inMarch2000(10)recommen dsthat metforminbe thefirstoralag entu sedinpediat ricp atient swith type2diabete s.Metforminsh ou ldn ot b e use din patien tswit hknownre naldisease ,he paticdisease ,hypoxemicstate s,seve reinfect ions,or alcoholabuseorwithradiocontrastmater ial. Inaddition,patientsofchild bearing agesh ou ldbe made awareth atmetformin maynormalizeanovulat ory cy cle sin p atient swith polycyst icovary syndrome,a common con dit ioninad olescen tfemaleswit htype 2diabe tes(49,141,142). Th us, adequ ate birt hcontrol shouldbeaddresse din sexuallyactiv etee ns. Ifmonoth erap ywith me tfor minfailstoaccomplish gly cemicgoalswith in 3to6mon ths, addition al th erap yshouldbeadd edtothet reat men treg imen. Supplementalagent sin clu deinsulin,aswellasoth er oralage ntssuch asasulfony lu rea, ot herinsu linse cretagogu essuch asre paglin id ean dmeglitinide, insulinsen sitize rssuchasthiozolidene dione s,or -glu cosidase in hibit ors. Insulincan bestartede ith erat bedt imealoneortwicedaily.Frequ ent b loodglucosemon it oring shouldbeencour aged, especiallyaime d at achievingfastingbloodglucoselevelsoflessth an 126mg/d L.Freque ncyofcon tact with thepr imary car eprovid erorhealt hcar eteamwilldepe ndonth ethe rape uticresponse t otr eat men tbut s hou ld occu r at leastquarte rly andmor eoft enwh enth erapie sarebe in galtere d.
MEDICAL NUTRITION THERAPY: NUTRITION EDUCATION

Disseminat ionofther esultsoftheDCC Tbr ou ghtwithitchange sin avar ie tyofdiab etesselfmanagement t oolsandre comme ndations(56, 72).Mostre cent ly, theADA's2002rev ision ofth e Eviden ce-BasedNutrition Princ iplesan dRecommen dationsincre asesflexibilityinter msoffoodan dmeal plans forth echildandadolesce ntwithdiab etes(143).Asamemb eroft hediabe tesh ealthcarete am,a reg iste reddietitian prov ides medicalnu trition ther apy(MNT)through nut rit ionassessment, education , an dcou nseling.Pat ien ts/familieswithn ewlyd iagnosedtype 1diabet esbeginMNTassoon asthe patien t ismedicallystablefollowin gthe diagnosis, and t heycont in ueMNTevery 3to6mon thsinve ryyoung children ande very6to12 P. 724 mon thsinolde rchildr enandad olescen ts.Patien tswit htype 2diabet esalsobe gin MNTat diagnosisand continu easn eededt oattainwe igh tlossgoals.Thisenablesappr opriate,ongoingchangest oth emeal planr efle ctiveofch an gesingrowthanddeve lopment, an dbasedonfamily lifestyleandcultu ralfood valu es. MNTpr ovidesinformation ,motivation, and p roblem-solvingt echn iqu esfor mealplan ningandfamily nu trition forch ildren an dadole scentswith d iabetes. Notsu rprisin gly ,childrenandadolescen tswith diabet esan dthe irfamilies, aswellasprofessionals,oft enident ifyfood asthe mostdifficu ltpartof diabet esself-manageme nt(100,144). Th us, MNTisaninte gralcomponen tofanysu ccessfuldiabet es self-managementplan (143,145). MNTmustb ein div idu alize d,provideapp ropr iatenu trition ,an dmatcht helife styleofth echildor adolescen twit hdiabet esan dhisorh erfamily. Amealplan isn ot adiet;itisaguidetochoosing he althy, age-appropriate foodsin away t hat con tribute stovariou spositivemedicalou tcomes, suchas bloodglucosele vels,lipidlevels,bloodpre ssure ,ren alfunct ion,andn ormalgrowthanddev elopment in children ( 143). Appropriate mealplan ningsh ou lde nablepatientsandfamiliestooptimizeglycemiccont rolbymatch in g th ein sulin dose with foodan dactivity.Mealplan ningissucces sfu lwh ent hechildor adoles cent'sme al planp rovidesflexibility, satiety, satisfact ion,andinclusion for t hepickye ater ,par tygoer,fast-food love r,an dschool-lun chor colle ge-cafe teriae ate rand p romot esase nseofnormalcy . MNTpr ovidesanindivid ualizedpre scrip tionofcalor iesandmacronu trient sfort hech ildor adole scent, whichiscommon lykn own asamealplan .Itstartswithanut rit ionassessme ntandgen eratestr eatmen t goals(60).Theassessment alsocollectsclinicaldata,dietaryhistory,n utrien tintake,andasocial history(60).Th easses smen tgen erat esgoalsforth erapy.Goals sh ou ld b eage appropriate ,att ainable, sociallyapp ropr iate,andclearly st ate d.Gener alnut rit iongoals(143)forchildrenandadolescen tswith diabet esfollow: Reachandmaintain opt imalbloodglu cose lev els Achieve optimallipidandlipopr ote in lev els Maintain normalbloodpr essure le vels Pr even tan d/or t reatthe complicat ionsofdiabete s Improv egen eraloverallhealt hth rou ghh ealthy foodchoice sandanact ive lifesty le De velopame alplanth attakesper son aland c ulturalissue sin toconsideration reflectiveofthe
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individ ual/family'swish esan dwillin gnesstochange
Pr ovideadequ atecaloriesformain tainingorattainingacceptableweightforadolescent sand n or mal growthanddev elopment rate sforch ildren an dadole scents Forch ildre nan dadole scent swith type2diabete s,facilitatelife stylechangesineatingandphy sical act ivity.
Ateamapproachby ther egist ered d iet itian,ph ysician ,nu rseed ucat or, and familyan dchildwith diabet esisr equired t oachieven utrition-relat edgoals(145).Forchildr enandadolescen tswhoare inten siv elymanage d,per son alalgorith msforthe rapy adjustmen tnee dtobe developed(59).U seof bloodglucosemonitoringre sultsallowsfor adjustmen tstot hese lf-man agement plan.Post pran dialb lood glucosevalue shelpindete rmin in gifth eprese ntalgorithmisworking. Knowle dgeoft hech ildor adolescen t'sinsu lin-t o-carboh ydrateratio,aswellasin sulin -sensitivit ycor rection factor, canbe importantinformation in calculatingt hepe rson alalgor ith m(se eCh apter 36). The rear esever aldist in ctme alp lanningsy stems,such asth eexch ange systeman dcarbohyd rate count in g.TheDCC Tsh owe dthatmanydifferen tap proachest omealplann in gcan besucce ssful(56, 72). The out date dno-con cent rate d-sweet sapproach isv eryre strictiv e.The 2002Nu trition Rec omme ndat ionsofferan expe rtcon sen susstatin gthatsucr ose(t ablesugar)an dsucrose-containing foodsmaybe eate nbut in thecont extofahe althydiet (143).The no-con centr ate d-sweetsapproach ignoresimportantfacetsofMNT,su chast hetimin gandconsiste ncyofmealsandsn acks.Th efou r gen eralapproache stomedicalnu tritiont herapyar e(a)ge neralgu id eline s(146);(b)mealplann in g (sampleme nus );( c)e xchangelists;an d(d)carbohy drate cou nting. Bothth eexch ang e-listandcarboh ydrate-count in gapproachesincorporate flex ibility andindividualizat ion an dstriveforop timalglycemiccontr ol.The exchangelistshavesixdiffe rent exchange g rou ps: bre ad/starch, prot ein,milk,fru it ,vege table, andfat.The carbohyd rate cou ntingmeth odarise sfromth e 1994ADANutr itionRe comme ndat iongu ide lines ,whichconsiderth att hetotalamount ofcarboh ydrate, notth etype ofcar boh ydrate,imp actonglycemiccont rol(60,145).Thisallowsfor theincorporat ionof allcarbohyd rate sou rces,includingsu crose,intothe me alp lan,pr ovidingmaximu mflexibilitytopat ien ts ofallag es.Coun tingcarbsisthemostcommonmealplan ningapproachu sedwit hpediat ricand adolescen tpop ulation swit hdiabet es(seeC hapt er36onnu tritionformore in format iononth esemealplann in gappr oaches). MNTr equiresacalorican dmacronut rie ntpr escription .Nutrien trequ ir eme ntsforchildrenand adolescen tswit hdiabet esappe arsimilartoth oseforth eirpeerswith ou tdiabete s.Table42.9giv es gen eralgu ide linesforcalcu latin gdailycalor ies(60). TABLE 42.9. General Guidelines for Calculating Daily Calorie Requirements for Children and Adolescents
Age 012y 1215y Female Male 1520y Female Male
Calorie requirements 1,000kcalfor1styear+100kcal/yoverage1y 1,5002,000kcal+100kcal/yoverage12y 2,0002,500kcal+200kcal/yoverage12y 1315kcal/lb(2933kcal/kg)desiredbodyweight 1518kcal/lb(3340kcal/kg)desiredbodyweight
The 2002Nut ritionR ecommendationsallowforth ecar boh ydrate,pr ote in ,an dfatconte ntsofme alplans tobeindividualizedtoach ie veop timalme tabolicgoals.Proteinintakeof15%to20%isade quat efor the gen eralpopulat ion(143).TheRe comme nded Dietar yAllowance (R DA)forproteinrangesfrom2.2g/kg per d ayforin fant sto0.9g/kgperdayfor adole scentmalesage15thr ou gh18years(60).Aspert he ADAre comme ndations, carbohyd rate andmonounsatur atedfatscombined shouldmakeup60%to70% oft hemealplan (143). The amoun toffatinamealplan forth echildoradolesce ntovert heageof2yearsshouldnotexce ed 30%ofth etotalcalor ie s,wit hlessthan10%fromsat uratedfat ,le ssthan10%frompolyu nsat urates; an d10%t o15%frommonoun satu rat es.Die tary ch olest erolsh ou ldbe limited t olessth an300mg/day.
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Thosepatie ntswh oar eofn or malweight andh ave n or mallip idlevelsar eenc our aged t ofollowt he recommen dat ionsoftheNationalC hole sterolE ducation Program(ht tp://www.nh lbi.n ih .gov/about /ncep/). Health yfatint akecanbee ncouragedbyth econsumption ofleancut sofred meat,more chicken and tu rkeywithout skin ,fishan dseafood,skimandlow-fatmilk andmilkpr odu cts,andvege tablepr ote in s (legumes). Th eresu lt softh eDietaryIn terve ntion StudyinC hildr ensh owth atth ere arech oleste rollower in gbene fitst oad iet redu cedin fat P. 725 an dchole sterolin c hildre nwithelevatedlipidleve ls. Th estu dyshowsthatadietlowinsaturatedfatan d cholester olissafefor childre nan dis n ot ariskfor altere dgrowt h,n utrition alstat us,orsexu al matu ration(147). Itisimport ant thatchild renandfamilieskn owth evalue ofahealth yme alplanth at incorpor ate sfatan dchole sterolin appropriate amou nts. Asforth euseoffatr eplacers, morere sear chis ne ededonth eirroleinachild'sme alplan.At tent ionsh ouldbed ire ctedtothe nut rit ionfactslabelfor an yproductscont ainingfat replacemen ts,sinceman ysuch produ ctste ndtobehighe rin carbohy drat es th ant heirfat -con tainingcoun terparts(143).Followin gthe ADANutritionRecommen dationsbecomes importantwitht heepidemicofchildhoodobesityandtyp e2diabe tes(11,12, 39). Strat egiesto succe ssfullyde creasefatandtotalcaloriesfor childre nan dadolescent swith type2diabet esnee dtobe deve loped. Diet aryfiberisacarbohydratefoun din su chfoodsaswhole grains, b read s,cereals,le gumes,fru it s,an d vege tables. Fiberh elpsin thedigest ionprocess, provide ssatiety, an dreduce sle velsofser um cholester olan dtriglyce rides.The recommend edfive -a-dayservings offruitsandveg etab lesisagood guidelinetouse .Servingch ildre nan dadole scent sfoodsthatprovideasource offiberprovidesesse ntial vitaminsan dmine ralsforh ealth and g rowth .Gramsoffiberarelist edonth enut ritionlabe lu nder Total Carbohydrate. When calculatingth edoseofr apid-or fast-actin gin sulin base don c arbohydr ateint ake, if th eservingt obe e ate ncontain s5ormoregr ams offib er,th enu mbe rsoffiberg ramsaresu btracted fromth egramsoftotalcarbohy drate .Use offoodscontain in galarg eamou ntoffibe rfort hetr eat men t ofh ypogly cemiaisnotre comme nded. Sweet ener s,such assucr ose ,fruct ose, oraspart ame,canallbein cor por atedint oth emealplanofa childoradolesce ntwithdiab etes. An in div idu alassessmen tmu stbemadeastotheglycemicimpact of th eseswee tene rs.The carbohydr ate con tent ofnu tritivesweet ene rs(e.g. ,sucr ose, fructose, andsu gar alcoholslik esor bit ol)mu stbecalcu latedintothe mealp lan(143). Ingest ionoflargeamount soffoods contain in gsugaralcoh olslike s orbitol, mannitol, an dxylitolmay cause gastrointe stin alupse twith flatus ordiarrh ea, particular lyinyoun gchildren. Choosin gnut rie nt-r ich foodsispr eferable t och oosin g swee tssuch ascakesan dcand ythatten dtob efoodswithbasicallyempty calories. Howeve r,itis importantforchildrenandadolescen tswithdiabe testofitin wit hthe ir peersandshareinth efood asp ectsofce le brat ions,h olidays, andpartiesth atte ndtoin cludeth eset reat s. Non nu tritiv esweete ner s,common lycalledsu garsu bstitut es,areoftenu sedinth eme alplansof children andadolesce ntswithdiabe tes.Th eyincludesaccharin ,asp artame ,ace sulfame pot assium,an d sucalose. Th eacce ptab ledailyintakeh asbee ndete rmine dbythe FDAforswe eten ersinter msofsafet y ofconsu mp tion, with a100-foldsafety factor(145, 148).U seofpacketsandbu lkformsofth ese product s,aswellasconsumption ofpr odu ctssuch asdietsodas,su gar-fr eegelat in s,an dice pops, will havelit tle effectonbloodglucoselevels.The majorproblemisth atpatie ntsandparent softe nignore other compon ent soffoodsanddrink scon tainingth eseswee ten ersan dcon sumeth emliberallywit hout calculat in gthe ircaloriean dcarb oh ydrat econ ten tsin tothemealplan .Itispossibletocalculate car boh ydrates,pr ote in ,an dfatinsu chfoodsfromt henu trition -factslabe lbasedonth epor tionsize eaten . What,wh en, andh owmuch foodiseaten bychild renandadolescen tswithdiabe tesar eallimport ant . So, too,iswhe reth eyeat.Schooliswhere allch ildren spend themajorit yofth eirtime; sch ooliswh ere allchildr enhavelun chmore than150timesaye ar.Th echildoradolesce ntwithdiabe tescaneatschool lunch es. Mostschoolsyste mspostth eweek lyormon thlyschool-lunch me nuinth ene wspape r,on communityb ullet in boards,and,incr easingly,onth eInt erne t.School-lun chmenu scanbe calculate dto fitthe childoradolescen t'smealplanasnee dedforreason sofconven ie nce, sociability ,or cost. Anothe rimportantissueforth echild oradolescen twithdiabe tesisfastfood. Th ere areavariet yoffast foodgu ide sthatprovide nut rit ioninformation formen uit emsfr ommostofthemajorfast-food rest aur ant s.Thech ildoradolescent with diabete sandh isorhe rfamilyben efitfromkn owledgeofthe conten tofc arbohydr ate, fat, prot ein,andtotalcalorie sin fastfoodssothatth eymaybest matchinsu lin dosageoractiv ity t oth emealeaten. Pap ercopie sorinformation fromth eInte rnet canpr ovidet his importantfast-foodnu trition in formation. The se lf-man agemen tplanmaycallfor thede liver yofar apid-act in gin sulin (lisprooraspar t)atth een d ofame alforsome childr en. Foodst rugglesarenotne wtoparen tsnorar ethe yspecifictodiabe tes. Post-mealprotocolsut iliz in grapid-ac tin gin sulin can h elptoelimin atesomeofth efoodstr ugglesan d provideabe tter mat chofinsu lind oset oth efoodeaten . Ch ildren an dadole scents with type1diabete shave asligh tlyin creasedriskofce liacdisease,acommon cau seofmalabsorpt ioninch ildren (149,150,151).Celiacdisease isanau toimmu ne-mediate ddis orde r
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th atoccursinge neticallysusce ptib leindividuals. Immun e-me diateddamagetothe mu cosaofth esmall intest in eoccursaft erexp osu retothe g liadinmoiet yofglute n,leadin gtod estru ctionofthe absorptive sur facesofthe v illiofthesmallin testine. Glut enisfou ndinwhe at, r ye,barley,andpossib lyoats(152). Symptomsofceliacdiseaseincludediar rhea,weight lossor poorweightgain ,growth failur e,abdominal pain, chronicfatigu e,irritability ,an in abilityt oconcen trate,malnu tritiondu etomalabsorption ,an d other gastr ointe stin alproble ms(152).Diabe tes-spe cificsymp tomsmayincludeu nexp lain ed hy poglycemia.Diagnosisisbase don the r esultsofabloodtest [mostspecific IgAtotissu e transglut aminase(tt g)followedbysmallbowelbiopsy ].Atprese nt, theonlytre atmen tforce liacdisease isagluten -free d iet with the avoidanceofthe foodsliste dpreviously.Ch ildren an dadole scentswith diabet eswhoalsoh ave u ndiagn ose dceliacdise aseorth osediagnosedwhodon ot followaglute n-free dietoften h ave unpr edictablebloodsug arswithh ypog lyce miaanddete rioration in g lyce miccon trol (151). Itisv eryimportantforfamiliesofchildre nwithdiabe tesan dceliacdise aset oworkwit ha reg iste reddietitian wh oh asex perience with bot hdiabet esan dceliacd isease,asglu ten -freefood sare oftenve ryhighincarbohydrates. Eatingdisor dersconstitut each alle ngeinth eadolescen tpop ulation ,particularlyinfemales.Itis rep ort edthatadolescen tfemaleswit hdiabet esare twice aslike lyasadole scent fe male sin gener alto haveaneatin gdis orde ror subth resholdeat in gdisorder (153).In sulin omissionwithth egoalofweight lossisthe hallmarkofe atingdisordersinth ediabet espopulation(153, 154).Th eresu ltantadverse he althoutcomes,su chash igh HbA 1 c v alues, incr ease dhospit alization s,episod esofDKA,an deye and kidney complications, callforidentificationofandclin icalint erven tion fore atingdisordersinth is population(155, 156,157).Use ofsuch que stionn airesastheGen eralSur veyofEat in gProblems(E AT26),E atingDisorder Examination(E DE ),Children 'sEatingDisorder E xaminat ion, orth eDiabetesE ating Pr oblemSurve y(DE PS),wh ich isdiabe tesspecific(155),providetoolsforscree ning.Aswithth egen eral population,mor eyouth swith diabete sh ave subth resh oldeat in gdisorde rsthanhaveDSM-IV-classifie d eatingdisord ers(158). Lit tle in theliterature addre ssesth eproble mofeating d isorder sint hepe diatric oradole scent malepopulation;h owev er,pr acticessu chasweight gaindu rin gfootballseason orweight lossdu rin gwrest lingseason ,bywayofman ipu latinginsulindosesan dfood,havebe ensee ninmany pediat ric andadolesce nt P. 726 en docr in ology practices. Ingen eral,foodcanbe asourceofcon flictforchildrenandparen ts.The oriesin th elite ratu resu ggestth atth ose you thswith t ype1diabeteswh oh avee atingdisordersh ave oth er un derlyingpsych iatricdisorde rs(159). Th eemphasisplace don foodissu esforyou thswitht ype1 diabet esmayincreaseth eoccu rre nceofeating disorder sin t hispopu lation (160). Insu mmary ,MNTmustbe in dividu alize dtot hefamilyofth echildoradolescen twit hdiabet es.The measu reofsuccessofthe mealplan with in the self-man age men tplanisoptimalglycemiccont rolwit h pre vent ionoffreque ntep isodesofhyper glyc emiaandh ypoglycemia.
EXERCISE/PHYSICAL ACTIVITY
Allchildren andadolesce ntsn eedtobeph ysicallyactiv e!The Su rgeonGene ral'sR eportonPh ysical Activityan dHealthe mph asizesth efun dament alr oleofphysicalactivityinpromotionofh ealth and pre vent ionofdise ase(38).Physicalact ivityisne cessar yfort heoptimalh ealthforallchildr enand adolescen ts. Forch ildre nan dadole scent swith diabete s,physicalact ivityplaysanaddedroleasatoolin t hediabe tes tre atment plan.Forthe childoradolescen twit htype 1diabet es,ab alance ofex ercise,insu lin,andfood, usinginformationfrombloodglucosemon itoring, e nh ance stheattain men tofoptimalbloodg lu cose control.Thebe nefitsofexerciseforth echildoradolescen twit htype 1ortype 2diabet esare subst ant ial. Wit hthe rise in childh oodobesityan dseden tary lifestyle, leadingtoane pide micoft ype2 diabet esinchild renandadolescen ts,anincreaseinph ysicalactivit yand e xerciseisnece ssary. The Kaiser Family Foun dation Study r eportsth atth eav erage Amer icanchilduseselect ron icmediaoutsideof schoolmor ethan38hours aweekandth at53%ofch ildre n2to18yearsoldh aveatelevisioninth eir bedr ooms(161). Fort hech ildor adole scentwith t ype2diabetes, changesinlife style,includingaerobice xercise,can resu lt in improvedoutcome sin termsofglycemiccon trol,we igh tloss,lipidabnormalities, and hy perte nsion .Thebe nefitsofe xerciseforthe childorad olescen twit hdiabet esin clu de: Improv eme ntinbloodglucosecontrol Red uction in dosageofin sulin Red uction in long-t ermhealth risks,includingobesity,osteoporosis,h ypert ension,arterioscle rosis, an dcard iovascu lardisorde rs Appropriate weigh tgain ,weightmainte nan ce,orweight loss Improv eme ntinske let algrowt han dstre ngth En hancement ofmuscledeve lopme nt
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De velopmen tofse lf-est eemand s ocialan dteambuildin gskills De velopmen toflife longh ealth yhabits Psy chologicalwe ll-beingandimpr ove dqualityoflife Stre ssreduct ion.
The ch ildoradolescen tmu stenjoythe physicalact ivity, have accesst oth eact ivityonaregular basis, an dfin dit con venien tan dfunsothatitbecome sp artofhisor herlife style.C hildre nan dadolescen ts withdiabe tesshould,liketh eir peerswh odonothavediabe tes,be abletoprofitfromt heph ysic aland socialbe nefitsofp hysicalactivity. Itisimportan tforphysicalact ivitytobeapart ofth efamily'slifestyle. Th echildoradolesce ntwith diabet esshouldnotbet heonlyfamilymemb eren cou rage dtoincorporat ephysicalac tivityint odaily act ivities:fat her ,moth er,andsiblingssh ou ld als obeactive.Sincech ildre nan dadole scent sspendth e majorityofthe ir timeinschoolandat school-base dactivities,sch oolpe rson nelan dcoache smust be awareoftheb eneficialnat ureofexe rcise forallstud ents. Stude ntswithdiabe tesshouldparticipatefully inrece ss,gymclasses,andsports. E ducation andpr epar ation are impor tan t.Edu cat ionforteachersand coache sshouldin clu dean und erstandingofsign sand s ympt omsofh ypoglycemiaan dappr opriate tre atment s.Pr epar ation for t hestu den twit hdiabet eswou ldinclude accesst oth eappr opriatesupp lies forthe t reatme ntofhypoglycemia. The r oleofphysicalactivityforchild renandadolescen tswithtyp e2diabe tesisparamoun t.Physical act ivityu sescalorie s,decr easesinsu linr esist an ce,an disatoolforwe igh tmain ten an ceor loss(162). Ph ysicalactivityan ddietar ymodificationsaren ecessar ylifesty lech an gestoimproveshort -andlongter moutcomesfort hech ildoradole scent (10, 11,12,48). Ph ysicalactivitycan in creasethe risk ofhy poglycemiafor childr enandadolescen tswhotake in sulin (163, 164,165,166)orforthosepatient swith type2diabete swh ot akeblood-glucose-loweringoral medication s(167).Howeve r,th eoccu rren ceofhypogly cemiadu ring,immediatelyfollowing,orhour s aft erphy sicalactiv ity canbe minimized. Rememberth atth echildor adolesce ntisatmax imalriskfor hy poglycemiafor upto6to12hoursfollowin gphysicalact ivity(168)th eso-called lag effect.Newe r management t oolssu chasin sulin analogue s,insulindeliveryde vice s,an dbloodglu cose monitorscan he lptopre vent and/orman ageh ypoglyce mia.Since physicalactivitycanin creaseth eriskof hy poglycemia,itisnecessarytodeve lopindivid ualizedexe rcis e/physicalact ivitygu id eline sfort hech ild oradole scent with type1ort ype2d iabeteswh oistreatedwith in sulin .Thisrequ ire sbeingintun ewith individ ualresponse stop hysicalactivity,insu lin, andcarbohydr ateint ake, arrived atempirically. Ch eckingth ebloodglucosele velbefore,some timesdu ring,andaft erph ysicalactivit yshouldbe en cou rage d.Use ofbloodglucosemonitoringisnece ssarytomakeappropriateadjustment sforph ysical act ivityaspart ofth ediabet estreatmentplan.The seadjust me ntscandecre aseth efreq uen cyof hy poglycemia. Ch ildren an dadole scents with diabetes sh ou ld alwaysweardiabete side ntification abr acelet, necklace, orshoetagincase ofhy poglycemicepisode sandforavarietyofot hersafetyconce rns.Ift heat hletic associationrequ ir esplayer st ore moveth eident ificationdur in gpract icesorgames, it isimpe rativefor th ecoachtobeawareofwhoon hisorh erte amh asdiabe tes,t ode velopsome formofplan (58)to ident ifywh enhisorher playerfee lsanee dtobe remove dfromthe gamebecauseofsymptomsof hy poglycemia,andtohaveavailableasou rceofrapid-actin gcarbohy drat e.Depend in gon theint ensityof th espor tan dthe amoun tofwaterlostthr ou ghdeh ydrationandper spir ation ,many athlet eswillprepare th eir water bott le with adilu teformoffor tifiedsportsdr in k(50%water/50%sportsdrink)t ore plen ish fluids,electrolytes, andgluc osee xpend edduring theactivit y. Adequ ate fluidintakeisextre me lyimp ort ant toavoiddeh ydration. Deh ydration canh aveanad verse affe cton bloodglu cose lev els. Fluidintakebefore, during, andaftere xerciseisrecommend ed(169). En viron men talfact orsextr eme sofh eat, humidit y,cold, andalt itu de canaffectbloodglucoselevels dur in gexer cise, and precau tion sshouldbetakenwh enex erciseorany kin dofph ysicalactivit yisdone inan yoft hesee nvironments(169). Issue sofoxygen con sumption ,mu scle uptake,glycogen st or es,triglycerides, andfr eefat tyacidsaffe ct glycemiccontr ol.Mainte nanceofeuglycemiadur in gphysicalactivityinth epersonwith andwithout diabet esisforth emostparth ormon allymed iated.In the p ersonwithtyp e1diabe teswhois insu lindeficient, excessiver ele aseofcou nte rregu latoryhormon esduring p hysicalactivitymayre sultin hy perglycemiaan dtheformation ofke tonebodie s,whichcanleadt oDKA(169). Ph ysicalactivitycan lowerbloodglucoselevelsofpatient swith diabete swhobeginwit heithe rnormal bloodglucosele velsor moderatehy perglycemia.Withex tremehy perglycemia,ph ysicalactivit ycan exacerbateaninsulinopenicstate,andbloodglucoselevelsmayactu allyin creas e.Itisbestt oav oid phy sicalactivit yifke ton esar eprese ntan d/orifth ebloodglucosele velisgr eate rthan300mg/dLand totreatth eketonu ria/hy perglycemiafir st.Ifthe bloodglu cose lev elislessthan100mg/dLbe fore phy sicalactivit y,pat ien tsshouldtakeacarbohydr atesn acktoav oidhypoglycemia.Patient sshouldbe
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alert tot hesymptomsandsignsofhypoglycemiaduringph ysicalactivityan dforse veralh ou rs th ereafter. Pat ie ntssh ouldh aveasou rceofsugar(such asglucosetable tsorg lu cosege l)re adily av ailable duringandaft erphy sicalactivit ytot reat hypoglycemia.Therisksandben efitsofph ysical act ivityarespe cifictot heindividualch ildor adole scentwith d iabetes. Itish ig hlyrecommend edthatan exe rcis ephysiologis t,withexp erience in d iabetes, setth ephys icalactiv ity p rescription .Necessary adju stme ntstofoodandinsulinmu stconsiderbloodglucoselevelsatt hetimeofph ysicalactivity,th e type ofactiv ity ,an dtheint ensityanddur ationofactivit yin addition tot hetimin ganddoseofin sulin , aswe llasth etimingandamoun tofcarboh ydrateintake. Avar iet yofsn ackbarssupplyeffe ctiv ecarbohy drate sou rcesforthe preven tion and /ortr eat men tof hy poglycemia.Ith asbee nhy poth esizedth atfood scon tainingre sist ant st arch (corn star ch)orfoods modifie dwith resistantstarch(h igh amylosecornst arch )mayhavean effectonpostprandialgly cemic resp on se,includingpre ven tionofhypoglycemia.Thu s,avarietyofene rgybar produ ctsar enowavailable th atcontain resistan tstarch:u ncooke dcorn star ch.People with diabete smayeatt hebarsatb edtime t o he lppr even tnoctur nalhyp oglycemia.Conv entionalsnackbar sore nergy bars, wh ich con tain15to30g ofsu gar s,are designedt oraise blood g lu coseleve lsbe fore ordu ringexe rcis e.Somere sear chfindings supp ort theu tilityofboth types ofproduct sforth eprev entionofexercise-indu cedhy poglycemia (170, 171,172).However, the rear enopublish ed,e vid ence-b asedlon gitudinalstu diesin subjectswith diabet estoproveben efit sfromthe useofresistan tstarch(143). The soleuse ofcar boh ydrat etotreatorpreve ntanepisod eofh ypog lyce miadu rin gphysicalact ivityis nolon gerrecommen ded. Forthe childorad olescen tstrivingtoimproveglycemiccon trolorlosewe igh t, th euseofadditionalcarb oh ydrat efor p hysicalactivitycansabotagedesiredout comes.In tensive insu lin th erap y,eithe rbymultipledailyinjectionsorCSII,per mitsap prop riateadju stmentsint heinsu lindose forvariousact ivities.Newe rin sulin an alogu esan din sulin delive rysyste mscoupledwithbloodglucose mon itoringtoolsallowforad ju stme ntsofbot hinsulinan dcarbohy drate s.Theamoun tofadjustment ne cessar yvariesfromp atient topatient andishighlyindividualized.In dividu aliz edphysicalactiv ity algorithmscanbe developedfrome xerciseguidelines. Ingen eral,h owe ver,mild-t o-mode rate exer cise mayre quireth atpre -exer cised osesbe decreasedbyabou t20%forlisp ro, aspart,orregu larinsulinan d by10%forint ermediate- actinginsu lin. He avye xercisemayre quiredecr ease sof30%to50%for r apidact in gin sulin sand 20%to35%forinter med iate-actin gin sulin s.Itisdifficulttomakeadjustment sin ultrale nte orglar gin ein sulin for p hysicalactivitybecause ofth eir longdu rationofaction .Forpatient s whouse aninsu linpu mpandan ticipate60min ute sormor eofex ercise,atempor arybasalrat emaybe setb ydecreasin gthe curre ntbasalrat eby25%t o40%.After thee xercise,t hepu mpu sermaycontinu e withad imin ish edbasalrate ,by25%,for 2to4h our s,depe ndingonth ein ten sit yofex ercisean dpast expe rience(59). Ifactivityisst ren uous,addit ionalcarboh ydratesmayalsobene eded. Youn gchildren withdiabe tesoftenh ave u npr edict ablelevelsofactivit y,sosnack in gisoften thepr eferre dadjust men t, espe ciallyforplay.Thu s,pre vent ionofhypoglycemiaduetophy sicalactiv ity necess itatesadju stmentsin bothinsu linandfood. Th esepre ven tiv estrategiesmusttakeintocon sid erat ionth etype ,amou nt, and dur ationoft heactiv ity ,in combinat ionwithsu chvariable sasth echild'sage ,fitnessleve l, andbody mass(173). Alth ou ghth ereisnoeviden cethatphy sicalactivit yin itse lfcansignificantlylower Hb A 1 c valu es,th ereiseviden ceofover allh ealthbe nefits. Astan dar drecommendation forph ysicalactivityincludesa5-to10-minu tewar m-u p,followe dby exe rcis e,followe dbya5-to10-min ute cool- down p eriod(169).Thispert ainstospor tstrain in gand other exercisesforchildren ,adolescent s,an dyou ngadults.Mostphysicalact ivityforyoung childre nis spontaneousandiscalle dplay;formostofthistype ofphy sicalactivit y,warm-ups andcool-downsar e notn ecessar y.Youngindividualsingood met aboliccon trolcanu suallypart icipat esafelyinmostph ysical act ivities,includ in gwe igh ttrain in g(169). Howeve r,th eolder adole scentandyoun gadu ltsh ou ldh ave formalopht halmology assessment beforeun restr icte dpart icipat ioninimpactexe rcise sorwe igh tlifting. Inaddition, cardiacst resstest in gshouldbeconsidered forth eyoung adult. Fort hemost p art, childr enandadolescen tswit hdiabet esfollowth erecommen dationsforphysical act ivityasstat edbyth eADA(169) .Howev er,ch ildre nan dadole scent swith diabete soften expe rie nce gre ater variabilit yin blood g lu coseleve lsth an doth eiradu lt c oun ter parts. Forch ildre n,th eren eedst obeabalan cebetwe englycemicc ont rolan dthe appropriat etask sof childhoodandadolescen ce.Th isn ecessitat esplann in gbypar ents, schoolpersonn el,at hleticcoaches, other adults, andsometimese venp eers. Diabet esself-manag eme nttr ainingan dedu cation on the cau ses,sy mptoms,an dtreatme ntsofhypoglycemiaand h yper glyce mia;insu linadju stments;n utr ition; an dphysicalact ivity, can mak eaph ysicallyactiv elifesty leasafeandre wardinge xperienc eforch ildre n an dadolescent swith type1or type2diabete s( 169).
MONITORING
The PositionStat eme ntofthe ADAon testsofglycemiain d iabetesst ressest heimportanceofmonitoring glycemicst atu s(174).Thisincludesse lf-mon it oringofbloodglucos e(SMBG)an dketone saswellas laborat orymeasure men tofHbA 1 c and,incer tainsituation s,glycosy latedser ump rot ein .The Hb A 1 c h as becomethe stan dardforasse ssin ggly cemiccontrolove raper iodofapproximat ely2to3mon ths. Th e HbA 1 c shouldbemeasu redatdiagnosisande very3month sthe reaft er(174) .Goalsoft her apyu sin g
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HbA 1 c datawerediscu ssedearlierint hisc hapt er.
Asacompone ntofcompreh ensive se lf-man agemen ttrain in g,allchildre nan dadolescen tswith diabete s an dthe irfamiliessh ou ld r eceivetr aininginSMBG(33,34). SMBGisn ecessaryfor achieve men tofanyof th etreatment g oalsoutlinedpr eviou sly. Fre quen cyan dtimingofmonitorin gshouldbeindividualizedto th epat ien t'sn eeds. Du rin gperiod sofacu teillne ss,mon itoringfre quen cyshouldbeincre asedt oatle ast fourtosix timesdailytoavoiddecompen sation(175). SMBGhasmadeat remendousimpactonh owdiabet esisman age d.Insu lindoses, hypogly cemic tre atment s,phy sicalactiv ity ,an dgene raltre atment behaviorsarebase don up-to-th e-minu teblood glucoseresu lt s.Inte nsiveth erapy,asd efin edbyth eDC CT,withitsadju stmentst otr eatmen tregime ns, ispossibleon ly byutilizingSMBG(56). Wide lyint rod ucedinth e1980s,bloodglucosemonitorshave becomesmaller, faste r,more accur ate, moreavailable,more affordable,andlesste chnique - depe nden t.Today, moreth an 30differe ntmon it orsareavailable forh omeus e(176).He althcarete ams maker ecommendationsformon itoru sebase don then eedsofin div idu alpatien tsan dfamilie s.Ther eare somecommonfeature sthatbett eraccommodate the n eedsofape diatricpopu lation ,such assmallsize, smallbloodsamplereq uirement, and sh or ttimeforre sults(69).Meter memoryan dcompute rdown load cap acityare alsoimp ort ant fe atu res. Alte rnativ e-sit ebloodglucosemonitors,wh ich allowthe useof alte rnat ive sit es,such asth eforear m,u pperarm, thigh, calf,an dplacesonth ehand,arere cent adv ance sin met erte chnology. Pat ie ntsre port le ssp ainwit hth euseofsuch altern ativesites. Howev er, th ereh avebe enre por tsofalagin the d etect ionofhypogly cemiawh enu sin galtern ativesite sc ompare d withfinger tips (177).Thu s,th eFDAhasencouragedman ufactu rer st ore comme ndfinger stick asoppose d toaltern ativesite blood glu cosemonitor in gwhen hypogly cemiaissuspe cted, in patient swith hy poglycemicu nawaren ess,orinver yyou ngch ildren whoare u nable tocommun icatesymptoms. Blood glucosemonitoringstr ipsh avealsobee nimprovedforeasie rbloodsamplingt hrough capillar y-action strips(176). Itisimportan ttonoteth atbloodglucosemon it oring, wheth eronfinger tip sorforearms, with neworold mon itors,isab out the p ersonwit hdiabet es.Itisimportanttoremindpatie ntsandth eir familie sthat th eyuse blood g lu cosemonitor in gtopr ovidedataandinformman age men t,rathe rthantocriticize diabet escontrol(175).The diabete sh ealth care teamcan helpremoveth eblamean dshameof diabet esbyre in forcingt ochildren andt heirpar ent st hatbloodglu cose lev elsaren otg oodorbad but in steadare high, in -ran ge,orlow ;t hat bloodglu cose isch ecked not test ed;an dthatlevels alway sv aryinapersonwithdiabe tessoexpect someout-of-ran geresu lt s(121).Ifpatientsfe elb lamed byth eirou t-of-ran genu mber s,ift heyt hinkth atbloodglucosemon itoringt akest oomu chtime ,or if th eydonotknowwhat todowithth ein for mation, the b estan dnewe sttech nologywillnotbeofclinical valu e. Anothe rnewmonitor in gtechn ologyin volve sblood k etonet estingrathe rthantradit ionalu rin ete stin g. Rec entclinicaltrialshav ebegu ntoevaluatet heclin icalu tilityofmeasuring b loodk etones(hy drox ybuty rate )with ahome-base dmonitor(179,180).Itishopedth atongoingclin icalr esearchwill det ermin ehowtou seblood-hyd roxy butyr ate measure men tstobette rmanagesickdays, preve nt metab olicde compen sation ,an ddecre aset heeconomicandhu manbur denofDKA(175).Foradditional discussion ,see se ction on sickdayrules. Ch ildren wit htype 1diabet esrequ ir emonitoringforoth erdiseases,asthey areatincreasedriskfor other aut oimmun edisord ers.C linicalmanageme ntsh ou lddictateth efrequ ency with whichthy roid fun ction ,adre nalfun ction ,an dlabor atorystu die stoassessgastroin testinaldisorderssu chasce liac disease orinflammatoryboweldiseaseshouldbemon it or ed.Un explaine dglyc emicexcu rsion sorch ange s ingrowthsh ou ldt rigg erinvest igation. Foradditionaldiscuss ionsofhypogly cemia,seeC hapt er40.Hype rglycemicemerge nciesan dDKAare discussedinC hapter53. P. 728
PREVENTION OF DIABETIC KETOACIDOSIS: SICK-DAY RULES

The corn erstone sofsick-dayman age men tare (a)ne veromitinsu lin, ( b)preven tdeh ydrationand hy poglycemia,(c)mon it orbloodglucosefre quen tly ,(d)monitorforketosis,(e)providesup plemen tal fast -actingorrapid-actinginsulindosesaccordingt ogu ide lines, (f)treatun derlyingtrigger (s),an d(g) havefre quen tcon tact with the d iabetesh ealth care t eamtoreviewclin icalstatus .
Never Omit Insulin

Illn essprese ntsspe cificdilemmasfor childre nan dadolescen tswith diabete sand t heirfamilies.In sulin mustalway sbeadministere dduringillne ss,eve nifthech ildoradole scent isnote ating. In fection induce sin sulin resistan ce,t here byoft enn ecessitat in gin crease dor s upplementaldosesofin sulin . Gene rally ,the usuallypre scribedin sulindosageissupplement edbyrapid -orsh ort -actinginsu lininth e formoflispro,aspart, orr egular .Theaddit ionalorsupp lemen taldoseisn eede dtoman aget he hy perglycemiaan dketosis. Theoptimalsu pple men taldosageofinsuliniscalculated fr omthe b lood glucoselevelan dthepr esen ceor absen ceofk etones. Ketonesarede tected in u rinebyse miquantitativ e
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measu rements orwithat-home bloodmonitorsthatme asu re-hyd rox ybutyr ate (3HB).Addition alstudies ar enee dedtohelpcre ateandre fin esick -dayalgorithmsaccordingtoblood3HBmeasu remen ts (175, 180,181).Ing ener al,supplemen talin sulin dosages,ge ner ally10%to20%ofthe t ot ald ailyinsu lin dosage, are basedonth ebloodglucosele velan dtheu rinar y(orblood)ke tonere sults(seeTable 42. 10 an dsectionon supplement alin sulin ).Supplement soflispr ooraspartmayn eedtobere peat edeve ry2 to3h ou rswhiler egular in sulin may need t obe admin iste redev ery3to4hours. Finally,ifthe blood glucoselevelislow,the patien t'sinsu lindosage may bedecre asedby 20%.E xamplesofsick-day algorithmsusingeith erur in eor b loodk etonere sultsare showninTable42.10. TABLE 42.10. Supplemental Insulin Dosages
Blood glucose level 80250 mg/dL 250400 mg/dL >400 mg/dL
Ketones (more than a trace)
Suggested extra insulin
Nooryes
None
No
10%ofTDD*
Yes Nooryes
20%ofTDD* 20%ofTDD*
*Totaldailydose(TDD)iscalculatedbyaddingupalloftheinsulinadministeredonausual day,includingrapid-orfast-actinginsulinandintermediate/long-actinginsulin.Donot includesupplementsaddedtotheusualdose.IncalculatingTDDwhenslidingscalesare used,selectthesliding-scaledoseforbloodglucoselevelsof~150mg/dL. Bloodglucoseandurineketonesshouldbemonitoredevery24hr. Supplementalinsulinboostersarerepeatedevery23hrwithaspartorlispro,andevery3 4hrwithregularinsulin. Ifhyperglycemiaand/orurineketonesdonotimproveafter2supplementaldoses,contact thehealthcareteam.Thehealthcareteamoccasionallymayrecommendintramuscular injectionofsupplementalregularinsulin. Ifhypoglycemiaispresent(glucose<80mg/dL)withorwithoutketones,consideromitting aspart,lispro,orregularanddecreasingintermediate/long-actinginsulinby20%;contact healthcareteam,especiallyifpatientisvomiting.
Blood glucose level <250mg/dL >250400mg/dL >400mg/dL
Alternative algorithms incorporating more complexity Urine ketones Negative/trace Nochange 5% 10% Small 0%-5% 10% 15% Moderate/large 010% 1520% 20%
Blood glucose level <250mg/dL 250400mg/dL >400mg/dL
Future algorithm incorporating results of blood -hydroxybutyrate (3HB)a Blood Ketones (3-HB) 0.60.9 mM Recheck in12hr <1.0 mM Nochange 5% 10% 1.01.4 mM 0%-5% 10% 15% 1.5 mM 0%-10% 1520% 20% 3.0 mM Callhealthcare team immediately
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aSamplealgorithmawaitingresultsofclinicaltrials.
Prevent Dehydration and Hypoglycemia

Flu idintaketopre vent d ehydr ation mu stbeen cou rag ed.Oralh ydrationisprefe rredbu tmaybe impossibleattime sofnause aan dvomitin g.In fact,t hepre sence ofvomitingandth ein ability toh old downorally admin iste redfluidsmaybeth elimit in gfactorfor thecont in uedh omemanagement ofasick day .Ifvomitingper sists, theh ealth care teammu stbecalledimmediat ely.Non eth ele ss,at temptsat oral hy drationwithfreq uen t,smallqu ant it iesofclear fluidsarerec ommen ded. The b loodglucoseleve ldet ermin eswhe ther sugar -con tainingorsugar-fre eflu idsareu sed.Wh enth e pat ie ntisanore xicandusu alsolidfoodintakeiscu rtailedorabse nt, sugar -con tainingdr in kssuch as reg ularsoda,clearjuices,flavoredsu gar-cont aininggelat in ,orot herglucosecontain in gdrinksare sugg estedt oprovideforusualcarbohydr ateint ake, especiallywhen blood glu coseisun der180to200 mg/dL.Volu mesof3to8oun cesper h ou ror,forchildr en, 2mL perpound ofbodyweightpe rhouror3 L/m 2 perdayshouldbeen cou rage d.Flu idscont ainingsaltandpotassiumare helpfulwhen gas troin testinallosse sfromvomitingordiarrh eaoccur .Fluidssuc hasbouillon,br oth ,soda,andfru it juices,often in combin ation,areuse ful. Sugar-free drin ksar erecommen dedwhe nthe patien tisable tofollowausu alme alplanortak ein solids th atprovideadequatecarboh ydratesandcalorie s.Wesu ggestth atfamilieske epa sick-daycu pboard stockedwithn on perishable ite mssu chasge latinsthatcome assugar-free andsu gar-cont aining varie tie s.Antipyr eticsareimport ant attimesoffe verinordert ored uceanyad ditionalinsen siblefluid losse s;inadditiont oantipyret icsfororaluse, ant ipy reticsin suppositor yformare part icu larly usefu lat time sofnause aan dvomitin g.U seofanti-emeticsshouldbeindividualizedandusu ally onlyafter consultationwith t heh ealth caret eam. Reassessment ofhy drat ionstatusisimportanttoavoiddecompe nsat ion.E vidence ofdeh ydrat ionsu chas weightloss,sun ken e yes,ordry t on gueindicat esan eedforprompt medicalass essme nt. P. 729
Monitor Blood Glucose Frequently

Self-(orfamily)monitoringofbloodglucosesh ou ldbe performe datleastever y2to4h ou rsforsick-day management .Morefr eque ntmon itoringisrecommen dediftheglucoseleve lislow.Maintain in gcar eful recordsishe lpfu lfortrackin gprogression ofilln essan ddetect in gear lysignsofdecompe nsat ionpr iorto progressiontofran kDKA. Pat ie ntsandfamiliesshouldbecomfortablewith the accur acyoftheirblood glucoseme terby utilizingth ech eckstriporcon trolsolution speriodicallyan dinsuring thatthe ir supp liesar euptodat e.
Monitor for Ketosis

Trad itionally,ur in etest sforke ton eshavebee nan importan tasp ectofmonitor in gforsick-day management .Recommen dationsfor urinet estingforketone shav ein clu dedte stin gat 2-to4-h our inter valsduring illn ess,withst ress,orwhe neve rthe bloodglu cose isconsisten tly great erth an300 mg/dL(>16.7mmol/L)(174). Howeve r,withth eadv entofbloodmonitorsth atcanquantitateblood 3HB, thewe akn essesinhe ren tin urinek etonete stingbecome apparent .Bloodme asur eme ntof3HBmay beabette rguidetoinsulinthe rapy in t heh omemanagement ofket osis.Aseparat e,large rissu eis whe ther homeu seoft he3HBb loodt estcan proveuse fulin thedailyman agement oftyp e1diabe tes. Patient sandmedicalstaffmust b etau ghth owtodealwitht hen ewvolumeofin format ionth att heywill becollect in g.Incasesinwhichbothse rumglu cose le velsandk etonelevelsar eelevatedornormal,it willbereasonablyclear wh atisreq uired.Bu twhatshouldbedonewh enth ere issomede gree of discor dance in thefindings, fore xample,if3HBle velsare ele vate din the se ttingofnormalorne arnormalglu cose values?C learly,more studiesarene cessary ,an dperh apsgu idelinesforpat ie ntselfmanagement of3HBleve lsne edtobecre ated t hat areb asedonth efindingsofempiricstud ies. A rece nt, ran domiz edtrialcomparin gsick -dayman agement usingblood3HBmeasuremen tswit hurine ket on etest in gsuggest sreduce dnee dforh ospitalizationoremerge ncydep artmen tassessmen twit h bloodket on eversu surine k etonete sting(182). Rein force men tofk etonete stin gdur in gilln ess,appropriate st or ageofsupplie s,an dthe useofin sulin algorithmsbased onbloodglucoseandket on eresu lt saren ecessary.Su ppliesforketone testingmust b e storedaccor din gtot heman ufact urer 'srecommen dat ionsan dreplace datt here comme ndedint ervals. Admin istr ation ofsu pple me ntalinsulinan dhydr ationare gene rally adequ ate in terve ntionsfor successfu l tre atment ofke tosis.Ifth epat ie ntfailstoclearketone swith in 12hours, t hediabe tesh ealthcarete am
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mustbecont acte dforassessment.
Provide Supplemental Fast-Acting or Rapid-Acting Insulin

Du ringanyinter curre ntillne ss,th efrequ encyofmonitoring P. 730 bloodglucosean dketone leve lssh ou ldbe in creasedtoevery 2to4hour s.Whe nth ebloodglu cose lev el isgreaterth an 300mg/d Lon twoormore cons ecutiveoccasions,patients andfamiliessh ou ldalways mon itorforthe presen ceofk etones. Ketones ,in gene ral,aremarke rsofinsu lindeficiency andth ene ed forsupplement alin sulin (Table 42.10).However, in the se ttingofgastr ointe stinalillnesswith v omit in g, diarr hea,in creasedtransittime ,an dmalabsor ption ,hypoglycemiamayprevailinth eprese nceor abs enceofketone s.Un dersu chcircumstan ces,e speciallywh enth ebloodglucosele velislessth an 80 mg/dLin the settingofpositiveke ton es,incr easingfluidintakewit hth eprovisionof10t o15gof car boh ydratesshouldbee ncouragedun tilth ebloodglu cose le velin crease s.Recommen dat ionsinclude th econ tinue dadmin ist rationoffluidun tilth eket on escle ar. Supplemen taldose sofrapid -acting(lisp roorasp art)orfast -acting(r egular )insu lin sh ou ld b e administere din addition tou sualinsulindosages wh ene verh yperglycemiaan dketosisarepr esen t.The degr eeofhyper glyce miaandth eprese nceorab senceofket on esdete rmine stheamoun tofsu pple me ntal insulin.Dosagesofsupplementalinsu linarege nerallycalcu latedaccording t oweigh t(0.10.3U/kg),as ape rcen tage oftotaldailyin sulin dosage(u suallybetwee n10%and20%oft hetotaldailyinsulin req uirementint hebaseline stat e),oraccordingtoteam-de rivedalgorithms(Table42.10)(60).Special algorithmsmaybereq uiredforpatien tstre atedwith CSII(59).Multid isciplin aryte amin volvemen tcan he lptoindividualizeth eappr oach,asparticu larnee dsvary accordin gtothepatient 'sinsulinsen sitivity, th esever it yanddu rat ionofthe illn ess,andth eprese nceofan ore xia.Ifbloodglucosele velsremain elevated, with orwithout positiveke ton es,addit ionalsu pple me ntaldosesofregular in sulin maybe ne edede very3to4hours. Iflisprooraspart in sulin isgiven asth esupplement alin sulin ,dosagesmay ne edtoberepe ate dat2-to3-hourint ervals. Pat ie nts(orfamilymemb ers)shouldcontinu etomonitor bloodglucosean durinaryorbloodketonese very2to4hour sandke epcar efulrecords.
Treat Underlying Triggers

Anyacute in fectiou sproce ssnee dstobe evalu atedandtr eat edaccordingly.In tercu rren tviralillnesse s, notre quirin gan yspecificpr escriptiveth erap y,maystillproduce ele vate dglu cose le velsandk etosisand req uiresick-dayman agemen t.Symptomatict reat me ntwithantipyret icsandanalgesicsisb eneficial. Patient swith ahistoryofrecur rent DKA, with knowneatin gdisorde rsor psychosocialproblems ,an dwith poorglyce miccon trolareat risk forde compens ation and s hou ld beadvisedt ocallthe irh ealth care t eam at thee arlie stsymptomsan dsignsofilln essordecompe nsat ion(101, 183). It isadvis ablethatpat ie nts alway sh ave accesst oap hon ean dtransportationforfollow-u pcare .
Frequent Contact with the Medical Team

Patient sandfamilymember ss hou ld beadvisedt olookoutforsig nsth atmedicalatte ntionisn eede d. The sein clu devomitingth atcont in uesformoret han 2to4h ou rs;bloodglu cos ele velsthatexcee d300 mg/dLor persisten ceofke ton esformoret han 12hours;signsofdehyd rationsuch asdrymouth , crackedlips, sunk eney es,weight loss,ordryskin;orsymptomsth atDKAmaybede veloping, suchas nausea,abdomin alor chestpain,vomiting, ketoticbreath,h yperv entilation,oralter edconsciou sness. The lat tersu ggestst hen eedforimme diatemedicalatt ention.Ifre cogn iz edearly, milderformsofDKA can betre ate din theambu latorysett in g,obviatingth ene edfor h osp italization(184). Illn essan dstressarecommon.For t hech ildoradole scent with type1diabete s,the secan betrigger sfor count erreg ulation an dsubsequ ent met abolicdete rioration ifnoat tent ionispaidtodiabete smanage me nt tasks.Sick-dayman agemen trequ ir esin creasedmonitoringofbloodglu cose andassessmentforket osis. Ext ensivee xperien cehasshown thatbyassidu ou slyfollowin gthe guidelin esou tlin edinthisprotocol, familiescan successfu llymanagemost in tercu rren tillnesse sin c hildre nat homewithout recourse t oa hospitalemerge ncydepartment .
BEHAVIORAL ISSUES
Diabetescaresh ou ldinclude carefu latten tion t oth eedu cational,de velopmen tal,an dbeh avior alissu es ofch ildh oodan dadole scence .(SeeC hapt er37for addition aldiscu ssion. )Since diabete streatme ntand self-managementt rainingforthe child, adole scent, an dfamilywit hdiabet esist ime-inte nsive,copiou sin conten t,andev olvesoverth ecourse ofchildhood, adole scence ,an din toadulthood,at eamofdivers e he althprovidersbe staccomp lishest hegoalofoptimald iabetesman agemen t.This,too,ist hepositionof th eADA'sSt andardsofMe dicalC are, whichcallsforamu ltidisciplinaryteamapproacht oth ecar eofth e childoradolesce ntwithdiab etes(55). Treatmentofdiabete swith train in gin self-man age men tne edstoaddre sstheover allissue sofchildand adolescen tgrowth, d evelop men t,te mpe rament ,an dbehavior, aswellasthe issu esofth enatur alcou rse ofd iabetesitselfd iagnosis, adap tation,ongoin gdisease progr ession ,an dpot entialcomplic ation s.What distinguishe sdiabete sfr ommanyothe rchronicdisease sofchildhoodareth eincessantde mandsmade
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onpat ie ntsan dfamiliesfor self-man age men tan dthe clinicaldecision-mak in gresponsibilitiesgiv ento par ent salmostimmediatelyafterdiagn osis(185). Tomeetth esede mands,familiesn eedt omake adju stme ntsinth eirlifesty le. Theroleofth ediabe teshe althcarete amistohelpth echildoradolesce nt an dhisor herfamily learn, pract ice, an drevisediabet esself-manageme ntskillstosucce edinbalan cin g th ecomplicatedre quirement sofinsulininjection /infusion ,mealplann in g,andphy sicalactiv ity ,usingth e information fr omfrequ entbloodglucosemon it oring. Thede velopment ofth etre atment planisbasedon th ecommon alitiesofchildh oodan dadolescen cean dtheindividualizationth att akesint oaccou ntfamily fact ors, age, developme ntalstage,andissuesoftemperame nt. Asisclearfr omthe p receding discussion sin thischapter, diabete sself-man age men taffect smanycompone ntsoffamilylife eat in g, phy sicalactivit y,fin an ces,andtime manage me nt.On emaingoalofth ediabete shealt hcar eteamisto pre vent ,predict, orman agebe hav ioralan dfamilycomplication sthatar iseinr espon setothe pediatric diabet es. The PsychosocialTh erap iesWorkingGroupre por tsthatchildrenandadolescen tswithty pe1ortype 2 diabet esface u nique demandsinde alin gwith diabete sboth becauseofthe n atu reofthe irbe in gchildr en an dadolescent sand b ecau seoft hechr on icityofthe dise ase.Th epsych osocialch alle ngesinclude an increasedriskforpsychiat ricd isorder s,in clu dingdepr ession, adjust men tan dadaptat ionproblems, an d eatingdisord ers.Allofthe sedisorde rscan resultinpoor met aboliccontrol(89) .Avariety of psych osocialint erve ntion shavebeen showntobeeffect ive in improvin gme tabolicoutcomes.Asnoted pre viously,t hisiseviden tfromth eoutcome sfrompediat ricbe hav ioralstu die sandclinicalprog rams car rie dou tatt heJoslinDiabet esCen ter.
Behavioral Risk Factors: Uncontrolled Diabetes and Family Studies

Copingwithth eun relent in gdemandsofthischr on icincu rabledisease,forwhichtre atment iscomp lex , difficu lt, and impacts P. 731 onth elifesty lesofthe patien tan dhisorh erfamily, isstr essful.Itisnotsur prisin g,the refore,t hat emot ionaldifficu lt ie sarecommon.C on seque ntly,animportantgoaloft herapyisthepr even tionandth e ident ificationan dtreatmentofemot ionalproblemsandt heprovisionofcon tinuouspsy chosocialsupport an dencour agemen ttopatient sand t heirfamilies.Despitet hepre viousge ner ald escription ofth egoals oft her apy,itiscriticallyimport ant t otailorthe goalsoftreatmentt oth ecap abilitiesoft heindividual pat ie ntandfamily. Variousdiabe testre atment toolscansignificant lyh elpmanag ean dimproveglycemiccontr ol(186, 187). Inparticular, bloodglu cose monitorin gisce ntralt oth esucce ssfulmanage me ntofdiabetes (65,101,188). Howeve r,datasu ggestth atonlyabou t60%ofpatien tswit htype 1diabe tesroutine ly per formbloodglu cose monitorin g(189). Inaser ie sofstu die sin t hePediatr icandAdolesce ntU nitatt he JoslinDiabete sCent er,we have systemat icallyinvest igatedbe havioralan dfamilyfact orst hat optimize glycemiccontr olan dadh eren cetobloodglu cose monitor in gand oth erdiabe tesmanagementt asksin children andadolesce ntswithty pe1diabe tes(65,66, 67,101, 189a). Insummary, freque ntbloodglucose mon itoringisrelate dtobette rgly cemiccontrol;in crease dfamilyinvolv eme ntimpr ove sadhe ren ceto diabet esmanagementt asks;anddiabet es-specific familycon flict,commonlyrelat edtofoodissu esan d bloodglucosemonitoring,h in derscontr ol.
Frequent Blood Glucose Monitoring Predicts Better Glycemic Control

Inacoh ort ofyoun gadole scent s10t o15yearsoldwitht ype1diab etes, thefre quen cyofb loodglucose mon itoringwassign ifican tly associatedwithHbA 1 c valu es,aft ercontrollingforgen der, durationof diabet es,andpub ertalde velopment (Fig.42.5).Thissignificantassociat ionwasr ecen tly confirmedina stu dyof300you th7to16ye arsofage with type1diabete satth eJoslinDiabetesC ent er(101).
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FIG. 42.5.Relationshipoffrequencyofbloodglucosemonitoring(BGM)andglycemiccontrol(HbA1c)inyoung adolescents10to15yearsoldattheJoslinDiabetesCenter.(ReprintedfromAndersonBJ,HoJ,BrackettJ,etal. Parentalinvolvementindiabetesmanagementtasks:relationshipstobloodglucosemonitoringadherenceand metaboliccontrolinyoungadolescentswithinsulin-dependentdiabetesmellitus.J Pediatr1997;130:257265, copyright1997withpermissionfromElsevier.)
Parent Involvement in Diabetes Management Tasks Is Related to Increased Monitoring

Paren t-adolescen tteamworksup port sin crease dadh eren cetobloodglu cose monitorin gan ddoe sn ot increasefamilyconflict(65).Pr eviou sstudieshavere vealedt hat adhe ren cetodiabetesman age men t tasksdecre asesovert heearlyadole scent year s(66, 67).Thiscoincideswith t hepr edictabledecr ease in par ent inv olvement duringadolesce nce(64,65, 66).Wedev eloped alow-inten sit y,office- based inter vent ionfor10to15y earoldsandt heirparent saimedatmaintain in gpare ntinvolveme ntin diabet esmanagementt asksoverth eearlyadole scenty earswith ou tthe triggeringofin creaseddiabet esrelat edfamilyconflict .Thistrialdemon strat edsust ainedinvolvement ,diminishedfamily con flict,and bet terglycemiccont rol.Th ein terv entionfocusedonn ewwaysofcom-mu nicatingaboutbloodglucose mon itoringinfamiliesth atavoided shameandblamean dpromotedr ealisticparen talexpe ctationsfor bloodglucosele velsin growing andde velopingadolesce nts(65,66).
Realistic Expectations and Blood Glucose Monitoring

Weh avede velope dmaterialsfocusedonbloodglucosemon itoringforpat ien tsofallagesan dtheir familymembers(121).TheBlood Glu cose Monitorin g Owner s Manualr eviewsthe impor tan ceof mon itoring, prov ides r ealistice xpectation sofbloodglucoselevelsforp atient sandt heirfamilies,and reinforcest heincre asedflexibilityinlife stylethatispossiblewit hincreasedmon it oring. Thisman ual providesan ewvocabular yaroun dmonitoringth atinclude st hen eedtoche ck(nottest)bloodglucose an dthatglucoselevelscan behighorlow(notbadorg ood).Inastudy of200at-riskadu lt swith bas eline HbA 1 c 8%orh igh er,u seoft hiseducation altoolwassig nificantlyassociated with more mon itoring(P<.05)an dless -negativ eatt it udes(P<.05)(190). Bloodglucoseresu ltsappeartotriggerbothn egat ive and p ositiveresp on seswit hinfamilies.We un cov eredfroms urvey sadmin ist eredtoyouth sages8to16y earsmultiplesou rcesofcon flictwithin familiesar ou nddiabet esmanagementt asks.Moreth anh alfthe responden tsen dorse dcon flictarou nd bloodglucosemonitoring,insu lin, and foodissu es(67)(Fig.42. 6).Decre asedconflict with in families wasassociat edwit hincreasedfre quen cyofbloodglucosemon it oring. Thus, education focuse don posit ive commu nicationwit hinfamiliesar ou ndbloodglucoseresu ltsisimportantandwilllikelyplaya criticalrolewitht heintr odu ctionofth enewte chnologiesforfrequ ent orn ear -con tin uousmon itoring.
FIG. 42.6.Areasoffamilyconflictreportedbyyouthwithtype1diabetes(personaldata).
Intensive Insulin Therapy and Blood Glucose Monitoring

Our recen texpe rie ncewithinsu linpu mpt herapy(CSII)inyouth wit htype 1diabet es,th efast estgrowin ggroupofnewpu mpu sers,confirmstheimport ance ofbloodglucosemon itoringfor P. 732
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sust ainedimprov eme ntinglycemiccont rol(191). Evalu ation of109patien tsund ergoin gCSIIshowed improvemen tin HbA 1 c resultsofabout1%aftert hefirst3month sofpu mpus e(192)(Fig. 42.7). This improvemen twasassociate dwit hasignific ant incr ease in bloodg lu cosemonitor in g,from3.7timesa day atbaselin eto6.1timesadayat3mon ths. Aft er9month sofpu mpu se,th erewasadecre aseint he frequ enc yofmon itoringto4.3timesaday.The decreaseinmonitoringwas assoc iatedwithasign ifican t increaseinHbA 1 c .Thu s,succe ssfulpumpthe rapyr equiressu staine dmonitorin g.Withincr easing nu mbe rsofpe diatricpatien tsbeginn in gCSII,th ere isan eedt oincorporate familyteamworkprograms aimedat incr easingandsu stainingadher ence t obloodglucosemon itoringwithpu mpu se(192).
FIG. 42.7.Relationshipoffrequencyofbloodglucosemonitoringandglycemiccontrol(HbA1c)aftertheinitiationof insulinpumptherapy(CSII)in109youthwithtype1diabetes.(FromLaffelL,LoughlinC,RamchandaniN,etal. Glycemicchallengesofpumptherapy(CSII)inyouthwithtype1diabetes(T1DM).Diabetes2001;50:A66A67 (abst).
DIABETES IN THE SCHOOL AND DAY-CARE SETTING

Ch ildren an dadole scents with diabetes aren otu nlik ethe irpe erswithoutdiabetes the yspend t he majorityofthe ir wakinghour sin s chool.Becauseofthe needforoptimalglycemic cont rolforyou thwith diabet es,th etasksofdiabe tesself-management b ecomeanecessarypartofthesch oold ay.Th e succe ssfulin tegration ofdiabet esmanagementint oth eschoolset tin gisb uiltonafou ndat ionofgood communicationbe tween the p aren t(s),ch ild,sch ool, an dhealth care team.K nowledge ,un derst anding, an dskillbuild in garen ecessaryforthe successfu lman agement ofdiabe tesat school. Lawspr ote ctth erightsofchildr enwithdiabe tesinth eUn ite dState s,particularlySection 504ofthe Reh abilitation Actof1973,t heInd ividualswith DisabilitiesActof1991,an dtheAmerican swith Disabilitie sAct en suringsafean dfullparticipation in allsch oolactivit ie s.Becau sediabe tesisclassified inth eselawsasadisability,itisillegaltodiscr imin ate again stachildor adolesc entbe cause of diabet es.The selawsens uret hat t hech ildoradole scent with diabetes isab let omon it orbloodglucose, injectinsu lin,followamealplan, andparticipate inp hysicalactivitiesatsch ool,bothdu rin gthe school day anddu ringaft er-sch oole xtracurricular activitie s.Alt houghch ildre nwit hdiabet esar eatriskfor discriminationatschool,gr eat e ffort shav ebeen madetoensu reap prop riatecarean daccommodationin th ele astre strictede nviron me ntpossible .Toth ise nd,t heADAh asdev eloped apos itionstatement, CareofChildren With Diabe tesinth eSchoolan dDayCar eSetting (58). The g oaloftheposition st ate men tistopr ovidedirect ionforthe care ofchildren andadolesce ntsdu rin g school. An in div idu alize d car eplanpr ovidesth eframeworkforaddr essingth enee dsofth echildwith diabete sin aschoolorday P. 733
car eenv ironmen tan dstate snee ds,responsibilities,andex pectationsofthe school,th epar ents ,an dthe childoradolesce ntdu rin gthe schoolday anddu ringschool-re latedex tracu rricularactivit ie s.The deve lopmentofan in dividu alize ddiabete shealth care planshouldprovideinformation on t hen eedsofthe childoradolesce ntwithdiab etesandinstru ction sforbloodglucosemon it oring, mealsandsn acks, symptomsandtre atment ofhy poglycemia,administration ofglucagon ,symptomsan dtre atment of hy perglycemia,measu rement ofket on es,andsick-dayr ules(58). Schoolper son nel,parent s,the diabete shealth care team,andth echildoradolesce ntwithdiab etesall haveth esamegoal:tohav eahe althy, happystude nt. Th roughaccommodationandsu ppor tofdiabe tes self-managementt asksat school,th estu dentwith diabeteswillbe affor dedth eopportu nitytosafe ly succe edindiabet esmanageme nt, acad emics,anddev elopment ofevolvin gsocialskills. Insu mmary ,pediat ricbe hav ioralstu die sandclinicalprog ramshav econ sist ent lydocumen tedth e challen gesofachievingoptimalmetaboliccon trolinyout hwit hdiabet es.Wh ilene wtechn ologie sprov ide hopetoourpatie ntsandth eirfamilie s,th eyalsoin crease the b urden splacedu pon themtoach iev ea ne wpatte rnofnormalcy whileint egratin gthe rigorsofdiabete smanage me ntintothe ird ailylives.To
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th isen d,su pport fromamultidisciplin aryd iabetest eamisimp ort ant .
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In terve ntion StudyinC hildr en(DISC).Pediatrics2001;107:256264. 148.Nutrition manageme nt. In:KelleyDB, ed.In tens ive d iabetes man agemen t.2nded. Alexandr ia, VA:Ame ricanDiabete sAssociation ;1998:138157. 149.Mohn A,Cer rutoM,Lafu scoD,et al.Celiacdisease in childre nan dadolescen tswith typeI diabe tes:importanceofhypoglycemia.J Pe diatr Gastr oe nter ol Nutr2001;32:3740. 150.Gille ttPM,Gillett HR ,IsraelDM,etal. High p revalen ceofceliacdiseaseinpat ie ntswithty pe1 diabe tesdet ectedby ant ibodiestoendomy siu man dtissuet ran sglu tamin ase .Can J Gastroen terol 2001;15:297301. 151.Aktay AN, LeePC,Ku marV,etal. Thepre valence and clinicalcharacte rist icsofceliacdise asein juve nile d iabetesinWisconsin.J Pediatr Gas troente rol Nutr 2001;33:462465. 152.Fasan oA.C eliacdise ase:th epast ,th eprese nt,t hefut ure .Pe diatrics2001;107:768770. 153.Jon esJM,LawsonML,Dan emanD,etal. Eat in gdisorde rsin adole scentfe maleswith andwith out typ e1diabe tes:crosssectionalstu dy.BMJ2000;320:15631566. 154.RydallAC,R odinGM,Olmsted MP,etal. Disor derede atingbe hav ioran dmicrovascu lar complication sin youngwome nwithinsulin-dep ende ntdiabe tesmellitus. N E ngl J Me d 1997;336:18491854. 155.AntisdelJ,Laffe lLMB,An dersonBJ.Improveddet ection ofeatingproblemsin womenwithty pe 1diabetesu sin gan ewly d evelop edsurv ey.D iabetes2001;50:A47(ab st). 156.Colt on P,Dane manD,Olmsted M,e tal.Eatingdisor dersinpre -teen gir lswithty pe1diab etes mellitus:acasecont rolstu dy.Diab etes200150:A47(abst ). 157.CrowSJ,Kee lPK,Ke ndallD.E atingdisordersandinsu lin-de pende ntdiabe tesmellitus. Psychosomat ics1998;39:233243. 158.Bryden KS,NeilA, Mayou RA,Pe velerRC ,Fairbur nCG,Dunge rDB. Eat in ghabits, bodywe igh t, andinsulinmisus e.Along itu din alstud yofte enagersandyoung adultswithty pe1diabe tes. D iabete s Care1999;22:19561960. 159.Daneman D,OlmstedM,RydallA,et al.Eatingdisord ersinyoungwomenwithty pe1diabe tes. Prevalen ce,pr oblemsan dpreve ntion .Hor m Re s1998;50[suppl1]:7986. 160.MarcusM,WingR .Eatingdisord ersan ddiabete s.In:HolmesC ,ed.Neu ropsychologicalan d beh avioralaspe ctsofinsu lin-andnon-insu lindiabetesmellitu s.NewYork :Sp rin ger-Ver lag, 1990:102121. 161.KaiserFamilyFoundation .Availableat :http://www. kff.org/con ten t/1999/1535 162.Brown ellKD,Ke lman JH,Stun kardAJ. Tr eat men tofobese childre nwithandwithoutth eir moth ers:ch ang esin weightandbloodpress ure. Pediat rics 1983;71:515523. 163.Schafe rLC, GlasgowRE, McC aulKD,etal. Adhere ncetoIDDMregime ns:relationsh ipt o psych osocialvariablesandmetaboliccont rol.D iabete s Care 1983;6:493498. 164.RiddellMC, Bar-OrO, Ay ubBV,et al. Glucoseinge stionmat chedwitht otalcarbohydrate ut ilizationat tenu ate shypoglycemiaduringex erciseinadolescen tswith IDDM. Int J Sport Nut r 1999;9:2434. 165.Temp leMY,Bar-OrO,RiddellMC .Ther eliab ilit yand repeatabilit yofth ebloodglucoseresponse toprolonge dexer ciseinadolesce ntboyswithIDDM.Diabe tes C are1995;18:326332. 166.SillsI N, Cern yFJ .Response stocont in uousan din termitten texer cise inh ealth yan din sulin -
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dep ende ntdiabe ticch ildren .Med Sci Sp ort s Exerc1983;15:450454. 167.Kau fmanFR.Diabetesinch ildre nan dadole scent s.Areasofcontrover sy.Med Clin Nor th Am 1998;82:721738. 168.MacDonaldMJ.Post exer ciselat e-onseth ypoglyce miaininsu lin-de pende ntdiabe ticpatient s. Diabetes C are1987;10:584588. 169.Diabe tesmellitusandex ercise.Physicalactivity/ex ercisean ddiabete s.Diabe tes Care2003;26 [Supp l]:573577. 170.Kau fmanFR,HalvorsonM,Kau fmanND. Evalu ation ofasnack barcontain in gun cooked cornst arch insu bjectswithdiabe tes.D iabete s Res Clin Pr act1997;35:2733. 171.Kau fmanFR,HalvorsonM,Kau fmanND. Ar and omiz ed,blin dedtr ialofuncookedcornstarcht o diminishn oct urn alh ypogly cemiaatdiabet escamp.D iabetes R es Clin Pract1995;30:205209. 172.Kau fmanFR,DevganS.Use ofun cookedcorn starch toaver tnoctur nalhypoglycemiain childr en andadolescen tswit htype Id iabetes. J Diabet es Complications1996;10:8487. 173.Hand book of e xercise in diabet es.Alexan dria,VA:American Diabet esAssociat ion,2002. 174.Testsofglyce miaindiabe tes.D iabete s Car e2003;26[Su ppl]:S106S108. 175.LaffelL.Sick-daymanage me ntintype 1diabe tes.E ndocrinol Metab Clin North Am 2000;29:707723. 176.Gr adyJC ,KordellaT.Newproducts. Diabet es Fore cast2003;56;3740. 177.Jun gheimK ,KoschinskyT.Glucosemonitoringatthe arm:risk ydelaysofhypoglycemiaand hy perglycemiadete ction .Diabet es Care2002;25:956960. 178.Lawlor MT,LaffelL.Newtech nologiesan dthe rape uticapproach esforthe manage men tof ped iatricdiabete s.Cur r Diabe tes Rep 2001;1:5666. 179.Fine bergAE, Bergen stalRM,Ber nste in R M, etal.U seofanautomatedde vice foralte rnativesite bloodglucosemon itoring. D iabete s Car e2001;24:12171220. 180.LaffelL,K aufman FR, etal.Freq uen cyofelevation in blood B-h ydroxybu tyrate(B-OHB)dur in g homemonitoringan dassociation wit hglycemiain insu lin- treatedchildren andadults.D iabete s 2000;49:A92(abst ). 181.Kau fmanFR,HalvorsonM.Thet reat men tan dpreve ntionofdiab eticketoacidosisinch ildren and adolescen tswithtype Idiabete smellitu s.Pediatr An n1999;28:576582. 182.LaffelLMP, L ou ghlin C,TovarA, e tal.Sickdayman agemen t(SDM)usingbloodhy droxybuty rate (OHB)vsurinek etonessignificant lyre ducesh osp italvisitsinyouth with T1DM:a randomizedclinicaltrial.Diabe tes2002;51[supp l2]:A105(abst ). 183.Polonsk yWH,Ande rson BJ,Lohrer PA,et al.Insu linomission in womenwithIDDM.D iabetes Care1994;17:11781185. 184.ChaseHP,GargSK,Je lleyDH.Diab eticketoacidosisinch ildren andt heroleofout patient management .Pe diatr Re v1990;11: 297304. 185.DrashAL, Be ckerD.Diabetesmellitu sin t hech ild:course, specialproblems,andre lated disor ders.In :Kat zenHM,Mah le rRJ,ed s.Diabe tes, obesity, and vascular disease. Advances in mode rn n utrition .Vol2.NewYork :Wiley;1978:615643. P. 736
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186.Nath anDM,McK itr ickC ,Lar kin M, etal.Glycemiccontr olin diabete smellit us:havechange sin th erapymadeadiffere nce?Am J Med1996;100:157163. 187.Klein R,KleinBE ,MossSE, etal.Th eme dicalman agemen tofh yperglycemiaovera10-y ear per iodinpeople with diabete s.Diabe tes Care1996;19:744750. 188.Schiffrin A,Belmonte M. Mu ltipledailyself-glu cose monitorin g:it sessen tialr oleinlon g-term glucosecontrolin in sulin -depen dent diabeticpat ien tstre ate dwith pumpand multiplesubcu tan eous injections.D iabetes C are 1982;5:479484. 189.HarrisMI,CowieCC, HowieLJ.Self-mon itoringofbloodglu cose byadu ltswith diabetesint he Un it edStat espopulation.D iabetes C are 1993;16:11161123. 189a.LaffelLMB,Vangsn essL,Conn ellA,e tal.Impactofambulat ory, family-focusedt eamwork inte rven tiononglycemiacontrolin y ou thwithty pe1diabe tes. J Pediat r2003;142:409416. 190.LaffelL,Le vin eBS,LawlorM,etal. Ambulator yin terve ntionimproveskn owledge ,monitoring, adhere nce, andg lyce miccon trol:ashort-te rm, ran domiz edtrialofh igh -riskadu ltswith diabetes. Diabetes2000;49:A174(abst). 191.Kau fmanFR,HalvorsonM,Fish erL,e tal.Insu linpu mpt herapyintype 1pediat ricp atient s.J Pediatr E ndocrinol Metab1999;12[Su ppl3]:759764. 192.LaffelL,Lough linC ,Ramch and aniN,etal. Glycemicc hallenge sofpumpth erap y(CSII)inyouth withty pe1diabe tes(T1DM).Diabe tes2001;50:A66A67(abst).
Chapter43 Treatment of Older Adults with Diabetes

Caroline S. B laum Jeffr ey B. Halte r De spit ethe con tinuale xpan sionofknowle dgeabout diabetes, in clu din gthe importan ceofcont rolofr isk fact orsandglycemiain decre asingth ecomplication sofdiabet es,much ofth iskn owledge d oesn ot specificallyaddressissue sin olderadults,ev enth ou ghabou t50%ofpeople with diabete sin theU nited Statesar e60year sandolder(1).Fore xample ,in the UnitedK in gdomPr ospe ctiv eDiabe tesStu dy (UK PDS), the meanag eofparticipantswas53,alth ou ghafewolderpeoplewere enrolled andt heir nu mbe rin creaseddur in gthe st udy. Peoplewit hsignificantcomplicationsor comor biditiesat diagnosis were excluded(2).The refore,t heimplicationsoft here sultsofth eUK PDSforth emillionsofolder peoplewit hprev alent aswellasin cide ntdiabe tes,man yofwh omhav emu lt iplecomorbidcon ditions, are notye tcle ar(3). Clearly ,diabet esin olderadultsisamajorh ealth problem(Table43.1),andolde rpatien tswit hdiabet es face majorhe althproblems.Thosewhodeve lopdiabete sduringmiddle agewillface itsde bilitat in g complication sasth eyag eor willdiepre mature ly. Thosewhodevelopdiabete slaterinlife facean increaseinco-occu rringrisksan dcomplication sandcomorbiditiesasth eybe comevery old.The seolder pat ie ntsandth eir physiciansh aven oclearclinicalguidelinesfordiabet esmanagement; recommen dat ionsmustbe extrapolat edfromstu diesofothe rage grou ps.Cliniciansconfronte dwith gre athe terogen eityinthe olderpopu lationandwithrapidlych an gin gknowle dgeabout diabete sandits management must unde rstandth esimilarit ie sanddiffere ncesinth epat hophysiologyan dmanag eme ntof diabet esinolder versu smiddle -aged adults. TABLE 43.1. Diabetes: A Key Problem in Older Adults
41%ofdiabetespopulationare65andolder 25%ofMedicareexpendituresarefordiabetes
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44%ofpeople70andolderwithdiabetesneedassistancewithoneormoreactivitiesofdailyliving Morethan20%ofnursinghomeresidentshavediabetes
EPIDEMIOLOGY AND DIAGNOSIS OF DIABETES IN OLDER ADULTS

Diabetesisah igh lyp revalen t,andexp anding ,chroniche althproblemforolde rpeople .The Th ir d NationalHealth an dNu trition ExaminationSu rvey(NHANESIII),condu ctedbyt heNat ionalC ente rfor Health Statisticsfrom1988th rou gh1994,pr ovidedt hemost r ecen testimatesofthe prevalen ceof diagn osed andu ndiagn ose ddiabetesmellitu sin theU nitedStatesamongindividuals20yearsan dolder . Among t hose60to74andth ose 75y ear sandold er,re spectively,12. 6%and 13. 2%hadpreviously diagn osed d iabetesand6.2%an d5. 7%hadnewlydiagnoseddiab etesaccord in gtot hecriter ionfor fast in gglu cose lev else stablishedby t heAmerican Diabet esAssociat ion(ADA).Anad ditional5%to6% ofp eopleage60to74met diabetescr ite riabase don lyonanoralglucosetoler ance test(OGTT)valueof more than200mg/dLat 2hour s.Anoverallprev alenceofdiabet esofapproximat ely 25%amongpeople age 60to74ye arswasc onfirmedinth eCardiovascularHealt hStud yofolde rpeople in theU nitedStates an dexte ndedt oth epopulationoverag e75year s.Inaddit iontoth ehighpre valen ceofdiabe tes, 20% hadimpaire dglu cose tolerance(IGT)byth e1997ADAdiagn osticcriteria(4).The in cide nceofnew diagn osisofdiabe tesmellitusalsoincreasedwithageun tilabou tage 75andth enst abilized. The incidence rate wasappr oximate lytwoper1,000among t hoseindividu alsage d25t o44andincreasedto app rox imate lyfivepe r1,000amon gin dividu alsoldert han 45(5). Most ind ividualswith d iabeteswh oareolde rthan65yearshavetyp e2diabe tes.However ,type 1 diabet esoc cursinth isagegroupaswe ll,includingsomewit hnewlydiagn ose ddiabete s(6).In addition , asmallpercen tage ofolde rin dividu alswhoin itiallyhavetype 2diabet esbecome in sulin -depen dent ove r time .Whilethe HLA- DR3alle leismore commoninolde radu lt swh or equireinsu lint reat men tth anin th osewh odonotreq uireinsulin,th efreq uen cyofantibod iest oisle tcellsinth isgr ou pisn otincr ease d (6). Asin pat ien tswithtype 2diabe tesingen eral,athe roscler oticcomplication sare t hemost sign ifican t cau seofmorbidity andmortalityinolder patien tswit hdiabet es.Obser vationalstu die sofolde radu lts havesu ggested t hat poorglycemiccont rolin P. 738 olde rpeople with diabete scon tribute st oex cessriskofst roke and c ardiov ascular even ts(7, 8). Athe roscler oticmacrovascu lardisease account sfor75%oft hemort alit yamon gpeople with diabetes in th eUn ite dState s(9).In the U KPDS,20%ofpatie ntswithn ewlydiagnoseddiabe tesdev eloped macrovascu larcomplication safter 9years,wh ereason ly9%d evelop edmicrovascu larcomplication s(2). Micr ovascularcomp licationsar ealsoasign ifican tprobleminolderadu lt s.Int heUn it edStat es,diabe tes isthemajorcau seofr enalfailure anddialysisin people oldert han 65year s( 10). Diabe ticr etinopath yis amajorcau seofvisuallossin olderadults,andeve nifitdoesn otleadtob lindn ess,itisassociated withdisability andde pression (11,12).Peripher alneu rop ath yand p eripher alvascu lardise aseare par ticularlyprev alentinolderag egroups(13).The prevale nceofamputation sin creas eswith age ,asdo balanceproblems,mobilityimpairme nt,andch ron icpain relate dtodiabeticner vedisord ers(14). The p revalen ceofdisabilityan dfunct ionalimp airme ntisgreaterinolde rpeoplewit hdiabet esthanin olde rpeople with ou tdiabet es.Olderadultswit hdiabet esare abouttwotothre etime smorelik ely to haveph ysicallimitat ions(15)and1. 5timesmorelikelytoh ave ADL(act ivitiesofdaily livin g)disability (16)th anareth ose with ou tdiabete s.Muchofthisexce ssdisabilityisadirectr esultofcomplicat ionsof diabet es,su chase yedisease ,stroke, cardiov ascular dise ase, neu ropathy ,an dperipher alvascu lar disease (15). Becauseth ehy perglycemiacutoffpoint sforr iskofdiabete scomplicationsappeartoapplysimilarly to olde rand you nger p opu lations ,the ADAdiagnosticcriteriafordiabet esin adu lts aren otmodifiedbyt he pat ie nt'sage. Recen tly,seve ralstud iescomparingth egroupsiden tifiedby thepr eviou scrit eriaofthe World He althOrg anization(17)ve rsusth eADAfastin gglu cose criteria(18,19, 20,21)havebee n pub lished .Mosth avefoun dadecr ease dprevale nceofdiabete swith theADAcrit eria(19,22), although effect shav evariedindiffere ntpopulat ions(21).Althoug hthisdifferen ceinprev alence issmallin middle-agedpeople,itincreaseswithagebecauseold erpeopleare morelik ely toh aveanelevated2hour p ostch alle ngeglucoseleve lth an anelev atedfastingbloodglucoselevel.Inaddition, the t wo criteriaiden tifydiffe rent grou pswhomayhavediffe ren trisksforcomplicat ionsan ddiffe ren tou tcomes. Stud iesh ave suggest edthatfast in gglu cose lev elsmay notpredictprogre ssiontocard iovascu lardisease ormortalityaswellasanabnormalpostch alle ngeglucoselevel(20).Similarly,th eADAcategoryof impaire dfastingglucose(IFG)maynotpredictprogre ssiontotype 2diabet esaswellasIGTasdefined byanOGTT(23). Again thisdiscrepancymaybe morepronoun cedinolder adu lts. Reg ardlessofthee ffectoft hecu rren tdiagnosticcriteriaonde termin ationsofdiabetespr evalen cein
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olde radu lts, it isfar morecommon in rou tineclinicalpracticet oobtainafastingglucoseleve lth anan OGTT. Theclin ician can u seth eresu lt softh efastingg lu cosede terminat ionalongwitha2-hour glu cose levelifIFGoroth erdiabet esriskfactorsareprese nt. Itisimp ort ant toh aveahighinde xofsu spicion becauseofthe highpre valence ofkn own t ype2diabetes ,previouslyun diagnoseddiabet es,andIGTin olde rpeople ,allofwhichareassociate dwith excessr iskforat heroscleroticdise aseandmort ality . The refor e,anyelevatedfastin gbloodglucos eshouldbeevalu ate d,an difpr esen ton moreth an on e occasion ,shouldmandateth estartofp atient education regar din gglu cose in toler ance anddiabetes, management ofassociate drisk sforather oscleroticdise ase, and iffrankdiabet esisp resen t, management ofhyp erglycemia.
CHANGES IN CARBOHYDRATE METABOLISM WITH AGING

The p revalen ceofdiabetesandglucoseintoleran ceincre aseswithadvan cin gage .These abnormalit iesin car boh ydrateme tabolismhavefeature sin common, andt heglucoseintole ran ceassociate dwith aging increasesth eriskfor develop men tofover tdiabete s(24).Ther eisn oe vide ncetosug gestth atth e pat hophysiologyoft ype2d iabetesisan ydiffe ren tin olderadultsth aninyoun geradults.However , phy siologicchangesth atappeartoaccompanyth eagingp roce ssprod ucealte rationsofg lu cose metab olismeve ninvery health yolder in dividu als(25). These ch an gesar emanifested p rimar ilyasan elevation inpostpr andialbloodglucoselevels,whichmay incr ease byasmuchas15mg/dL(0.8mmol/L) per d ecade after t heageof30. Thete nden cyfor olderadultstohav ein creasedpostchallen geglucose levelsrelat ive tofastingglucosele velshasimplicat ionsforprev alence ofdiabet esin older adultsas define dbythe 1997ADAdiagnosticcrit eria(discussed in p reviou ssection ). The p ath oph ysiologyofthe chan gesinglucosetole ran ceassociate dwith agingh asbeen reviewe d(25). Glu cose absorption followingglucoseingestionmaybeslowedwit hincreasin gage ,an dsuppre ssionof he paticglucoseproductionisdelayed(mostlikelyas aresu lt ofdelaye din sulin secret ion). An umberof age -relate dchangesinre gulationofinsu linse cretionan din sulin actionhavebee ndescribed . Inadditiont ointrinsicchange sofag in g,extr in sicfactor smaycon tribute toglucoseint olerance. Both th edeclin einlean bodymassandth eincreaseinbodyfatt hat accompanyagin gmaycon tribute to insulinresistance. Levelsofp hysicalactivitydeclinewithage,andsu chchangesmayp recipit ateor acce le rate chan gesinbodycomposit ion. St udiesofboth masterathlete sandoldernonathlete ssugge st th atsome ofth esechange scanbe either p reven tedormodifie dwit hexe rcise .Dr ugscommon ly u sedby olde rin div idu als,includingdiure tics, estrogen ,sympath omimet ics, glu cocorticoids, n iacin,ph enyt oin, an dtricyclicantidepre ssan ts,can adve rselyaffect glu cose met abolism,exacerbatin gglu cos ein toler ance . Stre ssstate ssuchasmyocar dialinfarction ,infection,bu rns, andsu rger ycanworsen glu cose in tolerance an dprecipitat efastingh yperg lyce mia.
DIABETES AND THE PHYSIOLOGY OF AGING

Many effectsofdiabete sappeartoaccelerateage-re latedph ysiologicchanges. Forexample, the pre senceofdiabet escon fersondiabe ticwome nar iskofcardiovascu lardisease e qualtoth atforme nat th esameage (26).Someofthemech anismspresu medt ou nderliethisac cele rate dvascu laraging includee ffe ctsofdiab etesonplat ele ts,incre asedglycosylation ofvasculart issu es,andlipoprotein alte rationsassociated with diabete s( 27, 28,29). Ch ang esthatoccurwithdiabe tesandchangest hat occu rwit hagingmayint eract,espe ciallywithre spect tothe gene ralage-r elated d ecreaseinphysiologicreser vein manyorgansyste ms.Althoug hmost phy siologicsystems(car diovascu lar,r enal,p ulmonar y,cen tralne rvoussyste m)inolde rpeoplefunct ion P. 739 app ropr iatelyun dernormalstab leconditions,th eymaybe u nable tocopewitht heincre asedde mands posedbyacuteilln essor in ju ry.C omplicationsofdiabete sle adingtoen d-organdamagemayfur ther acce le rate thislossofp hysiologicre serve .Inaddit ion,t heclin icalman ife stationsofdiabetesmay stress phy siologicsystemseve ninthe absen ceoffr ank path olog y.Fore xample ,eve namildincre aseinur in e volu me in anolde rdiabet icpatie ntwithpoorly con trolledhy perglycemiamayexacerbatebladde r dysfu nction an dleadtourinaryincontinen ce.Glycosu ria,ev enwithout p olyuria,can leadtoele ctroly te imbalanceandcardiacarr hyth mias.
TREATMENT OF THE OLDER ADULT WITH DIABETES Determining Treatment Goals

The g oalsofdiabete sman age men tforolderpatient saren ot d iffere ntfromthosefor oth erpatients, and aswith p atient swith diabete sofanyage ,includefarmoret han treatmentofhype rglycemia.These goals ar esummarizedinTable43.2. TABLE 43.2. Treatment Goals for Older Patients with Diabetes
Alleviationofsymptomatichyperglycemia
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Monitoringforandtreatmentofdiabetescomplicationsandrelatedcomorbiddisease Preventionofthedevelopmentorworseningofdiabetescomplications Diabetesself-managementeducationandcounseling Identificationandtreatmentofriskfactorsforatheroscleroticdisease Improvedgeneralhealth,includingfunctionalabilitiesandnutritionalstatus Identificationandmanagementofcomorbidity
Itisimportan ttocon side rthe similarit iesanddiffere ncesbet ween olderandyoung erpeoplewit h diabet esan dthe irimpactondiabe tesmanagement .Lik eyounge rpeople with diabete s,mostolder peoplewit hdiabet esare highlyfun ctionalandactiv ean ddeserv ethe sameatt entiontodiabete s management asdoy ou nger p atient s.Forboth agegroup s,macrovascu larcomplicationsareth emajor cau sesofmorbidit yandmortalityrelat edtodiabete s.Forboth agegroup s,co-occur rence ofothe r at heroscleroticrisk factorsare freque nt, andt heman agemen tofsu chassociated r iskfactorshasbeen showntohaveafavorableimpactonmorbidityan dmortality(30). Finally,th emanagement ofdiabet es formostpeoplewit hdiabet es,re gardlessofage, hasb eensh own tobe in adeq uat e,withpoor physician an dpat ien tadh ere ncetopublishedgu id eline sand r ecommendation s(31,32,33,34, 35). Someke ydiffe rence sbetwee nolde rand you nger patient swith diabete scanaffectmanagement .The olde rpopu lation isve ryhe terogen eou sbot hwithre specttothe irdiabetesandth eirgene ralhe alth status. An olderpatient with newlydiagn ose ddiabete smaytrulybe anewdiab eticpatien t,withn o eviden ceofd iabetescomplicationsan dcomorbidities;mayh ave hadIGTor undiag noseddiabet esfor yearswithcomplication sprese ntatdiagnosis;ormayh ave n on eormanyre latedorun relate dcomor bid disease sandd isabilitie s.Someolde rpat ien tsmaybemoresymptomaticfromhyper glyce miat han are young erpat ie ntsbu tare alsomor epronetocomplication softr eatmen t.Fin ally ,specialevalu ation an d tre atment goalsmust b edevisedforfraileld erlypatien ts(i. e., thosewhohavemultip lecomorbidities an ddisabilitiesan dasignificantlyimpair edphy siologicreser ve). Becauseofthiscomplexityandhe terogen eit y,selecting appropriate manage me ntgoalsforolderpatie nts withdiabe tesshouldbebasedonade tailedevalu ation.Acomplete histor yand physicalexamination shouldbedone atth etime ofdiagn osis,whe ncontrolofhy perglycemiaan drisk factorsisinadequ ate ,or whe nare assessmen tofth epatie nt'sstat usisn eede d.Diabetescomplicationsan dthe presen ceofrisk fact orsfordiabet iccomp lications,aswellasco-occurring d iseasesanddisord ersan dgene ral fun ction in g,mu stbeassessed. Akeycompon entofthe med icalh istoryforallpatien tswit hdiabete s,but especiallyolderpatient s,isa th orough evalu ation ofth eirme dication s,includingpre scrip tionandover-t he-coun terdru gs,alt ernative medication s,anddietarysupplemen ts.Olderpatie ntscommonlytake sever almedications, anddr ug dru gin teraction s,dru gdisease in teraction s,an din creasedexpe nsecanbepr oblematicin pat ien ts takin gmu lt ipledru gs. Lab oratoryevalu ationsan dsubspe cialty referr alsrecommende dfor olderpatie ntswithdiabetesarenot subst ant iallydifferen tfromth ose formid dle- agedpatients with type2diabete s,excep tin unu sual circumstan cessuch assev erede bilitationoradvancedde me ntia.L aboratorye valuationsh ou ldinclude det ermin ation soffastin gseru mglucoselevel,glycosylated h emoglobin (HbA 1 c )(t oassessprev iouslevel ofcont rolan dtobeuse dasabaselin e),fastin glipidprofile,andser umcreat in in e;urinalysiswith examination forpr ote in uriaormicroalbuminur ia;andanelectr ocardiogram. TheADAr ecommends ophth almologicevalu ation att hetimeofdiagn osisan dyearly forallpat ien tswithtype 2diabe tes(12), ar ecommendationt hat applie stoe lde rly patien tsaswell,whoareathighr iskforoculardiseasesot her th anr etinopath y. Rec ently,t heAmerican Ger iatricsSocietyandth eCalifor niaHealth care Foun dationconven eda multidisciplinaryex pertpaneltodevelopevidence -base dguidelin estoimprovediabet esmanagementin olde radu lts(36). Amajorrecommen dationwasth atman age men tbeindividualizedaccord in gtoh ealth statusandpre fe ren cesoft heolde rdiabete spatien t.The yalsor ecommende dthatane valuationofan olde rdiabete spatien tin clu descre eningandmanagement ofgeriatricsyndromes:polyph armacy, cognitiveimpairmen t,depr ession ,falls, urinaryincontinen ce,andpain .Geriatricsyn dromesaremore common in olderadultswithdiabe testh aninth ose with ou tdiabet es.(See refere ncedgu ide line sfor det ails. ) Forman yolder patient swith diabete s,espe ciallyth osewith se veralcomorbidcondition sand geriatric syn dromesand/orproblemsman agingth eirdiabet es,acomprehe nsiveger iatricevalu ation ,somet imes
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alsoreferr edtoasage riatricorfunct ionalassessment, isindicat ed(36a, 37). Thisisamultiface ted asse ssme ntofthepatient 'scapabilitiesfor self-care, in clu din gADL(bathing, groomin g,dres sin g, feed in g,toileting, an dtran sferring)andinstr umentalADL(e.g .,shopping, telephoning, fin ance s,an d house work ),an din dicatesth eamount ofassistance, ifan y,th att hepatientn eeds. Italsoinclude s asse ssme ntofnut rit ionalstatus, evaluation forpossible depress ionorcogn it ive impairment ,an d evalu ationoft hepatient'ssoc ialsu pport systems,finan cialandinsu ran cestatus,andadvan ceme dical directives. Nursingandsocial-workas sistanceisinvalu ablefor both geriat ricassessmentanddiabe tes teachingandself-management su pport.Th esehe althprofessionalscan helppat ie ntsandth eir familie s acce sssupportser vice savailableinth ecommunity. Forsomep atient s,refe rraltoager iatricianmaybe ne cessar y.
Symptomatic Hyperglycemia in Older Patients

Aging-re latedchange sandincr ease dcomor bidcondition smakeolde rpatien tswit hdiabet espar ticu larly vu ln erablet o P. 740 symptomsofhyper gly cemia, even ifth ose sympt omsare notthe classic sy mptoms.Symptomssuch as falls,fatigu e,dizziness, andincr ease din con tin ence mayofte nbet raced b acktohype rglycemiaassociate dpolyur ia.Glycosur iamay alsobe associatedwithweight losscau sedbyth elossofcaloriesin th eurine .Old erpeoplemaybeatin creasedriskfor depletion oftracen utrien tsan dminer alscause dby osmoticdiu resis.Magn esiu mandpotass iu mdeficienciescan havedelete riouse ffectsoncar diac conduct ion. Glycosuriacanalsoinc rease phosphateexcr etion ,whichcanacce le rate calciu mlossfrom bone(38). An impaired ce ntr althirstre spon sein older peop lemaycont rib utet oth evolu mede ple tion due toosmoticdiure sisfromh yperg lyce mia.C le arly,e limination ofglycosu riaisanimport ant th erap euticgoal(bloodglu cose lev elapproximat ely200mg/dLor 11mmol/L)in older p eop lewith diabet es. Weight losscau sedbyun con trolledh yperglyce miacan beasign ifican tproble m.Patien tswit hweight loss maybeinacon stan tcatabolicstat e,whichcanlead t oloss ofmu sclemass,weakness, and p ote ntiallyto fallsandinjur y.Olderpatientsmayn ot perceiveincr eased h un ger,insomecasese xace rbatingp oor nu trition alstatu s.The associatedcatabolicstatemaypre disp oset oinfect ionsandother complicat ionsof malnut rit ion. Anincre asedconce ntration ofglucoseorit smet abolitesint helensandaqueoush umorofthe eyecan leadt ovisualproblems.Hyperg lyce miamaypr edis posepatient stobacterialandfun galin fection and increasedpain percep tion(39)andmayalte rplateletadhes ive ness, worsen in gin ter mitten tclaudication. Lipid abnormalit iesalsoworsenwithpoorglycemiccontr ol,an dhightr iglycer ide lev elscanpre disposeto pan creatitis. Acarefu lse arch forsu chsymptomsofhyper glyc emiaisclearlyindicate din elderlydiabet ic pat ie nts. Inman yolder p atient s,symptomsas sociate dwith diabete sand h yper glyce miamaybe atypical.For example, hyper gly cemiadoesn otu suallyleadtodramaticp olyuriaandpolydip sia;moreoftent here will beincre ased incont in ence ,au rin ary t ract infe ction ,or inc rease dle thargyormen talconfusion.Similarly, un diagnosedorun manag eddiabet esmaymanifestasin crease dbacte rialorfu ngalinfectionsoftheskin, un explaine dweigh tloss, in crease dfatigue ,or slowwou ndhe alin g.Incr ease dpare sthesiasand weakness, ort hostat ichy pot ension wit hfalls, ord ecreasedvisionalsoshouldraisesu spic ionfor un diagnosedorinade quatelymanageddiabet es. The mostsever ecomplication ofdiabe tesinolder in dividu alsishy perglycemic h yper osmolar n on ketotic coma.Thiscon dit ionisseen almostexclusivelyinolde rpatien tswit hdiabet es.Itisoftenpr ecipitatedby acatast rop hice ven t,such asmyocardialin farct ionorstroke, andcansomet imesoccurinpe oplenot pre viouslykn ownt oh avediab etes. Detailsofin patien tmanag eme ntarediscussede lse where in this volu me (Chapter65).
Management of Atherosclerotic Risks and Complications

Fin din gsfromth eUKPDSandother studieshavemade itclearthattre atment ofassociate drisk sfor at heroscleroticdise aseisamajor goalofdiabete smanage me nt(40).Ahigh erproportion ofolde rthan young erpat ie ntswithdiabe tesh aveassociat edhype rten sion, hype rlipidemia,an dath eroscle rot icarter ial disease (41,42,43,44, 45).Alt hou ghfewe rolder thanyounge rpeople smokecigar ettes ,smokingcessation p rogr amsshouldbeen cou raged forth ose whod osmoke (46).Old erpat ie ntswithdiabe tes havebee nshownt oben efitasmuchasor moreth anp atient swith ou tdiabet esfromtre atmen tof hy perte nsion (47). Me ta-analysishasshownaspirinu setob ebene ficialinolder patien tswit hdiabet es whoare atriskforath erosclerosisorhaveat her osclerosis (48). Treat men tofh yper lipid emiaindiab etic pat ie ntswithcardiovasculardiseasehasbeen showntobeben eficialan dmaydecr easemortalityamong th osewh omayde velopcardiovasculardisease;noage limith asbee ndefined ( 3),alth ou ghth edata av ailable on p eopleolderth an75ye arsarelimit ed.Periphe ralvascu larocclusive d iseasean d amput ation sin creasewithag e;the refore,mon it oring ande valuationforcirculatorypr oblemsare indicate d.Pr even tat ive t reatme ntandmonitoringforcomplication saren ot appropriate forth efewolde r pat ie ntswhoar ein apre terminalstateorhav eadvance ddeme ntia. Mostolde rpeople ,eve nthosewith
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comorbidit iesanddisabilit y,willbene fitfr omin terve ntionsshowntoprev entorslowanincreasing bur denofillnessoveraperiodofseve ralyears.
Management of Microvascular Risks and Complications

Many dialysispatie ntsolde rthan60havediabe ticrenaldisease,andbecauseofthe in creasin g pre valence ofdiabe tes,th enu mbe rofolderpeoplewhohavediabet icre naldisease isincre asing. Cu rren tly,tre atment ofhy perte nsion andh yperg lyce miaareth emajorre comme ndedint erven tion sfor pre vent in gend-st agere naldisease duet odiabe tes(10).The seinter vent ionsareapp ropr iateformost olde rpatien tswit hdiabet es. Pe ripheraln eur opathyleadin gtopain,n eur opathicjoints, wou nds,mob ilit yproble ms,andampu tations contribut estodisabilityan dpoorqu alit yoflife in olderpatients. Thelit tle evidence availablesu ggests th atfoot careandmon itoringmaybe associatedwithbe tter ou tcomes. Although macu lardege ner ation ist hemajor cause ofblin dness afterage65,poorvis iondu etomacu lar ede maorothe rdiabet es-relat edeyediseaseishighlyprevalentamongolderpeoplewit hdiabet es. Simulat ionsh avesu ggeste dthatfewolde rpersonswithn ew-on setdiabe teswillbecome blindbe cau seof diabet es(49).However, it isimportanttoremembert hat mostolder peop ledonoth aven ew-on set diabet es,man yhav ehaddiabete sfor10yearsormore, andt hetr uedu rat ionofdiabetesisnotkn own formanyothe rs.Ey edise asee ith erdu etoorr elatedt odiabe tesisprevale ntinsuch pat ien ts. The refor e,ye arlyophth almologicrefer raliswarran tedformostolderpeoplewit hdiabet es.
Treatment of Hyperglycemia
Whilethe reisbroadag reement thatsymp tomat ich yperglycemiashouldbetr eate din allolderpatie nts reg ardlessofhealth stat us,th ere ismuchmorecontrover syregardingth ebene fitsofaggr essivecontrol ofasymptomat ich yperglycemiainolde rpatien ts.The UKPDSdemon stratedth atlowe ringglucoselevels red ucedriskofmicrovascu lardise ase(50). Observation alstudiesinolde rpeople alsosu ggestth at improved g lyce miccon trolisassociated with improvedoutcome sbothmacr ovascularandmicr ovascular. Thu s,alth ou ghth ebene fitsofglycemiccontr olin olderdiabetespatients h ave notbeen demon strat ed conclusively,th eweightofavailab lee vide ncesu ggestsitisbene ficial.The physicianandth eolder pat ie ntmustde cide wh ent igh tglycemiccontr olforpote ntialpreve ntionoflong-ter mcomplicationsof diabet esisareason ableth erap euticgoal.Ifthe decisionismadetoatt emp t,glycemicgoalswouldbe exactlythe sameasth ose formidd le-agedpe ople. Seve ralargu me ntsh avebe enmade against choosinganagg ressivemanagement p rogr amforold er adu lt swith diabete s.One suchargumen tist hat someelderlypat ie ntsmaybe lesscapableth an you nger pat ie ntsofcarry in gou tactivities P. 741 req uirin gthe highlevelsofskill, commitment ,an ddiabete seducation n ecessarytoach ie vin gan agg ressivetre atmen tgoal. Howev er,wh ilemethodsoflearningandmemory doch ange with age, most olde rin div idu alsarefu llycapableoflearningcomp licate dcon ceptsandtasks(51).Tot hee xten tthat olde radu ltsleadalesshe ctic, moreorder edlifeth an you nger adults, itmayactuallybee asierforthe m tomaketh etype ofadju stme ntsinlife stylenece ssary foradhere ncet oag ooddiabete streatme nt program.In fact, recen teviden cefromNHANESIII(52)andacommunitypopulat ioninMich ig an(53) sugg estth at, onaverage,glyce miccon trolinolde radu lt smaynotbean ywor sethanth atinyoun ger peoplewit htype 2diabet es. Acommon argu men tagain stag gressivediabe tesmanagementinolderad ultsisbasedoninaccu rat e estimate soflifee xpectancy(i.e. ,whyt rytopreve ntcomplicationsinsomeone wh oislike lytodie soon ?). Howeve r,th emedianre main in glifeexp ectan cyforin div idu alsaged65ismoret han 17year s; forthoseag ed75,10years;an dfort hoseage d85,6ye ars(54).Fur ther more, t hese medianestimates willbeexce ededby approximately50%ofthe people in agivenagecohort.Thu s,th ereissubst ant ial time forth edev elopment ofdiabet escomplication sin patien tswhosediagnosisismaded uringth eir60s or70s. Itisalsoclearthatelderlyindividualsar esusce ptib let ovirtu allyallofthech roniccomplicat ionsof diabet es.Ageanddiabe tesfreq uen tly in teracttoworse nthe risk forman yofth esecomp lications.For example, creat in in eclearancede cline swith normalaging(55),andage isanindepe nden triskfactorfor th edeve lopme ntofperiphe ralneu ropath y(56,57).U ntilst udiesare availablede monstr atingth att he risksoft igh tglycemiccontr olou tweighth eben efit sin olderadultsorthatglycemiccontr oldoe snot pre vent t hede velopmen tofcomplications,man yelderlypatien tsdese rveth esameconsiderationas young eradu lt sregardingaggr essivemanagementofthe ir disease. Someold erpat ie ntswhohavealimitedlifeexpe ctan cy,multiplech ron icd iseases,fu nctionalor cogn it ive impairmen ts,poor socialsupport, orwh otakemultiple medicat ions, areclearlynotcan didatesfor agg ressivemanagement ofhy perglycemia(seeFrailOlde rPeople).Forthe sepatien ts,tr eat men tof symptomatich yperg lyce miaandmonitoringandmanagin gcomplication sandcomorbiditiesare in dicated. One prop osedwayofde ciding abouttight glyce miccon trolforag ive npat ien tistoconsider wh eth erit wouldbeofe ith ern oben efitor highrisk(30).For olderpatients, char acte rist icssu chasfre quen t
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hy poglycemiaor severe cogn it ive impairment wouldsugg esthighr isk, where asapr eter minalstateor adv ance ddisabilitywouldsugge stthatit wou ldn otbe bene ficial. Once theleve lofcare isdecided ,subse quen tmanageme ntofolder adultsbecomescleare r.Insh or t,th e tre atment regime nchosen isth eonene cessar ytoachieve treatme ntgoals.The fou rstan dard modalit ies ofd iabetest herapyd iet ,exe rcise ,oralhypoglycemicagent s,an dadmin ist rationofinsu lin allmerit considerationforolde radu lts.
DIET
The r oleofmedicalnu trition althe rapyh asbee nsubst ant iallyre defin edbyth eADA(58), andt here isn o un iformlyr ecommende dADAdiet.In gene ral,dietaryth erapy mu stbeindivid ualizedtosupportth egoals ofd iabetesman agemen t;thisistrue forolderaswe llasyoun gerpatie ntswithdiab etes. Whilewe igh t lossinoverwe igh tpatien tswit hdiabet eshasmanyben efits(improvedsh or t-termglycemiccontr ol, improved b loodp ressur ean dlipidprofile,andimproved g lu coset olerance), ith asproven difficultfor peopleofanyage.The refore,t hegoalofdiet aryth erapyis n ot specificallyweightloss.Rather , nu trition alther apysh ou ldbe designedtocontribu tetoopt imalgly cemic,lipid, andb loodpr essur e management .Inobesepatients, thismayincludeh ypoc aloricdiets,bu titisimport ant tor eme mbe rthat upt oonet hirdofold erpat ie ntswithdiabe tesarenotobeseandsomeareu nder nou rished. Inth ese un dern ou rish edpatie nts, caloricsup plemen tat ionan dreve rsalofacatabolicstat ewou ldbe importan t. The ADAhasr ecognizedth isfactwit hspecialrecommen dationsfor in stit ution alizedpat ie ntswith diabet esthatincludeanincre aseincaloricin take wh en appropriate (58). Olderpatie ntswithdiab etesoften hav emu lt ipleissuest obeconsider edin anu trition alprescription. The sein clu deap propr iatecalorictarge ts,micr on utrien tasse ssmen t,andth eroleofdietarymanageme nt forassociatedh ypert ension ,hy perlipidemia,andre naldisease ifpre sent. Inadd ition,old erpat ie ntsmay haveproblemswith shoppin g,finan ces,ormealprep arationt hat may becomee vide ntonlydur in ga dietaryasse ssmen t.Th erefore, d iet arye ducationandsup port in nut rit ionalself-management r emain important.
EXERCISE
Exe rcisehasbeen s hown toimproveglucosetole ran cean dtobe usefu linchr on icglycemiccon trolin per son swith type2diabete s(59) .Howev er,amu chbroade rcon sensu sregardingth eben efit sof exe rcis eise mer gin gu nfor tun atelywithout s pecificclin icalre comme ndationsr egar din gexer cise pre script ionsforolder patien tswit hdiabet es.Adecre aseint helevelsofp hysicalactivityinth e populationhasbeen linke dtoanincre aseinth epre valence ofobesityan dtype2diabet es;the roleof exe rcis easpartoflifestyleinte rven tioninth epre vent ionoftype2diabete siscu rren tly u nde rstudy (60).In oth erch ron iccondition s,includingh yperlipide mia,h ypert ension,ather oscleroticheartdisease, an deven heartfailure ,exe rcise appearstocon ferth erapeuticben efits,alth ou ghmore specific information isne eded. Even in frailolderpatie nts, resistan cean daer obicexer cise shav ebeen shownto haveobjectivean dsubject ive b enefits(61),alt hough su chbe nefitsmaybesh ort -lived. Cu rren tly,exe rcise recommen dation smu stbeindividualizedforpat ie ntswithty pe2diabe tesre gardless ofage. In older patient sforwh omthe goalsoftreatmentinclude preve ntion ofdiabe tescomplications an dglycemiccontrol,an exer cisep rogr amispartofadiabete sself- carer egimen .Clinicalju dgme ntis ne ededre garding exercisere comme ndationsifclinicalorpreclinicalcardiovascu lardise aseissuspe cted. Infrailelderlypatients, someformsofexer cise may beappr opriatean dmaybedirect edatconditions other thanth eir diabetes. Unfortu nately,desp ite theman yprovenorsu spectedbe nefitsofexercise, th ereisnocle arconsen susonpre cise lywh atex erciserecommen dationorwhat preex erciseevalu ationis app ropr iateforan ypatien twit htype 2diabet es,re gardlessofageorh ealthst atu s.
ORAL MEDICATIONS
Seve raldiffe rent classesofmedicat ionsth atworkbydiffere ntmechanismsarecur ren tlyavailableforthe tre atment ofh yperglycemia.Most hav ebeen teste dtosomedegre einolder patien ts,sobene fitsand concern saboutt heiruse in olderpe oplewithdiabe tesh avebe eniden tified. Inolder patien tswit h diabet es,combination ther apyforhyp erglycemiathatisb asedoncomplement aryaction sofdifferen t dru gscan b eused. Ingen eral, thepoten tialbene fitofimprovedcont rolofh yperg lyce miawithoutt he use ofinsulinmustbe b alance dagain stpot entialrisksassociate dwith ahigh erprev alence of contrain dication stos omedru gs,polyph armacy ,decre asedcomp lian cewit hmu lt idr ugth erap y,an d increasedfinancialburde n.Atth ist ime,t here isn oconsen susonwhatcon stitut esthe bestap proachto pharmacologicther apyforhype rglycemiain olderadults. P. 742
Sulfonylureas
The su lfony lu reash ave man yadv ant agesforth emanageme ntofhype rglycemiainolderpatie ntswith diabet es.Fir st,th eyar eefficaciou s,withproven abilityt odecr ease Hb A 1 c leve lsbyu pto3%to5%,an d th ereisnoevidenc esugge stin gthatth esedru gsare anylesse ffe ctiveinolder adultsth an in y ou nger adu lt s.Thes edrugsh ave been availableformanyye ars,sophy sician sandp atient sarefamiliarwit h
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th em. Theyh aveagoodsafe typrofile, ane asydosin gsched ule,an dar emu chlessexpe nsiveth ann ewer oralage nts.Th eyremainfirst-lineagent sforanyolde rpatien twit hdiabet esfor whomth edecisionh as bee nmadetotre ath yperglycemiawit hmedication s. The majorriskfor olderadultstre atedwith sulfony lu reas ishy poglycemia.Although hypoglycemic at tacksarere lativelyrare ,withat tacksleadin gtohospit alization r eportedt ooccurwithafrequ encyof 1. 23casespe r1, 000pat ien ttre atmen tyears(62),age alon eisasign ifican triskfact orfor hy poglycemia.The rearemu lt iplefactor sassociatedwithagin gthatmigh tin creasethe risk for hy poglycemia.The seincludeage-associate dimpairment sinh epaticandre nalfun ction t hat alterdr ug metab olisman dexcre tion. Theimpair men tofh epaticoxidative p ath waysassociate dwith agingmay increaseth ehalf-livesofsu lfonylur eas, whichare me tabolized e xten siv ely bythe liver. Renalfu nction, asmeasured b ycreatin in eclearance ,declin eswithag e(55),an din sulin cle aranceh asbee nshowntobe red uced(63).Agingalsoisassociatedwithimp airme ntsinth eau tonomicnerv ou ssystem(64,65)an d red uction sin -adre ner gicre ceptorfun ction(66), suggest in gthatth esensation ofglycemiamaynotbe asacute in olderadultsasinyoun geradults.The elderlyare freque ntu sersofdrugsth atarekn own to increaseth eriskfor h ypogly cemia, in clu din g-adr ene rgicblockers, salicylat es,warfarin, sulfonamides, an dalcoh ol.Th elonge r-act in gsulfon ylu reas,glyburideandchlorpropamid e,havebee nre port edtocause more episodesofhyp oglycemia(67).Hyponatremiahasalsobee nsee ninolder diabetes p atient susing chlorpropamide ,ade velopmen tthatmaybere latedtoadr uginte ractionwit hth iazide diu retics(68)an d intrinsicchange sin watermetabolismwithaging.
Biguanide
Metformin, the onlybiguanidecur rent lyavailableinthe Unite dSt ate s,hasboth advantagesand disadvantagesfortreatmentofolder patien tswit hdiabet es.Ch apte r41hasrevieweditscharact eristics indetailanditsprovenbe nefitinobesetyp e2diabe tespatie nts(69). Amajoradvantageofmet formin forolderpatient sisth at, becau seofitsmechanismofact ion,itdoesnotprodu cehypoglycemiawhen use dasasing leagent .Inaddit ion, itsassociat ionwithweigh tlossispote ntiallybene ficialtoobe se olde rpatien tswit hdiabet es,alth ou ghu ptoone t hirdofolderdiabe tespatie nts, e specially t hefrail elderlyand/orthoseinnu rsinghomes,arenotobeseandmayn otbe goodcan didatesformetformin. Olderpatie ntswithh yperlipide miamaybe nefitfromth efav orable effectsofme tfor minonlipidprofiles. The majordisadvantageofmetformin in olderpatient sisitsinter action wit hcomorbidcon ditions,man y ofwh ich are prevale ntinolde rpatien ts.Itisrelat ive lycont raindicat edin the presen ceofc ong estive he artfailur e,live rdisease ,an despeciallyrenald isease.It shouldnotbeuse difth eseru mcr eatinine exce eds1. 4mg/dL(124mol/L)(women )or1.5mg/dL(133mol/L)(men). Since the s erumcreatinine valu ewillove restimateth ecreatinineclearan cein an olderpatientwh oh asdecr eased musclemass, an eve nlower serumcreatininelevelmaybeacau sefor conce rninsu chapatient. There fore ,th eprese nce oft hese con ditions,e venifasymptomatic,mustbecarefu llyasse ssedinolder patien ts. Anothe rpotent ialdisadv ant ageofme tfor minisitsg astrointest in al(GI)sideeffe cts,gen erallybloating an dflatulen ce,which may affectold eradu lt smoreth an you nger adults. Howeve r,itisn ot known whe ther olderpe oplearemore likelythanyoun gerpeopletodisc ont in uemetformin becau seofGI symptoms. Metformincostsmor ethanth esulfon ylureame dication sandinsu linbu tlessthanothe roralagen tsused fortreatingdiabet es.
-Glucosidase Inhibitors
Acar boseandmiglitolare-glucosidaseinhibitors,whichde layabsorptionofsu gar sthrough the GItr act. Becausepostprandialhyp erglycemiaisparticularlycommon in olderpe ople, these agen tsmaymerit consideration. Theylowe rHbA 1 c le velsb yabout1%(onaverage)(70).Bec ause ofth eir mech an ismof act ion, t heyd onotcauseh ypog lyce mia,bu tth eiruseincombination with an oth erhy poglycemicagen t maymakeitmor edifficulttotre athy poglycemia.Th emostcommon side effectsareGI.Although they donotcau sesymptomsofmalab sorpt ion, t heypote ntially canleadtowe igh tloss.Th esedru gsare cur rent lymoreexpe nsiveth ansu lfonylur easorinsulin.Although the irsafetymake sthe mat trac tive for elderlypatie nts, thepote ntialforwe igh tlossan dGIsidee ffectslimit stheiru sefor olderpatientswith diabet eswhoare unde rnourishe d.The seagen tscan beuse daspartofcombin ationth erapy .Theirus ein combinationwith met formin maywor senGIdiscomfort .
Thiazolidinediones
The t hiazolidined ionesimprov ein sulin sensitivityan dthu scou ldbe ofparticularbe nefittoolderpatient s withdiabe tes,wh oinaddit iontohavin gdiabete s,mayhaveagin g-associatedinsu linr esist anc e.The se dru gshav emoder atepote ncy,lowe ringHbA 1 c byupt o2%to4%(71),alt hou ghitisnotknownifthisis differen tin older p atient swith diabete s.Twoth iazolidinediones, p ioglitazon ean drosiglitazone ,ar enow av ailable .Thedr ugsar ecurr entlyve ryexpe nsive,limitingth eir useforlow-incomee lde rly patien ts. The ymaybeuse daspar tofcombin ation the rapywh enone agen talon eisin sufficien ttoachiev edesired controlofhy perglycemia.
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Meglitinides
Rep aglin ide isth efirstofanewclassofor alhypogly cemicsth ate nhanceinsu linse cretion ,bu tbya mechanismdifferen tfromth atofthe sulfon ylu reas.Repaglin ide actsrapid lytoen han ceinsulinsecre tion , soitisdesigne dtobe usedimmediat elybeforemeals.Itisofmod erat epotency andiscurr ent ly expe nsive.Nospecificinformation isy etavailable r egar din git suseinolde rpatien ts.Ifu sedasaddit ive th erap ywith sulfon ylu reas,repaglin ide presumab lycouldin creaseth eriskofh ypoglyce mia.Th eroleof rep aglin ide in olderpatientswith d iabetesawaitsfurt herclinicaland t esting.
D-Phenylalanine Derivative
Nate glinideisth efirst ofan ewclassofhypogly cemicage ntt hat isade rivativeofthe amin oacidDphe nylalan in e.Itbe cameavailable forclin icalu sein2001.Nat eglinideactsdirectlyonpancreaticD-cells torapidlystimu lateinsu linsecr etion .Becauseofther apidon setandshortdu rat ionofaction,itwas deve lopedt oaddressmealtime need sforinsu linsecr etion .Itistob etak ensh ort lybe fore ame alata standarddose of120mg,alt hougha60-mgdosealsoisavailable.Becauseofth eglu cose -le vel depe nden cyofitseffe cton in sulin secret ionanditsshortdu rationofaction ,itsuseh asbee nassociate d withalowrate ofhy poglycemiawhe nused alon eor incombin ationwit hother agen tssuch asmetformin. The rear ecurre ntlynokn owndr uginte ractions,andnateglinidecan beuse din patien tswit hren al insufficiency.
P. 743
Combination Oral Agent Therapy

The man yor alhype rgly cemicdru gsnowavailablehavecomp lemen tary mech an ismsofactions, the reby providin garation alefor multidru gther apytoat tempttoachieve thed esir edlevelofglycemiccon trolin pat ie ntswithoutr esortingtoin sulin .Inaddition, theavailabilityofnewe ragen tsbringsint oth eclin ical ar enaphysiologicconsider ation saboutt ype2diabetesth at p reviou sly we reconsidered primar ilyin rese arch settings. Howev er,t heclin icalimport ance ofspec ifically t arge tin ginsulinresistance, hy perinsulinemia,orglucosetoxicity remainstobedet ermin ed.Some advantagesan ddisadvantagesof combinationoralagent t her apyaresummarizedinTable43. 3. TABLE 43.3. Combination Oral Therapy of Hyperglycemia in Older Patients: Advantages and Disadvantages
Advantages Improvedglycemiccontrol Potentialmetabolicbenefitsduetodifferentdrug mechanisms Maybeeasierthanmultidoseinsulin Cost
Disadvantages
Increasedhypoglycemiarisk
Mayworsengastrointestinalsymptoms Riskofadversedrugeffectsduetopolypharmacyand comorbidity
Maybesaferthanmultidoseinsulin
Aswit hother diabetesman age men tdecision s,the choicet ou secombinat ionth erapytoachieve improved g lyce miccon trolinolderpat ie ntsre quiressome sp ecialconsider ation s.Itisimportantto ree valuateth eglycemictarget t ose eifcomb in ation the rapyisstillapp ropr iate.In thosehe althy older pat ie ntswithdiabe tesinwhomthegoaliscon trolofhyper gly cemiaforitspot ent ialbe nefitstodecrease fut urerisks, combin ationoralage ntth erapymu stbecarefullymonitoredtomakesu reitach iev esthe tre atment goal. Insomeolderpatie ntswithdiabe tes, e specially t hefrailest ,proble msanddifficu lties withinsulinuse are likely,andinsulin-induce dhypoglycemiamaybeagr eat errisk.The useof combinationoralagent t her apymaybe e asierandsafe rfor someoft hesepatient s,althoug hsomeoral age ntre gimen smayalsocauseh ypoglyce mia. Seve ralot herconsideration sare e specially p ertine nttoolder patient s.First ,the yare mu chmore likely tohaveacondition or cond itionsth atmaybe cont raindicat ionstoth euseofsomeofthe d rugsinth e combination. Second,old erpat ie ntswithcomorbiditie sandd iabetes-r elatedcomplicat ionsarelike lyt o bere ceivin gmanyothe rme dication s.Polypharmacyan ddrug-d ruginte ractionsar eamajor con cern, eve nifallth edru gsbeinguse dare ind icated.Finally,exc eptforin sulin and t hesu lfonylur eas, t hese dru gsare v erycostlyan dpatien tsmaynotbeable toaffordt hem.Fin anc ialconsideration scanleadto problemsinpatients e it herwitht hese medicat ionsorwithne cessar yme dications forothe rcon dit ions. Res earch isclearly need edtoassessth esafe tyan defficacyofspecificoral-age ntcombin ation the rapyin
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olde rpatien tswit hdiabet es.
INSULIN
Although t heinitiationofinsu lint herapyissometime scon side redtobeadifficultan dmome ntousste p foranolderpatie nt, in sulin isindicate dforanypatientwh ent reat men tgoalsare n ot beingmetwithout it.Nost udieshavedemonstratedt hat elde rlypatien tsare unable tou seinsulineffect ive lyandsafely . Insu lint herapycan resu ltine uglycemiain thosepat ie ntsforwhomth isisth egoalandsh ou ldalsobe use dfore lde rly p atient swith symp tomat ich yperglycemiawhoseglucoselevelscan notbecontrolle dwith dietandoralagen ts.Some advantagesan ddisadvantagesofinsu lint herapyinthe popu lation are summarizedinTable43. 4. TABLE 43.4. Insulin Therapy in Older Adults
Advantages Glycemiccontrolgoalsachievable Relativelyinexpensive Decreasespossiblepolypharmacy Avoidsgastrointestinalsymptomswithmultiplepills
Disadvantages Requireshomebloodglucosemonitoring Injections,oftenmultiple/day Overallcomplexityofregimen Risksofhypoglycemia
Nospe cialinsu linr egimen shav ebeen ide ntifie dasbeing moreorle ssefficaciousinolderpatie nts. Asin young eradu lt s,itispr obably d ifficulttoachieve normoglycemiawith asingledoseofint ermediate act in gin sulin .Ther efor e,whe nag gressivemanagement isindicate d,asp lit-mixe dregime nisusually ne cessar y.Newrapidlyact in gin sulin analogu esoffe ranopportu nitytotarg etpostprandial hy perglycemia,whichispar ticu larlyprevale ntinold erpeople.Asingledoseofinsu linmaybe app ropr iate,h owe ver,t opre ven tsympt omatichy perglycemiawhen thisist hetr eat men tgoal. Insu lint herapydoesrequ ir esomespe cialconsideration swh en u sedinolde radu lts .Agin galon e,or complication ssecondar ytodiabetes, mayimpairvision andt hefine-motor skillsnecessaryforin sulin administration. Bloodglucosemon it oring ,in dicated forpatie ntst reat edwit hinsulin,re quiresaddit ional skillsth atmayalsobeimpair edwit haging ordiseaseprocesses. Hy perglycemiaan dpoordiabe tes controlmaybeassociated with subtleimpair men tsofc ogn itivefu nctionin older adults(72,73). Such impairmen ts,combine dwit hthe highpre valence ofcognitivedisord ersinolde rpopu lation s,may adv erselyaffe ctthe abilityofan olderindividualtoadh eret oacomplicat edinsulinregimen. Olde r pat ie ntswithdiabe teswholive alon ewit houtadequatefamilyorsu pport servicesmaybe atincre ased riskfor seriou sseque laeofinsu linadministration (i. e.,h ypoglyce mia). Howeve r,n one ofth ese considerationsisan absolu tecontr aindicationtoin sulin the rapy. Ifp roblemsare recognizedbe fore orat th etimeofinstitut ionofin sulin ther apy, s olutionscan usuallybe foun dfor e ach .Familyme mber sare frequ ent lyt hemost valuabler esource. Communitysu pportservicessu chas MealsonWh eels,visitin g nu rseser vice s,an dhome health aidesorhome makerser vice smaybeabletoprovideprimaryassistance orfillint hegaps. Hypogly cemiaisapote ntialcon cern forolde rpat ien tstre ate dwith in sulin .Someriskfactor sfor hy poglycemiainthis populationar esummariz edinTable43.5.Hypogly cemiacoun terr egulat ory mech an ismsare gene rally P. 744
intactin ot herwiseh ealthy olderadultswit hdiabet esme llitus. Howeve r,olde rpeople on comple x medicalregimen s,whoeatme alsirr egular ly, orwh oh aveasign ifican tcognitivedisorde rare likelytobe at sign ifican trisk.The strat egiesforp reven tion ofhy poglycemiaincludeappropriatese lect ionofpatien ts forin sulin treatment;fre quen tmon itoringofbloodglu cose lev els;adequ ate d iabetese ducat ion, with specialemphasisonth erecogn itionan dtreatmentofhypoglycemia;die tar yassessmen tan din struct ion; an dthe in terve ntionoffamily ,friends, orsu pportservicest oprovidefreq uen t(atleastdaily )con tactfor th ein sulin -tre atedolderadultwit hdiabet es. TABLE 43.5. Risks for Hypoglycemia
Visualimpairment Impairedmanualdexterity
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Inabilitytodobloodglucosemonitoring Impairedcognitivefunction Poorfamilysupport
Insulin Combined With Oral Agents

Asin glein sulin dose ,possiblyad ministere datbe dtime, combinedwithone ormor eor alagen ts,maybe use fulin achievingde sir edglycemiccontrolin patien tswit htype 2diabet es(71).Asinmiddle-ag ed peoplewit hdiabet es,su chare gimen maybereason ableinother wiseh ealth yan dhigh-fun ction in golder pat ie ntswithdiabe tes.Howeve r,th ereislitt lespe cificinfor mationavailableabout suchcomb in ation reg imensinold eradu lt s.
Self-Management Education and General Health Status Counseling

Becausediabe tesisassociatedwithathe rosc ler oticrisks,comorbiditie srelate dtomacr ovascularand microvascularcomplications,andincreaseddisability ,allofwhichincre asewithageinpeoplewit han d withoutdiabe tes, improvementinge neralh ealth statu sisanimportantcompon entofdiabet es management inolderpatie nts. Forolder people wh omayh ave multipleot her cond itionsassociate dwith th eir diabete s,it isimportantt ou nderst and howallth esecondition saffecte verydayfun ctioningathome an din society .Keyt oth isisacomp rehe nsiveevalu ation,aspreviouslydiscu ssed. Be side sappropriat e medicalman age men tofd iagnoseddisease s,itisimp ort ant t oassessan olderpatient 'snu trition al status, affectiveandcognitivestatus, mobility,andfun ction in gbecau sediabet eshasbeen shown tobe associate dwith impairment sin allth esecondition s.Alt hough approach estopreve ntion an dmanage men t ofsu chdisablingcondition sanddisabilit ie sassociatedwithdiabe tesareinthe ir infancy, itisbecomin g increasinglyimportan tfor physicianstolearn toide ntifydis ablin gcon dit ionsandfun ctionin gdifficulties an dtoapplyavailab leman age men ttech niques. Diabetesisfun dament allyaself-man age ddise ase. Th ehe althcareprovidermuste ducat ethe patien tan d family, guideapp ropr iatemanagement c hoices, manag erisksand comorb idcondition s,an dsupportt he pat ie nt'seffor tsatse lf-management .Un fort unately,ve rylitt le iskn ownaboutself-managementinolder pat ie ntswithdiabe tes.Manyolde rpeople have ot herch ron iccond itions,h avefrien dsan dfamily membe rswit hchr on iccondition s,an dhaveret ire dfromwor kand thus may have the inclination, time, an dknowle dgebasetohan dle diabete sself-man age men tbett erth andomiddle-agedpatie ntswith diabet es.However ,becausesome olderpe oplemayh aveve rypoorh ealth and/orbe cogn itively impaire d,th esucce ssofdiabet esself-management willde pendont heavailabilityan dskillsofa car egiver.Fut urer esearchisurge ntlyne ededtoclarifythe relationshipsofh ealth stat usan ddiabete s self-managementinold eradu lt s.Itiscle ar, h owe ver, t hat manyfun ction in golderpe oplecanbe expe ctedtomanageth eirdiabete saswellasan yyou nger patien tswit hdiabet esan dshouldhav esimilar acce sstoe ducationandself-management s upport.
Management of Older Patients with Diabetes in Special Situations

FRAIL OLDER PEOPLE
The h ealth stat usofsomeolderp atient swith diabete sisve rypoorbe cause ofpre terminalillnesse s, adv ance ddementia,or sign ifican tcomorbid p roblemsan dfunct ionaldifficu lt ie s.Manysu chpatie ntsalso havedecr ease dphysiologicr eserve and areoften termedfrail. Mostfrailelderlypat ien tslive in the communitywith caregive rs,inassisted livingfacilities, orsome timesalone ;oth ersareinnu rsinghome s. Fort hesefr ailolde rpat ien tswithdiabe tes,man agemen tofth eirdiabet eswillbeon easp ectoft he coordinated, mu ltidiscip linarymanagementofthe ir multipleproble ms.Forsuch patien ts,abasic diabet esmanagementpr ogr ammay b emostapprop riate(74).Th ispr ogramwouldincludetr eat men tof symptomatich yperg lyce mia,atte ntion ton utr itionalstatus(th esepatient smay bemaln ou rishedand cat abolic),andtre atmen tofdiabe tescomplication san dcomor biditiesdirecte dtowardpatie ntcomfort, mainten an ceoffu nction ,andprev entionoffu rth erdeclinewhe npossib le. Itisimport ant tor eme mbe r th atfindingsattribut abletohype rgly cemiamay b esubstantialan dmayincludeinfect ions, worse ned mentalst atu s,blurre dvision,falls,andworsene din con tin en ce.Such patien tsben efit fr omgeriat ric evalu ationan dmu lt idisciplinarymanagement ,an dreferr altoageriatr ician isoften appropriat e. Res earch isn eede dcon cerningt hecontr ibu tion ofdiabet estothefr ailty syndromean don t he app ropr iatemanagement ofdiabe tesinthisgroupofpat ien ts.
NURSING HOME RESIDENTS

Approximately3%to5%ofth epopulationoverth eage of65ar eresidinginnu rsin ghome satanygiven time ,an duptoon efourth ofold erpeoplewille xperien cean exte ndedn ursing-h omestay.The pre valence ofdiabe tesinthe nur sin g-home popu lation isab ou ttwice thatin the gene ralpopu lation .
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Accordin gtothe1987Nat ionalMedicalExpe nditur eSurve y,diabe ticpatient sinn ursingh omesh ada significantlyhighe rprev alence ofdisease sassociatedwithdiabe tes, su chasheartdisease ,hyp erten sion, an dkidneyfailur e,th ane lde rly nondiabet icpatie ntsinn ursingh omes;were alsomor elimite din allADL exce ptfeeding ;andwe remore likelytobeblin d.Thefr equen cyofamp utationswashigher among t he diabet icpatientsinn ursingh omes,alt hought hediffere ncewasn ot statisticallysign ifican t(75). The approach tomos tnur sin g-home p atient swith diabete sshouldbeth atofprov idingbasiccarewith controlofhy perglycemiatopreven tsymptomsandassociate dacut ecomplication s.Tigh tglycemiccontr ol forthe p reven tion ofchr on iccomplicationsmaynotbeappropriate b ecau seoft hepoor health stat usan d red ucedlife expect ancy ofmostn ursing-h omepatie nts. Controlofhyp erglycemiain patien tsin nur sin g homesisachieved p rimar ilythr ou ghth euseofdietan dme dication s.Exe rcisewillp robablynotplaya majorr oleinth emanageme ntofdiabete sin these patien ts.However, patien tswhoare c apab leofan exe rcis eprogramshouldbeen cou rage dtop articipate toe nhancemob ilit yan dfunct ionalstatus. Dietis an importan tth erap euticoption, butwe igh tmain ten ance maybemore importantth an we igh tred uction forman yelderlypat ie ntswithdiabe teswhoar ein nur sin ghomes .One stu dyfou ndth atover20%ofp atient swith diabete sin nurs in ghomeswer emore t han 20%u nder weig ht (76),afin din gthatraisesth econcer nabout malnu trition in thispop ulation .Thu s,adietitian should evalu ate allpatientswith d iabetesatth etimeofadmissiontothe nur sin ghome. Adju stmentsin recommen dedcaloricin take shouldbemadeforwou nds, infe ction s,an dlev elofact ivity. Patie ntssh ou ld beweigh edatleastmont hly,an dfurt herdiet aryadju stments sh ou ld b emadeasn eede d. Asin ot hersitu ation s,th edecision r egar din guseofme dication sorinsu linsh ou ldbe basedonth elevel ofg lyce miccon trolde sir ed.Ofte nan oralagent ispre ferre dbot hbyth epat ien tan dthe nur sin g-home staff,butinsu linisne ededforthosepatients forwhomglyce micgoalscann ot b each iev edwit horal age nts. Glucosecontr olmaybemore easilyobt ainedinth epat ie ntwithdiabe teswhoisin anu rsin g homebecausemedicationsan dmealsarede livere don areg ularsch edule.In the nursing -homese tting, glucosemonitoringmaybe d on emorefre quen tlyan dther espon seoftheph ysicianmaybemor e immediate thanin the ou tpat ien tsett in g.Infact,Mooradianet al.(76)fou ndth atpatientswithd iabetes inth enur sin ghome h adlowe rle velsofHgA 1 c ,fewe repisode sofh ypoglyce mia,andwer ethinn erth an a young ergroupofou tpat ie ntswithdiabe tes. Inadditiont oglycemiccont rol,particularatten tion shouldbepaidtothe preven tion ofcondition sthat mayber elatedt o,orareexacerbatedby, diabete smellit us.In fe ction s,par ticu larlyskinan durinary tractinfections,aremore commoninn ursing-h omepatie ntswithdiab etesth an in oth ernu rsing-h ome pat ie nts. Th eincidence ofur in arytr actinfect ionsmaybe redu cedbylimit in gthe u seofin dwelling bladde rcath eter sandby ensu rin ggoodu rin aryout putth roughadequ ate h ydration. Skin in fection smay bepr even tedbyst rict p recau tion sagain stthe develop men tofde cubitusu lce rs,su chasfre quen ttur ning ofimmobilizedpatients;t heu seofadequatebe dand wh eelchair cushioning;an dthe useofhee l protect ors. Thepre valence ofallin fection sisr educe dwith goodstaffh ygiene ,part icu larlybythe en force men tofs tricthand-wash in gregime ns.Th euseofan nualinflue nzavaccinationandone-t ime pne umococcalvaccination forallnu rsing-homepatien tswillprovide popu lation immu nityan dprotect againstepidemicsofth eseillne ssesin the nur sin ghome. Immun ization andPPD(purifiedprotein der ivative)statussh ouldbev erified anddocumen tedforallpatient snewlyadmittedtoth enu rsin g home.Patient swith diabete swhoh ave apositive PPDreaction s hou ld becon sid eredforprophylax iswith ison iazid ifth eyhavenotbe entr eate dpreviouslyfort uber culosis. Pr even tat ive medicineappropriateforallnur sin g-home r esident s,in clu dingregu larophth almologic, den tal,andfootcare, isespe ciallyimportantforth osewith d iabetes. Manyinstitu tion soffert hese serv ice sint hen ursingh omeitself.These in terve ntionswillmain tainqu ality oflife and, in some circumstan ces,mayse rvetodet ectan dameliorat epotent iallylife- thre aten in geve nts. P. 745
HOSPITALIZED OLDER PATIENTS

The r ate ofhospitalizationamon gelderlypat ie ntswithdiabe tesis1.7time st herateamonge lde rly peoplewit houtdiabe tes.Th eseincludeh ospitalizationsboth fordiabe tesan dfor oth erre asons. Reg ardlessofther easonforhospitaliz ation ,anappr opriategoalforglycemicmanage men tshouldbe establish edfor each patien t.Inge ner al,effortsshouldemphasize minimizingth elike lihood ofinsulin deficiency, whichcan con tribute toacatabolicstate .Ifthisisthep rimary goal, tigh tglycemiccont rolis notn ecessar y.Re asonablegoalswouldbeamean plasmaglucosele vellowerth an 250mg/d L(14 mmol/L)andmin imalglycosu ria.Str essfulillnesse ssuchasmyocar dialinfarction ,pne umon ia,in flu enz a, an dstrokeorconditionsassociatedwithad ecline in renalfu nctioncan exace rbat ehype rglycemiaand mayeve npre cipitatehy perosmolarhy perglycemicn on ketoticcomainapatien twhoisalre ady hospitalized.Th us,old erpat ie ntswithth esecondition s(in clu din gpat ien tspre viouslymanagedwithoral age ntsordietaloneorev enpatie ntsn otpr eviou slyr ecog nizedash avingdiab etes)mayn eedtobe tre ate dtemporarilywith in sulin .Atten tion must alsobe give ntoflu idst atu s,wit hth euseofappr opriat e intraven ou sfluidth erapytopreven tdeh ydrationandworsen in gofhy perglycemia.Frequ entg lu cose mon itoringisrecommen dedtopreve ntwideper turbation sin bloodglu cose leve ls. Slidin gscalesof reg ularinsulincan beuse fulfort heacutelyillpat ie ntorpost ope rativep atient whoisun abletoeat.
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Howe ver, on ceor alin take isadequate, mosthospit aliz edpat ien tsar ebett ermanagedwithsplit-mixed dosin gofinsu linwithadju stment smad easne ededont hebasisofthe r esultsoffreque ntglucose mon itoring. Animportantr iskforth ehospitaliz edolder adultwithdiab etesishypoglycemia.Inge neral, hy poglycemiainthe hospit alresultsfromde creasedcaloricint akeorinap prop riatech ange sin in sulin dosage(77). Hypoglycemiamaybepr even tedbyfr eque ntglucosemon itoring, with carefu ladjustment s inth ein sulin dose asth epatien t'smedicalconditionch an ges,andwithth eestablishmen tofappropriate in-hospitalgoalsforglycemiccon trol. The b asicprin cip lesofgeriat ricmedicineapply t oth emanagement ofhospitalizedelderlypatie ntswith diabet es.Some g ener alrecommend ation sin clu destrictde cubituspr ecau tions, restr ictionoft heu seof indwellin gcath eter s,an dju dicioususe ofpsych oactivedru gs[theiradministration shouldnotbeona prn (asre quired)basis] .Mobilitysh ou ldbe encouraged, andph ysicalther apysh ou ldbe gin earlyinth e hospitalcourse, asindicate d.Plan ningfordischar geshouldbeginatthe timeofadmission,withinp ut fromth esocial-workser vice .Involvement ofaconsu lt ant ing eriatricmedicin eshouldbeconsidered , par ticularlyift hepatienth asmultip lemedicalproble msandistaking multipleme dication s,is fun ction allyimp aired,andre quiresormayrequ ir ehome careorn ursing-h omeplacemen tatt hetimeof discharge.
REFERENCES
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Dise ases, 1995:401-408.NIDDKDpublication95-1468. 14.VinikAI,ParkTS,Stansbe rryKB,e tal.Diabeticneu ropath ie s.Diabe tologia2000;43:957-973. 15.Gregg EW,Beck lesGLA,Williamson DE ,etal. Diabet esan dphysicaldisabilityamongolderU. S. adults.Diab etes C are2000;23:1272-1277. 16.Songe rTJ.Disabilit yin diabetes .In:Nat ionalDiabete sDat aGrou p.Diab etes in America. Bet hesda,MD:Nat ionalIn stit uteofDiabe tesandDigest ive and K idn eyDise ases, 1995:259-283. NIDDKDpublication 95-1468. 17.WorldHealth Organ ization .Diabe tes mellitus: r epor t of a WHO study gr ou p.Genev a:World He alth Organizat ion;1985.Tech nicalreportse rie s727. 18.BarzilayJ,Spieker man C,WahlP, etal.C ardiov ascular dise aseinolde radu lt swith glu cose disor ders:comparison ofAmericanDiabete sAssociationcriter iafordiabe tesmellituswithWHO criter ia.Lan cet1999;354:622-625. 19.WahlPW, Savage PJ,Psat yBM, e tal.Diabete sinolderadults:comparisonof1997American DiabetesAssociation classificat ionofdiabete smellit uswit h1985WHOclassificat ion. L ance t 1998;352:1012-1015. 20.DECODEStu dyGrou p.Glu cose tolerance andmor tality:comparisonofWHOan dAmerican DiabetesAssociation diagnosticcriteria. Lance t1999;354:617-621. 21.DECODEStu dyGrou p.Conse quen cesofthen ewdiagnosticcriteriafordiabet esinolder men and women .Diab etes C are1999;22:1667-1671. 22.HarrisMI, East manRC, CowieC C,e tal.Comp arison ofdiabe tesdiagn ost iccategoriesin the U .S. populat ionacc ordingt oth e1997Amer icanDiabetesAssociation an d1980-1985WorldHealth Organizat iondiagn ost iccriter ia.Diabe tes Care1997;20:1859-1862. 23.Sh awJE, d eCourt enMP. I GTorIFGfor predictingNIDDM:whoisright ,WHOor ADA?D iabete s 1998;47[Suppl]:A150(abst). 24.E delsteinSL,Kn owlerWC ,BainR P,e tal.Predictorsofprogre ssionfromimpairedglucose toleran cetoNIDDM:anan alysisofsixprospectivestu dies.Diab etes1997;46:701-710. 25.Halte rJ.Agingandcar boh ydrat eme tabolism.In :MasoroEJ, ed.Han dbook of physiology.Section 11:Aging.OxfordU niversityPress,1995:119-145. 26.VokonasPS,Kanne lWB.Diabete smellit usan dcor on aryh eart dise aseinth eelderly.C lin Geriat r Med1996;12:69-78. 27.Be tteridgeDJ.Diabeticdyslipidemias.Am J Me d1994;96[Su ppl6A]:25S-31S. 28.Brownlee M,C eramiA,VlassaraH.Advan cedglycosylation endpr odu ctsin tissueandth e bioch emicalbasisofdiabet iccomplication s.N En gl J Med1988;318:1315-1321. 29.Ly on sTJ. Lipoproteinglycationanditsmetab olicconse quen ces.D iabetes1992;42[Su ppl2]:6773. 30.VijanS,St even sDL,He rmanWH,e tal.Scree ning,pr even tion, cou nseling,andtr eatmen tfor t he complication soft ypeIIdiabet esme llitus.J Gen Inter n Med1997;12:567-580. 31.We in erJP,Parent eST,Steph enT, e tal.Var iation inoffic e-base dquality:aclaims-based p rofile ofcarep rovidedt oMedicare patien tswit hdiabet es.JAMA1995;273:1503-1508. 32.Ke llS,DrassJ,BausellR.Meas uresofdis easecont rolinMedicarebe neficiarieswithdiabe tes mellitus. J Am Geriatr Soc1999;47:417-422.
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33.Ke nny SJ ,SmithPJ,Goldsch midMG,e tal.Surv eyofp hysicianpracticebeh avior sr elated t o diabe tesmellitusinth eU. S.Diabe tes Care1993;16:1507-1510. 34.HarrisMI. Med icalcareforpatien tswit hdiabet es:epidemiologicaspe cts.Ann Inte rn Med 1996;124:117-122. 35.Be ckle sGL, Enge lgauMM, Naray anK M, e tal.Popu lation -basedassessment ofth ele velofcare amongadultswit hdiabet esin the U.S.D iabete s C are 1998;21:1432-1438. 36.BrownAF,Man gioneC M, SalibaD,SarkisianCA. Californ iaHealthcareFoundation /Amer ican Geriatr icsSocie tyPane lonImprov in gCar efor E ld erswit hDiabetes. Gu ide line sforimpr ovingt hecare oftheolderper son with diabete smellitu s.J Am Ger iatr Soc2003;51[5SupplGu ide line s]:S265-280. p 36a. BlaumCS,Halte rJB.Diab etesinth eelderly.D rug Th erapy 1994;24:18-30. 37.Stu ckAE,SiuAL, W ielan dGD,e tal.Comp rehe nsiveger iatricassessment :ameta-analysisof contr olle dtrials.Lan cet1993;342:1032- 1036. 38.MorelyJE,K aiserFE.U niqueaspectsofdiabete smellit usin the eld erly.Clin Geriatr Med 1990;6:693-719. 39.Morle yJE,MooradianAD,Levine AS, etal.Wh yisd iabeticperiphe ralneu ropath ypainfu l?The effe ctofglucoseonpain p ercept ioninhu mans.Am J Me d1984;77:79-83. 40.U KProspect ive Diabet esStudy Group. Tigh tbloodpressu recontr oland risk ofmacrovascu laran d micr ovascularcomp licationsintype 2diabet es:UKPDS38.BMJ1998;317:703-713. 41.ApplegateW. Hy perte nsion .In:Haz zardWR ,BlassJP, Etting erWH,et al,eds. Principles of ger iatric med icine and ge ron tology.4thed. NewYork: McGraw-Hill,1999:713-720. 42.Morit zDJ, Ost feldAM,Blaz erDI, etal.Th ehealthbu rdenofdiabet esfort heelder lyinfour commun ities. Pub lic Health Rep1994;109:782-790. 43.Fillenb aumGG,Pie perC F,C oh enHJ, etal.C omor bidityoffive chronichealt hcondition sine lde rly commun ity resident s:deter minantsandimpacton mortality. J Ger on tol2000;55A:M84-M89. 44.WingardDL,Barr ett-C on norE.He artdiseasean ddiabete s.In:NationalDiabete sDataGroup. Diabetes in America, 2nde d.Beth esda,MD.Nat ionalIn stitute ofDiabetesandDige stiv ean dKid ney Dise ases, 1995:429-448.NIDDKDpublication95-1468. 45.Ku ller LH.Strokean ddiabet es.In:NationalDiabet esDataGroup.D iabete s in America. 2n ded. Bet hesda,MD.NationalIn stitute ofDiabete sandDige stivean dKidneyDiseases ,1995:449-456. NIDDKDpublication 95-1468. 46.Th eAgency forHealt hcar ePolicyandRe search SmokingCe ssation Gu id eline .JAMA 1996;275:1270-1280. 47.C urbJD,Pr esselSL,Cu tlerJA,et al.Effect ofdiure tic-b asedantihype rten siv etreatmenton cardiovasculardiseaseriskin olderdiabeticpatien tswit hisolate dsystolichype rten sion. JAMA 1996;276:1886-1892. 48.An tiplateletTrialist sa'C ollaborat ion.C ollaborat ive over vie wofrandomisedtr ialsofan tiplat elet th erapy:preve ntionofde ath ,my ocardialin farction,andstrokeby prolongedantiplate le tthe rapyin variouscategoriesofpatien ts.BMJ1994;308:81-106. 49.VijanS,HoferTP,HaywardRA.C ost- utilityanalysisofscr eening in tervalsfordiabet icre tinopath y inpatie ntswitht ype2diab etesmellitu s.JAMA2000;283:889-896. 50.U KProspect ive Diabet esStudy Group. Inte nsiveblood-glucosecontrolwith sulphonylure asor insu lincomparedwithconve ntionaltre atment andr iskofcomplication sin p atient swith type2
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diabe tes.Lancet 1998;352:837-852. 51.Albert M.C ogn it ive funct ion.In :Albe rtM,MossM,eds. Ge riatric neu ropsychology. Ne wYork: GuilfordPress,1988:33-53. 52.Sh orr R,Fran zeL,R esnickH,et al.Glyce miccon trolofolderadultswithty pe2diabe tes:findings fromt heThirdNat ionalHealthan dNutritionSurve y,1988-1994.J Am Ger iatr Soc2000;48:264-267. 53.VelezL ,BlaumC,Halte rJB.Diabetescarepracticesincommunity-d we llingpat ie ntsaged75an d olde r:glycemiccontr oland treatme ntcompliance .J Am Geriatr Soc1995;43[Sup pl]:SA1(abst). 54.VanNost ran dJ,Furne rS,Suzman R.Healt h dat a on olde r Amer icans: Un it ed Stat es, 1992. Hyattsville, MD:Nation alCen terforHealth Stat istics,C ente rsfor Disease ControlandPreve ntion , 1993. 55.R oweJW, AndresR ,TobinJD,et al.Thee ffe ctofageoncreatinineclearan cein me n:acrosssect ionalandlon git udinalstu dy.J Gerontol1976;31:155-163. 56.NaliboffBD,Rosen thalM.Effec tsofageon complication sin adultonset diabetes. J Am Geriatr Soc1989;37:838-842. 57.Mack enzieRA, PhillipsLHD. Change sin p eripher alandce ntraln erve con duction wit haging. Clin Ex p Ne urol1981;18:109-116. 58.American Diabet esAssociat ion. Positionstatement :nut rit ionre comme ndat ionsandprinciplesfor peoplewithdiabe tesmellitus. Diabete s Car e2001;24[Suppl1]:44. 59.E xerciseandNIDDM. Diabet es Care1990;13:785-789. 60.E rik sson J,LindstromJ,Valle T, etal.Preve ntionoft ypeIIdiabet esinsubject swith impaired glucosetole ran ce:th eDiabe tesPreven tion St udy(DPS)inFin land studyde sign and 1-yearinter im re port on thefe asibilityoft helife stylein terv entionprogramme.D iabetologia1999;42:793-801. 61.Fiataron eMA,Oa'Ne illEF,DoyleN,etal. TheBoston FIC SITstudy:t heeffe ctsofre sist ance tr ainingan dnu tritionalsu ppleme ntationonph ysicalfrailt yin theoldestold. J Am Geriatr Soc 1993;41:333-337. 62.Sh orr RI,RayWA,Daugh erty JR ,etal. Incidence and r iskfactorsforse riou sh ypogly cemiain olde rpersonsu sin gin sulin orsu lfony lu reas. Arch Int ern Med1997;157:1681-1686. 63.Minak erKL, R oweJW ,Ton in oR, etal.In flu ence ofag eon cle aranceofin sulin in man.D iabetes 1982;31:851-855. 64.Dor fmanLJ,Bosle yTM. Ag e-relat edchangesinpe riph eralandcen traln ervecondu ction in man . Neu rology1979;29:38-44. 65.Oa'Brien IA, Oa'HareP,CorrallRJ. He artr atev ariability inh ealth ysubjects :e ffectofageandth e der ivation ofnormalran gesfortestsofau tonomicfunct ion.Br He art J 1986;55:348-354. 66.Heins imerJA,Le fkowitzRJ. Theimpactofagingonadr ene rgicr eceptorfun ction :clinicalan d bioch emicalaspects. J Am Geriatr Soc1985;33:184-188. 67.Sh orr RI,RayWA,Daugh erty JR ,etal. Individualsulfonylure asan dseriou shypoglycemiain older people.J Am Ge riatr Soc1996;44:751-755. 68.KadowakiT,Hagu raR, KajinumaH,e tal.Ch lorpr opamide-indu cedhyp on atre mia:inciden cean d riskfact ors. Diabet es Care1983;6:468-471. 69.U KProspect ive Diabet esStudy Group. Effectofinten siv eblood-glu cose con trolwithmetformin on complication sin ov erweightp atient swith type2diabete s(UKPDS34).Lancet 1998;352:854-865.
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70.C hiassonJL,JosseRG,Hu ntJA,e tal.The efficacyofacarboseinth etre atmen tofpatie ntswith non-ins ulin -depen dent d iabetesmellitu s:amultice nte rcon trolledclin icalt rial.Ann In tern Me d 1994;121:928-935. 71.DeFron zoRA.Ph armacologicthe rapy forty pe2diabe tesmellitus. Ann In tern Me d1999; 131:281303. 72.R eave nG,ThompsonLW, NahmD, etal.Re lation shipbetwee nhy perglycemiaan dcogn itive fun ction in olderNIDDMpatien ts.D iabetes C are 1990;13:16-20. 73.U a'RenR C,RiddleMC,Le zakMD, etal.Th eme ntale fficiencyofthe elderlypersonwitht ypeII diabe tesmellitus. J Am Geriatr Soc1990;38:505-510. 74.Blau mC S, HalterJB. Diabet esan daging.In :LeahyJL,C larkNG,Cefalu WT,eds.Th e me dical management of diabe tes mellitus. Ne wYork:Mar celDekke r,2000. 75.May fieldJ,DebP,Potte rDE B.Diabe tesan dlong -termcare .In:Nat ionalDiabete sDataGroup. Diabetes in America, 2nde d.Beth esda,MD.Nat ionalIn stitute ofDiabetesandDige stiv ean dKid ney Dise ases, 1995:571-590. 76.MooradianAD,Oster we ilD, Pet rase kD,e tal.Diabetesmellitu sin eld erlynur sin ghomep atient s. Asur veyofclinicalcharacte risticsandman agement .J Am Geriat r Soc1988;36:391-396. 77.FisherL, Che slaCA,BartzRJ, etal.The familyan dtype2diabete s:aframeworkforinter vent ion. Diabetes E duc1998;24:599-607.
Chapter44 Women's Health Issues in Diabetes Mellitus

Julie Lund Sharp le ss Seve ralaspec tsofth efemalerep rodu ctivelifecy cleareinfluen cedbyinsu linandth eme taboliceffe cts ofd iabetes. Fr ompuber tyth rou ghchildbearin gtomen opause, womenwith diabetesmay n eedt omake specialadju stme ntsinth eirregime nstomain tainoptimalcont rolast here productiveh ormonesch ange . Conve rsely,poor diabeticcon trolcanimpairnormalr eproductivefu nction.The waningofrepr odu ctiv e hormon esat men opauser aisesspecialissu esindecision sabouth ormonere placementt herapyinwomen withdiabe tes,aswellasadditionalr isksforosteopor osisan dendometrialcan cer. Most inv estigationsintothe effectsofdiabete sonr eproductivefu nctionhavefocusedonty pe1insu lindepe nden tdiabet esbecauseth isisth emostpre valent formin women ofrep rodu ctiveage .Insu lin resistancealsohasreproduct ive con seque nces, both in sever efor mssuc hasty peAin sulin resistan ce an din milderformsasin polycysticovary syndrome .The ch an gin gepidemiologyofdiabete sin the Un it edStat es,withanincreasin gprev alence ofobesityan dane arlie ron setoftype2diabet es,makes th erepr odu ctiv econ sequ encesofinsulin-resistantdiabe tesmore sign ifican t.Stu die sofdiabe tesin postme nopau salwomenh avefocuse dlargelyonwomen with in sulin -resistan tdiabet es.Although issu es ofcardiov ascular dise ase, h yper lipid emia, and e ndome trialcance rare importan tinthispopulation, an ot herclassicpostmenopau salissu e,osteoporosis,isofgr eate rcon cern forwome nwithtyp e1 diabet es.Thu s,th isch apte rwillreviewbothtyp e1andtype 2diabe tesan dthe irmetaboliceffectsin women .Inman ystudies, thet ypeofdiabetesh asn otbe ende fin edbystrictstandardssuch asCpept ide ,au toimmu neantibod ies, or insu linleve ls;t hus, subjectsde scribe dasinsu lin-de pende ntmay includepe rson swit heithe rtype1or type2diabete s.Inth esesituation sthe d escription sin sulin depe nden tdiabet esme llitusorn on- in sulin -depen dent d iabetesmellitu sare usedasspecified in t hose stu die s,asth ehe terogen eityoft hepopulationsmayh elpr econ cilet here sults.
MENSTRUAL CYCLES Menarche

In1925, Dr.E liotJoslinobserve dthatun aidedbyinsu lin, n ogirlin ou rseriesde velope dmen stru ation aft erth eon setofdiabete s(1). By themid -20thcen tur y,amajorseriesbyBer gqvistreporte ddelayin menarcheof15mont hsassociated with diabetes (2).Mor erece ntly,th isobser vationhasbeen con teste d
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bystu die sshowin gnormalmen arch ein seriesofclinicpatien ts(3, 4,5,6).Howe ver, suban alysesin seve raloft hesest udiesshowed P. 748 th atth ose girlswithth eonsetofdiabet esbefore10yearsofageorbeforemenarche st illhadadelayin menarche, aswellasmoreirre gularmens es(3, 6).Th emajorcomplicationsofdiab etesh aven owbe en showntocorrelat ewit hglucosecon trol, asth esestu die swou ldsu ggestforage ofmenarche. Mostof th esestu die s,however ,didnotspecificallyinve stigatede greeofcon trolinr elation toonse tof menarche. Oneindirect clu eisavailablefromastudyby Ye shay aetal. (6),wh ofoun dthat,among women with diabete s,th osewith d iabeticcomplication swe reolde ratmen arch ean dmorelik ely t oh ave amen orr heathanth osewithout complications, butadir ectrelat ionsh ipbe tween men arch ean dglycemic controlhasn ot b eene stablished.
Menstrual Dysfunction
Beyondmen arch e,menst rualper iodsare ofte ndisrupt edbydiabe tes.Th emajorproblemsareabsent menses(ame norrhe a)orin frequ ent men ses(oligomen orr hea),but ove rly fr eque ntmense s (polymen orr hea,ormorecommonlycalle ddysfun ction aluter in ebleeding)h ave alsobee ndescr ibe d. Somety peofirre gularmens eshasb eenr eportedin22%to47%ofwomenwithdiabe tes(3,7). These highpr evalen cerateslike lyr efle ctvar iousde finitionsofirre gularity, asthe cor respondinginciden cein controlsran gedfrom11%to35%.Th elowerfigur escomefromone ofth emostth or ou ghstu die sof menstr ualcyclesininsulin-depe nden tdiabet esbyKjae retal.(3),u sin gane pide miologicst udyofan en tir ecou nty in Den mark.Kjaeran dot hers(3,8)alsoh avefoun dthatthe in cide nceofirr egular ity correlat edin verse lywith d iabeticcon trolandwithbodyweight .Specifically,t wogroupsh ave s hown that th ein cid enceofme nstru aldisturbance sincr ease swith the h emoglobin A 1 c conce ntration (HbA 1 c )and becomesstat isticallysig nificantwithHbA 1 c valu esabove10%(3, 9). Reg ularmenst rualfun ction requ ire stheint egrationofneu ronalan dhormonalsign alsbetwee nthe hy poth alamus, t hepitu itary,t heovar ies, and theu teru s.Neur on alsign alsin the h ypothalamu strigger th epulsat ilereleaseofg onadotropin -releasing h or mone(GnR H),whichcausesth epituitarytorelease follicle-st imulatingh or mone(FSH)an dlu teinizin ghormon e(LH),whichint urnst imulate the deve lopmentofeggs, estrogen ,an dprogester on ein the ovary.The estrogen foste rsproliferation ofth e en dometr iu man dfeedsbacktothe hypothalamu sand pitu it aryt ocontr olit sownpr odu ction .Nosingle mechanismofimpairment ind iabetesh asbee nest ablish ed,bu tabn or malitiesfromth ehypoth alamusto th eov aryh avebe ende scrib ed. The mostcle arlydescr ibe dsyndromeofmenst rualdysfu nctionindiabet esisaformofh ypothalamic amen orr hea.Hypothalamicamenorrh ea(HA)re sultsfromlackofstimu lationby theh ypothalamicGn RH tothe pitu it aryLHandFSH.InHA,se rumle velsofLHan dFSHarelow,andstu diesusingfre quen t samplin gshowthatLHan dFSHpulsesaredecr ease dorabsent and insu fficien ttostimulat eov ulation ; th usme nsesdonotoccur(10). W omenwithinsu lin-d epend entdiab etesandamen orr heahav ebeen foundt ohavelowLHandFSHlev els, and d ecreasedLHpulses(8,11)(Fig. 44.1). Variou sin vestigat ors havetr ied t oassessGnRHres pon sive nessofthe pitu it arygonadotrophcellsby admin ist eringasingle doseofGnR Htowome nwithdiabe tes,bu tresu lt sareconflictin gan dnotasinformativeast hosefrom pulsepr ofile sofLH(12).However ,astu dybySouth etal.(11)th atsh owe ddecreasedLHpulsesin amen orr heic,diabe ticwome n(as compare dwith normalcy clingn on diabeticwomen ),alson ot edan increasedLHre spon setoGn RH.Bothde crease dpulsesan dan in creas edLHresponse toGnR Haresee n inother formsofh ypot halamicamenorrh ea. Th eclin icalfeatur esofHAindiabe ticwome nar esimilarto th oseint hegen eralpopulat ion. Asinwome nwithpoor lycont rolleddiabet es,hy poth alamic ame norrhe a alsooccu rsin nondiabe ticwome nwhohaveinade quatenu trition ,frequ ent lyasare sultofex cessive exe rcis eor anorexian ervosa(13). Se vere illn esscan alsosu ppressleve lsofLHand FSH,asseenin pat ie ntsh ospitalizedforot herd iseases(14).In diabete s,HAmayreflectacombin ationoft hese factors. Diabeticwomenwith h ypothalamicamenorrh eat endt obeu nder weig htand/ortoh ave poorglucose control.Inth eseriesofHAin diabetesby Sout hetal. (11)andO'Hare etal.(15), womenwer eselected fornormalbodyweigh tbuth adelevatedmeanglycosy latedhe moglobinof12.8%an dHbA 1 c of11.8%. Dju rsin getal. (8)includedboth normalandun derwe igh tsubject sbutdidnotfindacorre lationbe tween amen orr heaandglyce miccon trol. An obv iousapproacht oth esepatie ntsistoimprovediabet escontrol. Un fort unately,after6month sofimp rov edme taboliccontr oldecre asingHbA 1 c le velsfrom11.8%to 8. 5%,withacon comit ant meanweight gainof4.2kg,n on eofsixamen orr heicsubjectsint heser ies of O'Hareet al.(15)resu med men ses,su ggestingadditionalpr ocess escon tribute dtot heobserv ed amen orr hea.Women with hypoth alamicamen or rheahavean in creasedriskfor e strogen-d eficien cy osteopor osis(16)and n eedt reat me nttorest ore orre place(i.e. ,or alcon trace ptivepills)me nstru al cyclestoensu readequatee strogensu pplies(17). Alth ou ghth ebon e-den sit yresponse t ooral contraceptivepillsh asnotye tbeen specificallyevalu ate din diabete s,tre atment must beconsidered becauseofthe addition alin creasedriskofosteoporosisintype 1diabet es(seediscu ssionbelow).Othe r cau sesofHA, suchaseat in gdisorder s,whichh aveanincre asedpr evalen cein women with diabete s (18),mustalsobeaddresse d.Eve nwithoutmeet in gthefu llpsych iatricDSMIII-Rcriteriaforan or exia ne rvosaorbulimia,15%to40%ofyou ngwomen wit hdiabet esdis close P. 749
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disor derede atingandun derdosingth eirin sulin asat oolforweight loss(19,20).In addition t oworsen ed glycemiccontr ol,diabe ticpatient swith eat in gdisorder shav ean incr ease din cide nceofdiabetic complication s(21,22).
Figure 44.1.Serumluteinizinghormone(LH)pulsesindiabeticamenorrhea.RepresentativeprofilesofLH concentrationversustimeseriesobtainedfromaeumenorrheicnondiabeticwomen(left)andanamenorrheic diabeticwoman(right).(ReprintedfromSouthSA,AsplinCM,CarlsonEC,etal.Alterationsinluteinizinghormone secretoryactivityinwomenwithinsulin-dependentdiabetesmellitusandsecondaryamenorrhea.J Clin Endocrinol Metab1993;76:10481053,withpermission.Copyright1993.TheEndocrineSociety.)
Oligome norrhe ahasalsob eenassociat edwithpoor g lu cosecont rolan dlowbodyweightininsu lindepe nden tdiabet es(3, 8).Some casesofoligomenorrh eainwomenwithdiabe tesmayre presen taform fru steofh ypothalamicamenorrh ea. Forre search purp oses, the sestudiesde fin ehypoth alamic amen orr heaas3or6con secutivemonth sofmissed p eriodsandoligomen or rheaasirreg ularper iods occurringn in eorfewertimespery ear. Indiabet icwome n,asin nondiabet icwome n,th ecau sesof oligomen or rheaare dive rse.Oligomenorrh easp ecifictodiabete shasr eceivedve rylitt lest udy. Most invest igation sofoligomen or rheaan ddiabetesh ave focu sedon polycyst icovar ysyndrome(PC OS)and type 2diabe tesrather thantype 1diabet es.PCOSisde fin edbyoligomen or rheaan dhype rand roge nism (such ashirsu tismoracn e)or hyper and roge nemia(such aselevatedser umtestoster one con cent rationor DHE AS).Itisofte nassociate dwith obe sity andinsu linr esist ance and carriesah ig hincidence (30% 50%)ofsub seque nttyp e2diabe tes(23,24). PCOSisrar ein type1diabete swith negativeC-pe ptide levels(25).Prelevicetal.(26)foun dthatoligomenorrh eicpatien tswit hinsulin-depe nden tdiabet eswho were negativefor C-pept ide h adlowandrogen san dlowLH/FSHratios,wh ileth ose whowe reposit ive for C-pe ptidehadmoreclassicfeature sofPCOS,withelevatedandrogen le velsandLH/FSHrat ioan d historiesofobesityandoligomen or rheabeforeth ediagnosisofdiabe tes.On erece ntpaperh ascon test ed th eseviews,findinga39%pr evalen ceofPCOSinagr ou pofSpan ish patien tswit hinsulin-depe nden t diabet es(27).However, thisgroupdidnottest C-pept ide lev els, an dcon trolswer eexclude difth eyhad signsofhyper andr oge nism(h irsu tismoracn e)import ant becau senormalbody h airvarie sbyeth nicit y, sohigherh ir sutismscoresaren ormalinHisp anicwomen with orwith ou tdiabete s.Treatme ntwith insulin-sen sit izingmedicat ionsamelioratesth ehy peran drogenismofPCOSan dhasbe ensh own t o rest ore ovu latorycycles(28).Weigh tlosshasalsobe enfoun dtore storeregu larmense sandovulat ion, aswe llasinsu linsen sit ivityinPCOS(29).Becauseinsu linaugment sLH-drivenovar ianan drogen syn thesis,anelevation inandr ogen sthatinduce sin sulin resistan ce(30)isd ifficulttodist in guishfrom th eelevat edinsulinlevelsofinsu linre sist ance thatin duce h yper andr oge nism(31).Block adeofthisloop ineithe rdirection ,bytr eat in gtheh yperandrogen ism(i.e., with the ant iandrogen sestrogen ,flu tamide, orspir on olactone )ort reatin gthe in sulin resistan ce(i. e., with me tforminortroglitazon e)iseffectivefor PC OS(32). Oligome norrhe aalsoisse eninth esynd romesofsevere in sulin resistan ce.Type Ainsu linr esist anc e, whichisme diatedby insu lin- recept orde fects,andty peBin sulin resistan ce,wh ich ismediate dby an tibodies, shar esymp tompat tern sin clu din ghirsut ism,oligomen or rhea,an dhype ran drogenism. Treatmentofthe sesyndr omesincludest heu seofantian drogens, aswellasGn RHan alogu es,toblockL H product ion(33).Ade fe ctinthe in sulin recept orh asalsobeen fou ndinsomewome nwithPCOS(34). Ovariandysfu nctionissu ggeste dbyincreasedlevelsoft heandrogen s,includingte stost eroneand an drosten edione ,inwomen with in sulin -depen den tdiabete s(35).Howe ver,t hese leve lsareincre asedin normally cy clingwome nwithinsulin-dep ende ntdiabe tesan dare notusu allyassociat edwit hclin ical signsofhyper andr oge nismsu chash irsu tismoracn e,andth efree andr ogen le velsare n or mal(36). Rathe rthanan ovarianp roblem,th eseandrogen lev elsarelik ely duetoth eelevat edlevelsofse x
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hormon e-bindingglob ulin (SHBG)stimu latedby insu lin. Thisisfur the rsupported in astudy byDjur sin g etal. (36)thatfou ndth atSHBGle velswe redecr ease din theame norrhe icwome nbothwithandwithout diabet es.Thu s,hy pot halamic,pituitar y,an dov arian factorsmaycon tribut etomen stru aldisru ption in diabet es.
Carbohydrate Metabolism
Eve nwithre gularmenst rualcycles, manywomen with diabete snotech ange sin theirh omemonitoringof bloodglucoseresu lt sd uringth ecycle.In obse rvat ionalser ies ofwomen with diabete s,61%t o70%of pat ie ntsre port edcyclicglucosech ang es(7, 37) .Three fou rthsofthe sewomen describedh igh erglucose levelsin the lu tealph ase, e specially d uringth eweek b efor eme nses. Aconsisten tbut smallerse treport hy poglycemiaat t hebe gin ningofmen ses(Fig. 44.2). InLun tan dBrown 'sstu dy(37),36%ofth ewomen adju stedth eirin sulin toaccommodateper imens trualglucosech ange s,but thissubse tdidn ot hav e bet tercontr olan deven showe datr endtowar dslight lyh igh erlevelsofg lycosylate dhemog lobin .This stu dydid not assesscarbohydrateintakeorexe rcis ele velsbutdidnotet hat t heinsu lin-adjustinggroup rep ort edmorepe rimen stru alchan gesinapp etite.
Figure 44.2.Numberofsubjectsnotingaperimenstrualchangeinself-reportedcapillaryglucosemeasurements. (ReprintedfromLuntH,BrownLJ.Self-reportedchangesincapillaryglucoseandinsulinrequirementsduringthe menstrualcycle.Diabet Med1996;13:525530,withpermission.)
The mech anismbehindmen strualglucosech ang eshasbeenasou rceofcon troversy, perh apsbecauseof th ehet erogene it yof P. 750 individ ualresponse s.Inn or malcyclin g,n on obese ,nondiab eticwomen, some(38,39)bu tnotall (40,41,42), studiesofor alg lu coset oleranceh ave sh own adeclineinglucosetoleran cedur in gthe lut eal phaseofthemen strualcy cle. Progest erone, wh ich in creasesdur in gthelut ealphase,h asbee nimplicated ast hecauseofworse nedglucosetolerancebe cause ofitsability t oindu ceinsulinresistance(43). Int rave nousglucosetole ran cetestsh ave not,howeve r,shownconsisten tchanges acrossthe men strual cycle(44).E uglycemic, hyper in sulin emicclampstudiesinn ormalsubject sshowe dnodiffe rence sin basal levelsofglucose, in sulin ,or glu cose turn ove rduring thefollicularorlutealp hase (45,46).Incont rast, in hy perglycemicclampstu die s,impaire dglu cose met abolismissee nin the lu tealph ase(47).Wh ent hese sameinve stig atorsperformedhy perglycemicclampstu die sin womenwithinsu lin-de pende ntdiabe tes, th eyfou ndahete rogene ous r esponse, with nocycle phase differ ence sin somewomen ,an dadecr ease in luteal-phase in sulin sensitivit yin ot hers(48). Th ewomen whoshowedcyclicde crease sin in sulin sen sit ivityinclampstudieswe reth osewh on ote dpremenst rualh yperglycemia;howeve r,th eywere not differen tfromwomen wit houtcyclicd iffere nceswith r egar dtodu rat ionorcontrolofdiabet es,age,or bodyweight. Th eworsene dpremenst rualinsu linsen sitivitywasassociatedwithagreaterincr ease in estr oge nfromth efollicu lartolu tealph ase. The p resen ceor absen ceofp remenstr ualsyn dromedidnotaffe ctcarbohy drate me tabolismassesse dby oralglu cose toler ance testinginn ormalsubject sacrossthe cycle (41).Pr eme nstru alsymptomsin women with diabete shav ebeen cor relate don lywithde pression (specificallyn oth ypog lyce mia)anddo notdiffer(ex ceptth eperce ption bywomenwith d iabetest hat they we relessseve re)fromth ose in women with ou tdiabet es(7).
SEXUAL DYSFUNCTION
Somesu rveysh ave foun dah igh in cide nceofcomplaintsofsexualdy sfunct ioninwomen wit hdiabet es, whe reasoth ershavere port edasimilarinciden ceinwomen with and with ou tdiabete s[reviewedin
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refe rence (49)].Thespe cificcomponen tsofse xualdysfu nctioninwomen arepoorly unde rstood. In women ascomparedwithmen ,sexu alfu nctionismorevariablewit hinan in div idu alandacrossthelife cycle,h asalesspr edictablere spon setohormone s,an dismor esuscep tiblet osocialinfluen ces(50). The seissu esan dot hersh ave limited r esearchonsex ualdysfun ction in women, particular lyinwome n withdiabe tes(51).E xtrapolating fr omresearchonmalesex ualdysfun ction isn otn ecessarilyre le van t becauseofthe gende rdiffe ren cesin sexu alfu nction.Forin stan ce,incontr asttostud iesinmen ,the first stu dyofsildenafilin womensh owe dnoimprovementinse xualfun ction (52),althoug hon elate rstudy didshowsomeimprovemen tin sexu alfantasyan dsatisfact ion(53). Alsoin c ont rast t oth efindingsin men,t wostu die sofsex ualfun ctioninwome nwithdiabe tesfoundn ocorre lationbe tween sexualfu nction an dglycemiccontrol(with the caveatth atth esexu aldysfun ction p redat edth ediabete sin manyofthe subject s)(54,55).On estudy ofxer ostomianotedth atcomplain tsofvagin aldryn essweremorecommon indiabet icwome nwhohadabnormally lowsalivaryflowratesth an in oth erdiabe ticwome n(56).Th e lowsalivar yflowcorr elated with higherHbA 1 c bu tnotwithcar diovagalaut on omicdy sfunct ion.Th us, alth ou ghpoord iabeticcon trolandext ensivevascular andn eur ologiccomplication sare knownto contribut etosexuald ysfunct ioninmen(57), fe wdataexisttosupportparalle lsinwome n. Itisimportan ttoexclude oth ercomorbidillnesse sthatcaninh ib itse xualfun ction .Vulvovaginal can didiasis, wh ich can cause dyspar eun ia,occu rsmore fr eque ntlyinwomen with poorlycontrolled diabet es(58,59).Depre ssion, wh ich hasanincr eased p revalen ceinpeoplewit hdiabet es(60),isalsoa majorcause ofsexu aldysfun ction (61). Treat men tsforcomor bidconditions,particularlydepr ession and hy perte nsion ,alsocanh aveanimpacton sexu alfunction.Tre atmen tsforde pression ,espe ciallyselect ive serotoninre uptakeinhibitors,mayinh ibitsexu alfun ctionasasideeffect butalsoimprovesex ual fun ction asthe depre ssionistreated(62). Manyan tihype rten sive medicationsh ave b eenimplicat edin malesexu aldysfun ction. Inwomen ,th iazide diu reticsan dspiron olact on ehavebeen notedt odecr ease vagin allu brication (49).Insu mmary ,diabete shas n ot yetbee nshownt obeadir ectcau seofsexual dysfu nction in women, butkn owledge ofth ecommon issu esassociatedwith d iabetesofferspoten tial th erap euticapp roaches.
FERTILITY
Inwome nwithdiabe teswhohavereg ularmenst rualcycles,t heabilitytocon ceiveisn ot affecte d. Among womenwithinsu lin-de pende ntdiabe tesdiagn ose dpriortopre gnan cy,th ecumulat ive rate sof pre gnan cy(85%int hefirstye ar)andofinv olun tary infe rtility(17%)weret hesameasin the con trol Danishpopulat ion(63)(Fig. 44.3). Inwomen with me nstru alir regu larit ysuchasamenorrh eaor oligomen or rhea,missed periodsr eprese ntmisse dovu lation sandt here fore decreasedopportun it yfor fert iliz ation .Thu s,women with PC OSanddiabe tesmayh avede creasedfertilit y(32).Fertilityinwome n withPCOS(studiedinn on diabeticpat ie nts)isenh anc edbyweightloss(29)andinsu linse nsitiz ers(28). The r esultsofin vitr ofer tilizationinasmallseriesofwome nwithinsulin-dep ende ntdiabe tes,ingood controlaspar tofth eth erapy,were notdiffe rent fromthe resultsinwome nwit houtdiabe tes(64).Poor glycemiccontr oldoesnotimpairt heabilit ytocon ceiv ebutd oesimpairfertility becau seofanincre ase inspontaneousabor tioninproportion tot he P. 751 increaseinHbA 1 c (65).Forwome nsee kin gfertility ,the first approach shouldbeoptimizat ionofglu cose control,notonlytoimproveov ulation an ddecreaseth eriskofspont ane ou sabortion butalsoto decr easet heriskofbir thdefe cts.The prevale nceoffetalmalformat ionsisin creasedwhen gly cemic controlispoor duringe arlypregn an cy(66)(seeCh apt er61).
Figure 44.3.Cumulativerateofpregnancy(timetoconception)overmonthsfor139pregnanciesinwomenwith diabetesand199pregnanciesincontrols(19591989).(ReprintedfromKjaerK,HagenC,SandoSH.Infertilityand pregnancyoutcomeinanunselectedgroupofwomenwithinsulin-dependentdiabetesmellitus.Am J Obstet Gynecol 1992;166:14121418,copyright1992,withpermissionfromElsevierScience.)
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CONTRACEPTION
Cont racept ionisan essent ialissue in thecareofwomenwithdiabetes. Pre gnan cie smu stbeplan ned becausepoorgly cemiccontrolduringpr egnancyleadstoanincre aseinmate rnalandfetalcomp lications, an dgoodglycemiccont rolred ucesth atrisk(65,66). Ne vert heless,mostpregn an ciesinwome nwith diabet esare stillun planne d(63).Becauseofthemedicalimportanceofgoodcompliance with the contraceptiver egimen in thispop ulation ,logisticalissu esar easimp ort ant asme dicale ffectsan dsid e effect sassociatedwithvariou scon trace ptives(Table44.1). TABLE 44.1. Effectiveness of Family-Planning Methods
Effectiveness group Alwaysveryeffective
Family-planning method Norplantimplants Vasectomy DMPAandNET-ENinjectables Femalesterilization TCu-380Aintrauterinedevice Progestogen-onlyoral contraceptives(duringbreastfeeding) Lactationalamenorrheamethod Combinedoralcontraceptives
Pregnancies/100 women in first 12 mo of use (as commonly used) 0.1 0.2 0.3 0.5 0.8 1
Effectivewhenused correctlyandconsistently
2 68
Progestogen-onlyoral contraceptives(notduringbreastfeeding) Malecondoms Coitusinterruptus
Onlysomewhateffectiveas commonlyused
14 19
Diaphragmwithspermicide Fertilityawarenessbasedmethods Femalecondoms Spermicides Cap:nulliparouswomen Cap:parouswomen Nomethod
20 20 21 26 20 40 85
DMPA,depotmedroxyprogesteroneacetate.
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a Outsidethecontextofbreast-feeding,progestogen-onlycontraceptivesaresomewhatlesseffectivethan combinedoralcontraceptives.
AdaptedfromWorldHealthOrganization.Improving access to quality care in family planning medical eligibility criteria for contraceptive use,2nded.WHO/RHR/002.Geneva:WorldHealthOrganization,2000.
Forsomewomenwith advancedcomp licationsofd iabetes, con trac eptivesar enec essary forth e protect ionoftheirownhe alth. Pre gnan cymaywor senre tinopath y(67)and n eph ropathy (68) andis associate dwith in creasedmater nalmortality, especiallyifn ephr opathyorcoron ary arte rydisease is pre sent. Forwomen with the secomplication swhoh ave comple tedth eirfamilies,su rgicalst erilizationby tu balligat ionsh ou ldbe consider ed.Wome nwithdiabe tesne edcar efulcou nselingonth erisksofplan ned an dun planne dpregn an cy(seeCh apt er61).
Combination Oral Contraceptive Pills

Oralcontr acept ive pills (OC Ps)areth emostpopular formofre versiblecon traception an dareassociated withoneofthe lowestratesofunint ende dpregn ancy .OCPscombinesup raph ysiologicdosesofe strogen an dprogeste ron ean dwork bysever almech an isms,principallybysupp ressingth ehypoth alamicand pituitarystimu lationofth eovary. Acommonconcern ist hepoten tialt oworsen glyce miccon trolwith OCPs.Thisstemsfromre port sin whichearly OC Pformulation swereu sedat mu chhighe rdose sthanar e cur rent lyu sed.Worsen edglucosetole ran cewasfirstre por tedbyWain eetal. in 1963(69), wh on ot ed th atn on diabeticwomen t reatedwithah ig h-doseOCP(con taining100gofme stran ol)dev eloped impaire dglu cose toler ance .Women with ah istoryofgestation aldiabetesmellitu s(GDM),afirst-de gree relat ive with diabete s,orwhoareobese orold erar eath igh erriskforthe developmen tofimpaired glucosetole ran cewhile receivinghigh er-doseOCPs(70).Theimpairedglucosetoleran ceusu ally rev erseswithin6mont hsofdiscontinu ation,ex ceptinwomen wit hah istoryofGDM. Most OC Pscu rren tly in usearelowdose(<50gofes tradiol)OC Ps,wh ich alsocontain uptoa25-fold lower dose ofprogeste ron ean dhavemin imalton oe ffectonglucosetole ranc e,eve ninwomen with a historyofGDM(71, 72,73).Inwomenwithpre -existinginsulin-depe nden tdiabet es,OC Pscan also decr easeg lu coset olerance, butsignificant adver seeffectsonglucosecontr olare veryu nusu al(74).The low-doseOCPsmain taint hesamecont racep tiv eefficacyast heh igh -dose OCPsbu tar eassociatedwith a lower risk ofsomeofthe oth erdose-re latedsideeffe cts,such asstr oke andcardiovasculardisease, effect sthathavedete rredph ysiciansfromu sin gOCPsinwomenwithdiabe tes(75).Noton lydoch ange s inth eestrogen and p roge stindosesimpac tglu cose tolerance ,sododifferen cesinthe part icu lar progestin. Thegonane-de riv edprogestins(e .g., n or gestre l)pr odu cemoreh yperinsu line mia(71). VariousOCPfor mulationscanhavemin or ormark edeffectsonlipids, chan gesparticularlyimportantin women with diabete swhoalread yareatincreasedcardiovascularrisk. In alarge study ofnine differ ent OCPsused b y1,040women(with ou tdiabete s),compoun dswith desogestre lincre ased h ig h-den sit y lipoprotein(HDL)chole sterolandde creas edlow-den sit ylipoprot ein(LDL )cholest erol, compou ndswith levonorgestr elde creasedHDLandincre asedLDL,andn ore thindrone hadan inter med iateeffect (76)(Fig.44.4).Peters enet al.(77)examinedt heeffe ctsofOC Pswith noret histerone ,le von or gestre l, andge stodenein30diabe ticwomenandfoundn oadverse chan gesin plasmalipidsfromanyofthe compou nds.In rar ecases, OCPscanindu ceseve rehy pertriglyceridemia. Thisismostly ariskfor womenwithbaselin etriglyceridesgre ate rthan600mg/dL(78).E strogens are contrain dicated inpatient swith any ofth efamilialhyper trigly ceridemiasyndrome sbecau seofthe increasedriskofpancr eat itis.Womenwithdiabe teswhoar ereceivinge strogenth erapie sshouldhav e th eir lipidprofilesmonitoredbe cause poorglycemiccont rolalsoresultsinelevatedt riglyce ride s.This effect issecond arytoth edecre aseinlipoproteinlipaseactivit ycaus edbyrelat ive in sulin deficien cy. P. 752
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Figure 44.4.Lipidchangesinwomentakingoralcontraceptives.PercentdifferencesinHDLandLDLcholesterol levelsbetweenwomentakingoneofsevencombinationoralcontraceptivesandthosenottakingoralcontraceptives. LG,levonorgestrel;NE,norethindrone;DG,desogestrel;EE,ethinylestradiol.Numbersdenotedosage(g). (ReprintedfromGodslandIF,CrookD,SimpsonR,etal.Theeffectsofdifferentformulationsoforalcontraceptive agentsonlipidandcarbohydratemetabolism.N Engl J Med1990;323:13751381,withpermission.Copyright 1990MassachusettsMedicalSociety.Allrightsreserved.)
Hyper tension,anothe rin frequ entsidee ffe ctofOC Psinnormalwomen (79), me rit scarefu latten tion in th ediabeticpopulation.Stu die softh euse ofhigh -dose OC Psinh ealthy womende monstr ated n ew hy perte nsion in4%to5%andworsen in gin 9%to16%ofwome nwithpre -existinghy perte nsion ( 80). Thiseffectmay b eduet obotht heest rog enandth eprogestincompone ntsandisrever siblewith cessation ofth eOCP.Angiot ensinogen produ ction isincre asedb yethiny lest radiol(81),andprogest in s mayhavemin eralocor ticoidagonistoran tagonisteffect s.Sudde ndeve lopmentorworsen in gof hy perte nsion afterst arting OCPssh ou ldbe con side redacomplicat ionofthemedicat ionandmandates discon tinuation ofth eOCP.Fe wdataexistfor womenwithdiab etes, except forth elackofprob lems noted inst udieslookingat oth eraspectsofOCPsincarefullyselected popu lation s.Alarge(384women withtyp e1diabe tes)an dreassuringcr oss-se ctionalst udybyKleine tal.(82)showedn oass ociation bet we encu rren torpastu seofOC Psandseve rit yofh ypert ension or r etinopath yorle velofcur rent glycemiccontr ol.Anoth ersmalle rretr ospect ive study alsoshowedth at t heu seofOC Psinwomen wit ha mean ageof22.7y earsbu tameandur ation ofdiabe tesof13.8ye arsdidnotincre aseth eriskoft heir deve lopingearlyretinopat hyornep hropath y(83). Conce rnabou tin creasedriskofmacr ovascularcomp licationsstemsinpar tfromearlyretrospect ive observation sinaseriesofdiabeticwomen wh owe retakin ghigh-doseformu lation s,amongwhom cere brovascu larthr ombose sdevelopedinthr eeandmyocardialin farctioninon eof120women wh ou sed OCPscompar edwit hnosuch even tsinthe con trolgroup wh ou sednonh or monalcontraception(84).This increasedriskhasbeen supporte dbysubse quen tstud iesde monstr atingr elativerisksfrom1.8t o6.9in women with diabete sversu snondiabet icOC Puse rs(85,86).However ,neith erofthese studiesassessed th erelative r iskofcere bralor myocar dialinfarction in womenwithdiabe tesn ott akingOCPs.Anoth er stu dyshowedan in creasedrelat ive risk ofstrokeinwome nwithdiabe testh atwast hesame inu sersand nonu sersofOCPs(87). Theriskforcardiovascu lareven tsislikelybase don thrombot icev ents, which were in crease din woment akingOC Ps(88),andmayber elatedt oth eincreasedclot tin gfactors(factor X,factor II,plasminogen ,PAI-1)an ddecre asedplat ele taggr egat ionth atoccur with OCPs(89)andwith
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hy perinsulinemiaan dhype rgly cemia(90, 91).Olderstu die salsosh owedsomein creasedriskamon g nondiab eticOCPu sersascompare dwith nonu sers,bu tthe newe r(low-doseestrogen an dsecon d-an d th ird- gener ationprogestins)OC Psar eact uallyassociatedwitht hesameorlower risk ofcar diovascular disease in nonsmoking, nondiabet icOC Puse rs(88,92,93). It iscontr ove rsialwh eth erth esestu die scan app ropr iatelyaccoun tfor thee xcessriskofcardiovascular d iseasedu etos mokin g,whichishighand accoun tsforthe majorityofmyocardialinfar ctionsinyoun gwomen (94, 95).Inn on smokingwomen with well-cont rolled,u ncomplicated d iabetes, the reisprobablynotan excessriskofcardiovascu lardise ase associate dwith OCPu se,bu tth ish asnotyet been con firmedinprospect ive studies.Alarg e ret rosp ectivestu dybyKleinetal. (96)didn ot sh owanyex cessmortalityindiab eticOCPu sers. Th us,in other wiseh ealth ywomen with diabetes ,OCPsdecreasehe althrisksbyde creasin gther isksassociat ed withun in ten dedpre gnan cy.Forwomenwithcomplicat ionsofdiabete s,especiallyvascu lardisease ,or whosmoke, the seaddition alrisksofest rog en-progest in -based OC Psmustbe weig hedincomparison to th eaddition alrisksofpre gnancy. Newlyavailabletr ansd ermalformsofe strogen-pr oge stin con traceptivesofferth eposs ibilityofalowe r th romboticr iskbasedonext rapolation fromlower -dose tran sdermalhormon ereplace men tth erap y(97). Anothe rrece ntth erapyist heu seof OCPtablet stake ninextr adosesase mer gencypostcoitalcon traception .Thisappr oachprovideshighe r acu tebu tle sschronicexposur etoe strogenandpr ogest eroneandismoreconve nient .Un fortu nately,it isofte npoorlytolerat edan dnotaseffe ctiv easre gularOC Puse (98).Dataaren otye tavailableont he use ofth esen ewercontr acept ive optionsinwomen with diabete s. P. 753
Progesterone
Amajoradvan tage ofprogest erone-basedcontraceptivesisth elackoft hromboticor hyper ten sive effect s(75,81).Weight gainan dir regu larble edingare,h owev er,commonsideeffects. Progest erone contraceptiveoption sin clu dedailypills,sh ort -termdepotinjection slasting3month s(e.g. ,De poPr ove ra), andlong-te rmimp lantsinsilasticcapsuleslast in g5years(Nor plant). Intraute rin edev icesalso maybecoat edwit hprogeste ron e.Progester on e-onlymini-pillsar enotase ffectiveat suppre ssin g ovulationasarecombine dOCPs, butt heye ffe ctivelydecreaseth evolu meofcerv icalmucus andincre ase itsviscositytoblockimplantation(98). Progeste rone-onlypillshavenotbee nstu die dforth eireffect son glucosecontrolinwomenwithdiabe tes,bu tth eirhighriskoffailur eisacon cern (98).De pot formu lation sofprogeste ron edonotfailasfrequ ently, b utth eymayincre aseinsu linre sistance slightly (99)an dare associatedwithweigh tgaininsomeind ividuals(98). Su bdermallevonorgestr el(Norplan t) offe rsthe advantageoflong-lasting con trace ption (u pto5years),wh ich issu itableforman yyounge r women ,but requ ire saminorsu rgicalproce dure forinser tion. Lon g-act in gprog esterone formulat ions offe rgoodcontr acept ionforpat ien tswhoare unable tocomplywith dailypills. Eme rgen cycon traception can alsobe accomplishedwithpr oge steronealone ,usingt wodosesoflev onorge strel(PlanB),wh ich wouldhave littlemetabolicimpactondiab etesbu tislesse ffe ctivethanch ron icu se(98). Pr oge sterone cont race ptiv esallworsen glu cos etoler ance tosomedegre e,whichisan issu eespe ciallyfor women ath igh risk ofprogress in gtot ype2diab etes, suchasthosewithahistor yofgest ational diabet esor PCOS. Kimetal. (100)per formedacase-contr olstudy ofdepotmedroxyprogest erone ace tat e(DMPA)u serscomparedwithOC Puse rsamon gNavahowomen, agroupatvery h ig hriskfor deve lopmentofdiabet es.The yfou ndth atth eriskofdiabetesdoubledinwome nwhoused DMPA comparedwithth eriskinwomen with nohistor yofcontr acept ive useandth atth eriskincreasedwith lon geruse .Women gaine dapproximately3kgd uringth efir styearofu se,bu tthe excessriskof deve lopingdiabe tesper siste deven after adjustmen tfor b odymassinde x(BMI)([we igh t(kg)]/[h eig ht (m) 2 ]).Int erest in gly, the r iskofdeve lopingdiabet eswaslowe rin theOC Pgroup t han in either the controlorDMPAgroups.In womenwith preexistingdiab etes, chan gesinglucosetole ran cedue t o progeste ron econtraceptive s,whichwere greatestwithn or gestre l,didn otn ecessitat ean in creasein insulindoses(71).Use ofcontinu ou ssubder mallevonorgest relwasfou ndtoincreaseinsu linre sistance progressivelytoaplat eau after thefirst6month sofu se(101). Lipidprofilesinwome nwithdiabe tes showedincre asedLDLcholester olan ddecreasedHDLcholest erolwithDMPAbut decreasesinbothLDL an dHDLwithsu bdermallevonorgestr elorIUD(99)(Table44.2).Conce rnshavealsobeen raisedabou t possiblede crease dbon eden sit yin womenu sin gDMPA. Prospectivest udies(inwomen with ou tdiabet es) haven owshownth at, compar edwit hwomen usingOCPs,wome nusingDMPAlosebone (17, 102),bu t whe ther thisisr eversibleoncessationofthe rapy h asn otbe enassessed. TABLE 44.2. Lipid Profiles in Women with Diabetes Taking Oral Contraceptive Pills
Type of contraceptive CombinedOCPs
Fasting glucose
Total cholesterol
Triglycerides
HDL cholesterol
LDL cholesterol
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DMPA Norplant IUD
DMPA,depotmedroxyprogesteroneacetate;HDL,high-densitylipoprotein;IUD,intrauterinedevice;LDL,lowdensitylipoprotein;OCPs,oralcontraceptivepills. AdaptedfromDiabKM,ZakiMM.Contraceptionindiabeticwomen:comparativemetabolicstudyofNorplant, depotmedroxyprogesteroneacetate,lowdoseoralcontraceptivepillandCuT380A.J Obstet Gynaecol Res 2000;26:1726.
Nonhormonal Contraception
Non hormon almet hods,in cludingcondoms, I UDs, rhyt hmmeth od s,an dsterilization ,havenosyste mic effect sandpr ovidesafercontr aceptionforwomenathighr iskforvascularorclott in gprob lems. Howe ver, except s terilization, the yareassociatedwithh igh failu rerates(98).Malecondomsareth e onlyformofcont race ptionofferingpr ote ction fr omin fectiou sdise ase. IUDs, whichact prin cipallyby a mechanicaleffecttoblockimplantation ,oft enarecoatedwith proge sterone toincr ease t heirefficacy. The ydon oth ave anydisadvan tage ssp ecifictowomenwith diabetese xceptforth ehighratesof un plann edpreg nan cyat3.5%andofdiscontinu ationafter24mon thsofuse ,on ly 57%ofwomenwer e stillusing t heIU D(103) .Instu die sofIUDsinwomen with diabete s,sideeffectswe refrequ ent and includede xpulsionandre movalforble edingorpainbu tweren ot differ entfr omresultsinn on diabetic women (103,104).Cont racep tionbasedoneith ercoitu sin terr uptu sort imin gofovulat ion(r hyth m method)ishighlyineffect ive andisnotre comme nded.
DIABETIC MASTOPATHY
Diabeticmastop ath yisarare complicationu niquet odiabe tes.It isafibro-inflammat ory diseaseofthe bre astth atpr esent sasafirm,nont ende rbreastlu mp(orlumps)an dmaybedifficu ltt odistinguishfr om malign ancy on p hysicalexamination. Itoccu rsmostlyinpre men opausalwome nbut hasbe ende scribe d inmen(105).Nearlyallreporte dcasesh avebe eninpatientswith type1diabete s;thefewpatient swith type 2diabe teswere takinginsu lin(106).Diabeticmastop ath yisde scrib edin womenwith anaverage dur ationofdiab etesof13(106)to18year s(107)an doccu rsinthe settingofot her d iabetic complication s,includingre tin op ath y,ne uropath y,andne phropat hy(106).Onmammograms, P. 754 diabet icmastopathyappear sasden separ ench ymalch an ges,whileultrasou ndalsoshowsnonspecific change swith acousticshadowing(108).Pathologicspecime nsshowkeloidalfibrosiswithmononuclear per ivasculit isandmon on ucleardu ctitisorlob ulitis(106, 109).Th eselesion sarebe nignan dare not associate dwith anincr ease din cide nceofneoplasia.In the largestser ie sof19case s,fou rwere bilate ral an dsix recur red,h igh ligh tin gthe need forawaren essth atcouldspar ethe sewomen r epeatedbiop sies (110).
MENOPAUSE
Menopau seisdefin edasthepe rmanen tcessation ofmenstr ualperiodsan drepre sentst helossn ot on ly ofovarianfollicle sb utalsoofth eelevationsofestr oge nan dprogester on ethataccompaniedt hemon thly matu rationoft hosefollicles.In addition tot helos sofmenses, the immed iateeffect softh elossofthe ster oidhormon esare hotflashesandvagin aldryn ess.In thelongert erm,the hypogonadismof menopau seisassociatedwithincre asedcardiovascularr iskandosteoporosis,both ofwhichare increasedinwomen wit hdiabet eseven beforemenopau se. The ageofmen op ause in womenwithty pe1diab etes(111)andt ype2d iabetes(111,112)h asbe en showntobet hesameasthatin ot herwome ninth esamepopulations.However ,the possibilityof ext ensivecomp licationsofd iabetesse con darilyterminat in govarianfu nction wasnotev aluat edinthe se stu die s,whichincluded subjectswithameandu rationofd iseaseof9an d17yearsand d idn otassess complication s.One recen treportdiddescr ibe ane arlie rage ofmenopau seassociated with diabete s.In th eFamilialAu toimmun eDiabetesStu dy,wome nwhowere d iagnosedbefore1964an dhadamean dur ationofdiseaseof34ye arswer eamean of6year syou nger atn atu ralme nopause thanwere their contemporar ieswh odidnothavediabe tes(113).Howe ver,t hisstudyinclude son ly15wome nwhohave reache dmen opause, five ofwhomhadpr ematur eov arian failu rean dan oth erautoimmune d isease,wh ich can bepartoft hepoly glandu larau toimmun esyn drome. Dat afromfu rthe rfollow-u pofth iscohortwillbe
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ver yin tere stin g. Pr ematur eov arian failu re(POF),de fin edasmen opausebe fore t heageof40, isacompon ent ofsev eral un commonsy ndrome sthatalsoinclude diabete s(Table44.3).Oneofthe morefre quen toft heseis polyg landular aut oimmun edisease ,type II .Poly glandu larau toimmun esyn dromesareth eassociation sof multiplede struct ive aut oimmun edisease sin endocrinet issu es. TypeIIpolyglandu larau toimmu nedisease,orSchmidt syndrome,includest heconste llat ionof au toimmu net hyroid d iseaseandAddison dise aseinassociationwithau toimmu nediabetesasredefine d byC arpen terin1964(114).POFoccursinlessth an10%ofth esepatient s;oth erinfre quen t manifestation sarepe rniciou sane mia,ce liacspr ue, lymphocytichypoph ysit is,andvitiligo(115).Sch midt syn dromeh asincomplete lype netr ant ,au tosomaldominan tinhe rit ance with on setusu allyin the20sor 30s.The in div idu alcompon ent smayoccu rin an yord er.The refore, inpatient swith aut oimmun ediabet es an damenorrh ea, thyr oiddisease andadren alin sufficien cymu stbeconsider edasre versiblecau sesof menstr ualdysfu nction .The d iagnosisofPOFismade byamenorrh eawith anincre asedFSHbeforeth e age of40years.Afte rthe exclusion ofother cause s(chemother apy, r adiation,orkaryot ype abn or malities),anti-ovarian ant ibodiesare presen tin27%ofpat ie ntswithPOF(116).POFisnot rev ersible ,but someovarian folliclesmaystillbepr esent atdiagn osis.Forwomense ekingfert ility, car efulmonitoringmayrev ealthe serareovulations,andpre gnan cie shav eoccu rred ( 117,118).Once t he diagn osisofpr ematur eov arian failur eise stablished, itisimportanttoscree nforthyr oidan dadre nal failure. TABLE 44.3. Syndromes with Diabetes and Premature Ovarian Failure P. 755
Syndrome
Type of diabetes Autoimmune
Type of hypogonadism Primary
Other clinical features Primary hypothyroidism, Addisondisease,celiac sprue,pernicious anemia Bronzepigmentation, cirrhosis,dilated cardiomyopathy,loss ofbodyhair Shortstature,webbed neck,hearingloss, shield-chest,low hairline,thyroiditis Mongoloidfacies, cardiacstructural abnormalities,mental retardation,shortened phalanges Shortstature,short metacarpals,round facies,parathyroid hormoneresistance Polyneuropathy, organomegaly, endocrinopathies,Mproteins,skindisorder Earlyataxia, oculocutaneous telangectasia, immunodeficiencies, dysgeneticgonads Shortstature,bone marrowhypoplasia, radiusmalformations, abnormalpigmentation
Etiology
Polyglandularautoimmune syndrome
Destructive lymphocytic infiltration
Hemochromatosis
Insulin resistantor deficient
Primaryor secondary
Autosomal dominant defectscausing ironoverload 45XO karyotype
Turner'ssyndrome
Insulin resistantor autoimmune
Primary
Downsyndrome
Insulin resistant
Primary
Trisomy21
Pseudohypoparathyroidism
Insulin resistant
Primary (resistanceto LH,FSH)
Gs-inactivating mutations
Crow-Fukase(POEMS) syndrome
Insulin resistant
Primary
Plasmacell dyscrasia
Ataxiatelangiectasia
Insulin resistant
Primary
Autosomal recessivedefect inDNArepair (inATM helicase) Autosomal recessive proximalrenal tubule
Fanconianemia
Insulin resistant
Primary
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dysfunctiondue toDNA-repair defect Wernersyndrome Insulin resistant Primary Prematureaging, atrophicskin, cataracts,early osteopenia, atherosclerosis Musculardystrophy, mentalretardation, prematurebalding, hypothyroidism Autosomal recessivedefect inDNArepair (inWrn helicase) Autosomal dominant trinucleotide repeatin proteinkinase DMPK Chromosomal deletioninSNRP gene
Myotonicdystropy
Insulin resistant
Primaryor secondary
Prader-Willisyndrome
Insulin resistant
Secondary
Infantilehypotonia, mentalretardation, shortstature,morbid obesity Ocularmyopathy, pigmentary retinopathy,cardiac conductiondefects, ataxia
Kearns-Sayresyndrome
Insulin deficient
Secondary
Chromosomal deletionsin mitochondrial DNA
FSH,follicle-stimulatinghormone;LH,leutenizinghormone.
Turn ersyn drome, whichmaybelessev ide ntinitsmosaicform, caninclude in sulin -resistan tdiabet es an dPOFdue topr imary g on adalfailure. Hemachromatosis, associatedwithironoverloadinvarious organ s,includingth epan creas,live r,an dpit uitar y,maypre sentwith d iabetesandsecond arygonadal failure. Me nstru alble edingre ducesth eincidence ofironov erloadin women. Crow-Fu kase syndrome (POE MS)isaplasmace lldyscrasiawith polyn europathy, organome galy,en doc rin opathy ,Mpr ote in ,an d skinch ange s.Thisdise aseu suallyhasanonse tin the sixt hdecade,sothe gon adalfailure may notbe recogn ize difawomanisalreadyperi-orpost me nopausal. Severalmoreraredisease ssuchasKearnsSayr esyndr ome(withmyop ath y)and myotonicdystrophycanpre sent with POFand d iabetes. Also, syn dromeswithimp airedDNAre pairan d/or met abolisms uchasWerne rsyndr ome(withpre mature aging ),Fanconian emia(with prox imaltubu lardefec ts),an dataxia-te langiectasia,are associatedwith diabet esan dgon adalfailure .Inth esee ntities,othe rfeat uresofthe syndromewillsign althe d iagnosis.
Perimenopausal Symptoms
De spit ethe variousinfluen cesofdiab etesonmenst rualfun ction ,litt ler esearchhasbeen don ereg arding symptomsatthe cessationofmen ses.Noin crease in hotflashesisseen in womenwith diabetes(112). The inciden ceofvaginaldry nessmaybe in crease din relationtoHbA 1 c (56), butge nitou rinar yatr oph yat menopau sehasnotbeen specificallystu die d.One wouldexp ectnodifferen cesin short-te rmh or mone rep laceme ntth erapyfor treatme ntofthe sesymp toms,bu tthisalsohasn ot b eenformallyst udied.In onestu dyofu ncomplicate dtype2diabete s,the in cide nceofpost me nop ausalanxiety andde pression wasslightlyincreasedandwasassociat edwit hdur ation ofdiseasean dpremenopausaldepr ession(119). Itiswelldocument edth atdep ression in g ener alisabou ttwiceascommoninthe diabeticpopulationas inth enondiabe ticpopulationandth atde pression ismor eprev alentinwome nwithdiabe testh aninmen withdiabe tes(60).
Hormone Replacement Therapy

Est roge nrep laceme ntth erapyist hepr escription oflow-doseest roge ninpostme nopau salwomenwith th ein ten tofre versingt hech ange sofmenopau se.In womenwh oh aven ot unde rgon ehy stere ctomy,t he use ofprogest eronewithe strogenisnece ssaryt opre ven tendometrialcan cer.Th ecombinat ionof estr oge nan dprogester on eist ermedhormon e replace me nt th erapy(HRT).Beforeth ene edfor progeste ron ewasr ecog nized,most womenre ceivedest roge nalone, andh igh erdoseswer eused;t hus, someolderstu die sofest roge n rep laceme nt th erapy(ERT)sh owsideeffec tsthatmaybediffere ntfrom th osee xpecte difth estu die swe redonewith HR T.ERTu sin gthesame estrogen dose sasHRTis cur rent lyappropriate forwomen whohav ehadahy sterect omy.HRTh asbee nuse dforsh ort -term tre atment ofper imenopausalsymptomsandlon g-termredu ction ofcar diovasc ularriskan dasamajor
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th erap yforosteoporosis.Mostoft helit erat ureonHR Tisbase don largepopulat ionstu die sthatin clu de ver yfewwomen with diabetes .Becau seoft heirincre asedriskforcar diovascu lardisease ,dyslipidemias, an dost eoporosis,the ris ksandb enefitsofHRTarep articular lyimport ant forwome nwit hdiabet es.New prospectived ata(cove redbelow)h ave dramat icallyalter edthe prescriptionofHR Tforcardiovascular protect ion,andmor edat aare nece ssaryt oap plyt odecision sforwome nwithdiabe tes.
Cardiovascular Disease
The cardiov ascular bene fitsofHRThavebeen the majorreason for itsu seinnondiabe tic women. Pr eme nopau salwomenh avealowerr iskofheartdiseasethandome noft hesameage,bu tth at adv ant agedisap pear saftermen opause. Large -scaleepidemiologicstu die sh ave shownthatre stor ation of th epremen opausalhormon eswit hHRTisassociatedwitha30%to50%reduct ionindeath fr om car diovas culardisease (120,121,122).Un fortu nately,most ofth emajorstu die s(Ran cho-Bern ardo, Postmen opausalEst roge n/Proge stinInt erven tion s,Fr amin gham,andNur ses'Healt h)includer elatively fewwomen wit hdiabet es.Ont hebasisofthe sestud ies, it u sedtobere comme ndedt hat most postme nopau salwomenu seHRTtoredu cecardiovascu larrisk.Mor talit yduet ocardiovasculardiseaseis fourfoldgr eate rin pos tme nopausalwome nwithdiabe testh aninpostmenopausalwomen with ou t diabet es(123). Howeve r,pre me nop ausalwome nwithdiabe tesdonotshareth elowerpr eme nopau sal car diovas cularriskincomparisont omenth at issee ninwomen with ou tdiabete s(124).Th issu ggests th atpre me nop ausalwome nwithdiabe tesmayder ive le sscardiov ascular bene fitfromHR T.Twocasecontrolstudiesindiabe ticwome nhavesh ownt hat curre ntu sersofHR Th ave noinc rease dris kora red ucedriskofmyocar dialinfarction compare dwit hnev er-use rs(96,125). Seve ralcomponen tsofth ecar diovascularsyst emt hat may con tribute t oth eestr oge n-associate d mort ality bene fitsaread verselyaffe ctedindiabe tes,including lipid s,carb ohy drat eme tabolism, he mostasis,andvascularfu nction .Inaddition, the e ffectsofdiabete sont heinciden ceofcoronar yheart disease aree xace rbate dbyeachoft hestandardriskfactors:smok in g,hype rten sion, lipid concen trat ions, andBMI(126). Short-ter mstu die s(612we eks)ofERTan dHRTin womenwith type2 diabet eshaveshownimp rove me ntinlipidprofilesandinglucosecontrol(127,128).Thes eme tabolic effect sarer ele van twhen HRTisu sedforany in dication .
Lipids
Women 'stotalandLDLchole sterolleve lsincr easeaftermen opause. Th isch an geinthe lipidprofileis associate dwith anincr ease drisk ofcar diovasculardiseas ean disimpr ove dwith HRT(129).U pto25% oft hebe nefitsofHR Th ave been attr ibu tedtoth eeffectsonlip ids(122).Diab etescanfurt her exacerbateth epostme nopau sallipidprofile,andtre atment is P. 756 esse ntialbecauseofthealr eady h eighte nedr iskofcardiovascu lardiseaseindiab etes. Inpat ie ntswith type 1diabe tes,th emostcommonab normalityisan ele vationofvery-low-d ensitylipoprotein(VLDL) triglycerides, whichis corre latedwithdiab eticcon trol(130).Thiselevat ionisduet oth edepe nden ceof triglycerideclearan ceon the activityoflipopr ote in lipase ,whichisin sulin -depen den t,aswe llastothe increaseinproduct ionofVLDLfromt hemobilization offre efatt yacids.Int ype2diabetes, in sulin resistanceandobesitycombine tocauseaddit ionale lev ation sin LDLch oleste rolan d/ortolowerth eHDL cholester ol(Table44.4).StudiesofHRTin type2diabete sshowimprovementinLDLcholester olwith litt le orn och ange in tot alcholest erolandas mallin creaseor noch an geintriglycerides(ev enina subse tstartingwithelevatedt riglycer ide s)(127,131,132, 133,134).Although two(127,132)ofthe se stu die sfoun dan improvementinHDLchole sterol,the oth ersfoun dnochan georasmallde cline . Tran sdermalHRTregimensdonotpre sentt hesameh igh dose ofest rog entothe liver anddonotap pear toraiseth etriglycerideleve lasmuch asdoor alregime nsin women with ou tdiabete s.Infact,th eone stu dylookin gatt ran sdermalestrogen useinty pe2diabe tesfoundadecre aseintotalch oleste rolan d triglycerides(97). Be cau sethe reisalsoarare risk ofseve rehy pertriglyceridemiawithER T(78), transde rmale strogensareab etter choiceforwomen wit hmoder atelyelevatedt rig lyce ride s,but any estr oge niscon traindicat edinwomen with markedlyelevatedt riglycer ide s(>600mg /dL).Poorglu cos e controlwith ou tot her metabolicproble msty picallyincreasestr iglycerideconce ntration son lyby twofold tothr eefold, butincombination with manyillne ssesan dme dicationst hat cause hyper trigly ceridemia,or inth eprese nceoffamilialh yperlipopr ote in emiasyndromes,seve reh ypertr iglycer ide miaismorelik ely to occur. TABLE 44.4. Lipid Profiles in Postmenopausal Women with Diabetes
Characteristic Postmenopausal
Total cholesterol
Triglycerides
HDL cholesterol
LDL cholesterol
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PostmenopausalwithDM PostmenopausalwithDMon HRT
DM,diabetesmellitus;HDL,high-densitylipoprotein;HRT,hormonereplacementtherapy;LDL,low-density lipoprotein.
Glucose Tolerance
Although g lu coseint olerancewasseen ine arlystu die sofOCPsan dhigh-doseER T(100g ofeth in yl estr adiol)(135), curre ntlow-d oseoralHRT,wh ich hasapproximately1/20th edoseofe strogen, hasn ot bee nshowntoadv erselyaffe ctin sulin sensitivityan dmayimproveit.Datafromlarge coh ort studies showlowerfastingglucoselevelsin nondiabe ticanddiabe ticwomentakingestr oge n(136, 137).Also th ereisneith erad eteriorationinglucosetole ran ceafte r12month sofes trogenu sein normalwomen (138)n or anincre aseinth enu mbe rofwome nwhodeve lopdiabet esafte rusingHRTforseve ralyears (139). Decr ease sin Hb A 1 c h avebe ende monstr ate din womenwithty pe2diab etestakingHRT (128, 133,140,141).Brussaarde tal.(127)h ave demon strat eddecre asesinHbA 1 c ,h epat icglucose product ion,andwaist/h ip r atioafter6weeksu seofHR Tint ype2d iabetes.
Vascular Effects
Acon cern aboutHRTth ath asbe encarriedov erfromth eexpe riencewith OCPsisthe ris kof hy perte nsion .Fortu nately,HRTdoesnotappear t oincre aset heriskofhyper tens ionan dhaseven been shown(inn on diabeticwomen )tolowe rbloodpressu rebyafewpoint s(142).On esmallprospect ive stu dylookin gatHR Tint ype2diab etessawnoch an geinrest in gbloodpressur e(140). Sz ekacse tal. (143)obser vedapr ote ctiveeffect ofdecre ased p rot ein uriawith out achange inb loodpr essur e. Vascu larchangesh ave alsobee nproposedasamech an ismfor d ecreasedcar diovasc ularmorb idityand mort ality among womenre ceivin gHRT.Inn on diabeticwomen ,estr oge nhasbeen showntohav ea myriadofe ffectsonth evascu latur e,decr easingplasmafibrinogen andPAI-1concen trationsand stimu latingnitricoxid erelease and vasodilat ion, aswellaslong-t ermgenomiceffect spromotin g vasodilation and r epairofendoth elialcelldamage(91). Pat ie ntswithdiabe teshaveanincreasedriskof th rombosis, wh ich cou ld b eduet ovasculardy sfunctionoraltere dcoagulability butisstillpoorly un derst ood.Incr ease dle velsoffibrin og en,PAI-1, andsomeofth ecoagulationfactor s,aswe llas abn or malitiesofp lateletsan den doth elialfu nction ,havebe enfound (144).Although le velsofsomeof th esefact orsh ave been e valuatedwithHRTinwome nwit hdiabet es,n ocorrelat ionh asyet been mad e withabsolute risk ofclott in g.Thisrepr esen tsanimport an tare afor furth erstu dy. Veryr ecen tly ,prospectivedatat hat arecausingsome c onc ernre gard in gtheu seofHR Tinn on diabetic women are b ecomingav ailable .TheHe artandEst rog en/Prog estinRe placeme ntStu dy(HERS)h asshown noclearbe nefitsfromHRTforsecondarypre vent ionofcardiovascu lardise aseinth efirst4y earsof tre atment (145).Th eriskofarecur rent coronaryhe art d iseasewassk ewedtoamarke din creasein the first4monthsofth erapy ,whichtapere ddown unt ilarelativ eadvantageshowedinye ars4and5.This hasbeen furth ersu bstan tiatedb yHeckbert etal.(146),whofou ndanincreasedriskofrecur rent myocardialin farctionwithin60day softh ein it iation ofHRT,wh ich decline dthe reaft er.Th esestu die s highlightt heimportanceofprospectivedata. Alth ou ghth eabove st udiesofse rummarker sof car diovas cularriskfact orssh owimpr ove me ntwithHRTinpatie ntswithdiab etes, itwillbese veralye ars beforede fin itivee vide nceofpotent ialmor talit ybene fitsofHRTindiabet esbecome savailable.In the mean time, mostguidelinesarediscou ragingt heinitiation ofHRTsolely forcardiovascularriskre duction.
OSTEOPOROSIS
The e xten sionofthe aver agelife expect ancy ofpeoplewit hdiabet esthathasaccompanied improvemen tsin me dicalcareh asincreasedth esignificanceofost eoporosis .Alth ou ghonce controver sial, thee vide ncet hat b on ehealt hiscompromisedindiabet es P. 757 isnowst ron g.Bonemin eralde nsity(BMD)islowerandth eriskoffractur esisincr ease d.Sever al mechanismsh avebe enpr oposedfordiabete s-relate dost eop orosisandinclude bot hthe comor biditiesof diabet esan dmoredirect path oph ysiologiceffect softh edisease itse lf.
Fractures
Hipfractu res, inparticular ,are nowr ecognizednotonlyasamajorcau seofmorbidit yand mortalitybut alsoforth eirsignificantimpactoneconomican dsocialcircumstan ces.Mortalityishighinth egene ral
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populationwit hhipfracture s,but thepr esen ceofdiabe tesinap atient with ahipfracture isarisk factor forin creasedmortality(147).Case-contr olstudiesofpatien tswit hhipfracture shav efou ndan excessof pat ie ntswithdiabe tes,su ggestin gatleast atwofoldrelat ive risk inallpatie ntswithdiabe tes(148). Women wit htype 1diabet eshada6. 9-to12-foldre lativ eriskofh ipfractur escompar edwithwomen withoutdiabe tes(149,150). Dat aar econ troversialabou tthe risk ofhipan dspin efracture sin patien ts withtyp e2diabe tes.Moststudies(148,149, 150,151)in women with type2diabete salsohavefoun dan increasedriskofhipfractu res, with estimatesofrelativeriskalmost dou ble ther iskinothe r postme nopau salwomen. Inth eStudyofOsteoporot icFract ure s,women olderth an 65y earswith t ype2 diabet es(asde fin edbyexclud in gthosewithad iagnosisbe fore t heageof40ye arsorwithaBMI<30), hadan in crease driskofh ipandproximalh ume rusfractur esdespiteh avingahigher BMDthanwomen withoutdiabe tes(152).Ther ewasalsoatre ndtoward inc rease dris kofver tebral, fore arm,ankle,and footfractur es.In con trast ,ot herinv estigatorsh avefoun dfewerfracture sin womenwitht ype2 diabet es,withasimilarlyincr ease dBMDatth espine(153,154) .Theonesitewith anu ndispute d increasedfractur eriskisth efoot, whichmaybere latedinparttoobe sit yorn eur opathy(152,155,156). Focalosteopen iaandfr actu resassociate dwith sever ediabeticper iph eralne uropat hy(Ch arcotfoot )are lon grecognizedasacomplication ofanytype ofdiabe tes.
Bone Density
Although man yfact orsinfluen ceth eprobability offracture s,in cludingnu mbe ran dtypeoffalls, padding oft hebonyp romin en ces,an dgeome tryofthebone ,th emostsignificantfactoristh estr ength ofth e boneitself.Bonest rengt hisprop ort ionaltoBMD,wh ich canbe measure dradiograph ically. An in div idu al measu rementisclassifie dbasedont hedeg reeofradiograph icde nsityincomparisont oth atinanormal population,withosteopen iadefinedas1.0to2.5stan dar ddeviation sbelown ormalan dost eoporosis define das2. 5ormorest and arddev iations b elownormal(157).Boned ensitomet rytech nique sh ave becomemu chmore soph isticatedinth epast t wodec ades, allowin gmorepr ecis ean daccur ate measu rement, aswellasme asu rementatdiffe ren tsit es.Bas edon the sechanges, more-re cent d ataare more sensitivetodiffe rence sbetwee ngroups. Osteopen iawasinitiallyde scribedinadolescent swith diabete s,50%ofwhomwe refoundt ohave decr eased cort icalandtrabecu larfore armBMD(158). Se veralsu bsequ entst udiesfou ndth att heforearm BMDinchildren with on ly4to6yearsoft ype1diabeteswas20%to50%lowerth ant hat in cont rols (159). Onestu dyexamining v erte bralBMDdidnotseeadiffer ence inch ildre nwit hdiabet es(160). Most stu die sin adultsconfirmt hat BMDislowe rin patien tswit htype 1diabe testh aninsu bje ctswit hout diabet es(111, 161).In con trast ,stu dies inwomenwithty pe2diabe tes,cont rollin gforageandobesit y, showBMDth atiseither thesame orgr eate rthanth atinn ormalsubject s(153,154),eve ninpat ie nts tre ate dwith in sulin (111)(Fig. 44.5). Th eRanchoBern ard ostu die salsolookedatmenwithty pe2 diabet esan dfou ndth atth eirBMDwassimilartoth atinmenwithn ormalglucosetole ran ce,des pite the differen cesth estudiesfoun din women(162).
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Figure 44.5.Bonedensityindiabetes.Meanbonemineraldensity(BMD)(adjustedforageandbodymassindex)at theproximalfemurofsubjectswithtype1diabetes(29men,27women),type2diabetes(34men,34women),and withoutdiabetes(240men,258women).(Copyright1999AmericanDiabetesAssociation.FromTuominenJT, ImpivaaraO,PuukaP,etal.Bonemineraldensityinpatientswithtype1andtype2diabetes.Diabetes Care 1999;22:11961200.ReprintedwithpermissionfromtheAmericanDiabetesAssociation.)
Mechanisms
Isosteopor osisan oth ercomplicationofpoorgly cemiccontrol?Sh ort -termme asur esofcont rolsuch as glucoselevelsor Hb A 1 c leve lswouldnotbeex pectedt ore flect cumulativebone d amagemeasu redby BMD.Diabeticcomplication sare thecu mu lativeresu lt soflon g-termpoorcont rol.Sev eralinvest igators havedemonstratedanassociationbet we enBMDandmicr ovascularcomplications,with t heBMDinve rsely correlat edwit hthe prese nceandext entofmicrovascu larcomplication sin womenwithn or malmenst rual cycles(161, 163).Mat hiassen etal. (164)ob servedt heBMDsof19patien tswit htype 1diabet es(8 women ),initiallyfre eofcomp licationsan dfou ndth atafter11ye arsonlythosewh odev eloped ret in opathy orprote in uriahadwor seningofthe irBMD.Thepr esence ofsev erepe riph eraln europathyin pat ie ntswithty pe1diab etesh asalsobeen foun dtocorr elatewithde creasedBMDat allsites, in comparis ont opatientswitht ype1d iabeteswith ou tneu rop ath yand incomparisontohealt hysubject s (165). Alth ou ghth esewer esmallgroups, they werematch edforot hercomp licationsan dfor activity levels.U sin gthesame paradigm,For stetal. (166)fou ndadecreasedBMDinth ecorticalbon eatt heh ip an ddistallimbin associationwith p eripher alneu ropathy butn ormalBMDinthe spin eofp atient swith insulin-depe nden tdiabet es.In theBlue Moun tainEy eStudy inAu stralia,anassociationbet ween ret in opathy andallfract ureswasseen in both me nan dwomenwith alltyp esofdiabe tes(167). Hyper calciu riahaslongbe enn ote din patien tswit hpoorlycontrolle din sulin -depen dent diabetes (168, 169)an dnon-insu lin-de pende ntdiabe tes(170,171)andhasbeen showntoimprovewithimp rove d HbA 1 c (172).C ompar ably,onest udyhasshownatten uat ionofbon elossinpatie ntswitht ype1diab etes withgoodgluc osecont rol(173). Th us, met aboliccon trolappearstobeamajor factorinthe in creased incidence ofosteopor osisin patien tswit hdiabet es.Poorcontrol,however ,wou ld not appeartobeth e onlyfactor,u nlessth erewer ealsoacon comitan tcompen satoryfact or t oincre aseBMDinpatient swith type 2diabe tes. Ifthe relationshipbet weenosteoporosisanddiabet eswere r elatedonlytohyp erglycemia,onewould expe ctasimilarinciden ceofosteoporosisinpatie ntswitht ype1andty pe2diabe tes,b utmostst udies showmoreoste oporosisinpatie ntswitht ype1d iabetes(111,174). There maybedifferen cesbetwe en type sofdiabe tesother thanglucosecon trolt hat impact BMD.Sever alfactorshavebee ninvest igated, includingtr eatmen twit hinsulin,en dog enousinsu linlevels,ageofonse t,andHbA 1 c ,bu tthe actu al
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mechanismforlowerBMDint ype1d iabetesisnotkn own .Osteoporosisisalson otassociat edwit h exogen ou sin sulin treatme ntpe rse.Kr akauere tal.(173)andTu omin ene tal.(111)se parately comparedpatie ntswitht ype1andty pe2diab etestr eat edwit hinsulin,sh owingth atinsu linisnotth e cau seofthebone loss.Krakau eret al.alsofoun ddecre asedBMDinmen andwome nwithtyp e1 diabet esascomp aredwith thosewit htype 2diabe tesorwith con trols. EpidemiologicstudiesatRancho Bern ardo,C alifornia, an din R ot terdam, Th eNeth erlan ds,sugge stedacorr elation betwee nfast in gin sulin levelan dBMDin nondiabe ticwome n(175, 176).In patien tswit htype 2diabet es,n oconsisten t associationofBMDwith endogen ou sins ulin leve ls, usingfast in gand 2-hour p ostch alle ngeleve ls, has bee nfou nd(162,177, 178).An aut oimmun e-or in flammation-mediatedp roce sshasalsobee ncon sid ered becauseadecre aseinBMDh asbee nnoteddu ringth efir st P. 758 seve ralyearsafte rdiagnosis,wit han att enu ation the reaft er(158, 164).Th issu ggestsaninitialinsu lt not specificallyr elatedt ocontrol,but perhapstothe aut oimmun eprocess,similartoth atsee ninrh eumatoid ar thritis,inwhichbone lossisse eninth einvolv edjoints. Ag eofonse tofdiabe tesmigh tbeex pectedt o affe cteither they ou ngadu lt hoodaccrualofbon eorthe age-re latedloss.Howe ver,n ocorre lation bet we enBMDanddu rat ionorcurr entglyce miccon trol(byHbA 1 c )wasseenindiab eticchildre n(5.2 yearsdur ation ,ex clu dedifcomplicat ions)(160)orpostmenopau salwomen (8.9yearsduration ,14years postme nopau sal)(179).Be cause ofth emy riadoffactor soth erth an diabetesincorporatedintoBMDov er time ,aswellasth egradualnatur eofdiabe ticc omplicat ions, shorter-t ermmeasure sofbonemetabolism ar enee ded.
Markers of Bone Turnover

Seru mandur in emarker sofbonet urnover hav ebeen developedtoassess sh or t-ter mchange sleadingto osteopor osis.Seru mleve lsofalkalineph osph atasean dost eocalcinr efle ctboneformation ,while seru m levelsofcollagencr oss-lin ksreflectbone resorption .Oste oblastse cretionofosteocalcinisdecre asedby highgluc oseleve ls, s oboneformation asassessedbyosteocalcinisdecreasedinproportion todiabetic control(180).Th us,inpatie ntswithdiab etes, thismarkerisap plicableonlyin limite dsit uat ions. Similar problemsarisewit hurinarymarke rssuch asdeoxypyr idinolin e,whichareconfoun dedbyglucosuriaand th usrequ ir every goodglycemiccontr oltob eusefu l. Bon eresorptionme asur edbydeoxypy rid in olin e aft era12-h ou rglu cose clampwasgreaterinage-an dheight -for-age-match edad olescen tswit hdiabet es th anincontr ols,su ggestingth atbone lossin ear ly-onse ttype 1diabet esisr elatedt oincre asedt urn ove r (181). Thisisimportantbe cause in steadofth epresu me dhightu rnoverr ate, ascanoccu rwithex cess cortisolor with hype rparathy roidism, alowtu rnoverre sultinginady namicbon e,alsoseen in renal failure, isanalte rnat eme chanismforost eop orosis.Thispossibilityissugge stedbyt heobservation that fracture stake alon gertime toh ealinpersonswith d iabetes(182).Krakau eret al.(183)h avep roposed th atalowturn ov erstatedue tofu nctionalhyp oparath yroidismand h yper glyce miaaccou ntsforthe differen cesbetwe enty pe1andtyp e2diabe tes,bu tth ish asyet t obe in vestigat ed.The hete rog eneityof type sofdiabe tes,aswellasv ariablecontr ibu tions fr omassociatedcondition saffect in gBMD,makeit difficu ltt odes ign ateone unde rlyin gme chan ismfor diabeticost eop enia.
Conditions Associated with Diabetes and Osteoporosis

Factorsext rin sic t oth emetab olicch an gesofdiab etes, suchasageofon setoftype1diabete sin relation tostage ofboneg rowth an dthelifestylefact orssu chasobesityandinactiv ity in type 2diabe tes,h avese con dary conse quen cesre lativ etoBMD.One su chage-relat edriskfor osteopor osisislowp eakbone mass.InAmericanwomen,p eakbone massisach ievedbyt heen doft he th irdd ecade ( 184).Thu s,tothe exte ntth atdiabe tesmaycauseosteopen ia,women whoareyoun gat diabet eson setmayn ever achieve anormalpeak bon edens ityandth usre achosteoporotict hresh olds earlier in life(Fig.44. 6).Delaye dpuber tyisassociatedwithalowerpeakBMD(185); t her efore ,women withdiabe tesan ddelaye dmen arch emayalsohav ealowe rpeak BMD.Inacare fu llycontr olle dFinn ish stu dy(111), Tu ominen e tal.de fine dtype1diabete sbyC-pe ptid evalue sandt here fore wereable tou se onlysubjectswh oh adbee ndiagn osedafterage30.E venint hesepatient s,BMDwaslowe rin patien ts withtyp e1diabe tescomparedwitht hos ewith type 2diabet esor with con trols, s uggest in gasecondary lossofbon e.An oth erage-relat edfactorisestrogen stat us,th emajor cause ofosteopor osisin the gen eralpopulat ion.Be cause ofth eirin creasedriskfor men stru aldysfunct ion, womenwitht ype1 diabet esmayalsohave ost eope niadu etoestrogen d eficien cy.Most studieshaven otassessedt he menstr ualhistoriesin the sewomen ,but one study d idfindap ositivecorrelat ionbet weenoral contraceptiveu sean dBMDin women with type1diabete s,supportingacomponen tofe strogen deficiency(186).One ofth estronge striskfactorsforost eoporosisislowbodyweight (187),whichis more typicalofpatie ntswitht ype1diabetest han ofth ose with type2diabete s.Theobesitycommonly pre sentinpe rson swit htype 2diabet es(an dofte nforyearsbefore)mayhaveacumu lativeprotect ive effect on b on edensity. P. 759
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Figure 44.6.Diagramofboneloss.Modelfortheeffectsofdiabetesonbonemineraldensityatdifferenttimesof life.Indiabetes,theinitialaccumulationofboneduringadolescenceisdiminished(1),thusreachingalowerplateau withcontinuedlossassociatedwithhypercalciuriainearlyadultlife(2),followedbylateronsetandretardationof age-relatedboneloss(3).Dependingontheageofonset,stages1and2couldoverlap.(Copyright1995 AmericanDiabetesAssociation.FromKrakauerJC,McKennaMJ,BudererF,etal.Bonelossandboneturnoverin diabetes.Diabetes1995;44:775782.ReprintedwithpermissionfromtheAmericanDiabetesAssociation.)
Seve ralot herdiseasesth atincre aseth eriskofoste oporosisarepar ticularlyrelevantindiabe tes. Diseasesassociate dwith au toimmun ediabe tes,includingGravesdisease and ce liacspr ue, alsocarryan indepe nden triskfor oste oporosis. Tr eat men tsfor hyper ten sionandhyp erlipidemia,whichareassociat ed withbotht ypesofd iabetes, mayalsoaffectBMD.U seofloopdiur eticstot reathype rten sioncan increaseur in arylossofcalcium,whilethiazidesmay d ecreaseit.Int erest in gpreliminar ycase-cont rol stu die shave sugges tedth attr eatmen tofh yperlipide miawithHMG-CoAr educt aseinh ibitorsmay increaseBMD(188),but t hese resultsh aven ot b eensu pportedbyoth erstu die s(189,190)and may rep resen tcon fou ndingdu etohigher BMDin patient swith hype rlipidemia(191). Among womenwithosteoporosis,almostallh ipfractur esare duet ofalls(192).Th eriskoffallin gis increasedbydiab eticcomplications, in clu din gimpaire dvisiondue tor etinopath yor cataractsandpoor balanceandorthostatich ypotensiondue top eripheralandautonomicne uropat hy.Acu tehy poglycemia an dhype rglycemiamayalsocauseimp airedvision, in coordination, and muscleweakne ss.Patient swith amput ation sare atincre asedr iskforfallsandimmobility-indu cedost eoporosisbecau seoft heirlimited mobility(Table 44.5). TABLE 44.5. Risk Factors for Osteoporotic Fractures in Diabetes
Riskforosteoporosis Directlyduetodiabetes Type1diabetes Hypoglycemiaorhyperglycemia Nephropathy Duetocomplicationsofdiabetes Nephropathy Diabeticdiarrhea Duetodiseaseassociatedwithdiabetes Gravesdisease Celiacsprue Riskforfalls Poorvisionduetoretinopathyorcataracts Poorbalanceduetoneuropathy
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Orthostatichypotension Impairedjointmotilityduetoneuroarthropathy
Treatment
Allpatie ntswitht ype1diabetesandth ose with type2diabete sandadvan cedcomplication sshouldbe evalu ate dforosteoporosisandcounse le daboutmodifiableriskfactors(ge ttingap propr iateex ercise, calcium,an dvit amin Dan davoidin gsmokingandexce ssive alcoh ol).Nopreven tivestrategiesspe cificto diabet esare yetkn own ,alth ou ghasr eviewedab ove ,goodglycemiccont rolapp earst obebe neficial. Treatmentofost eop orosisin womenwithdiabe tesalsohasnotbeen specificallyevalu ate dand t her efor e followsgu ide line sforpatientswith ou tdiabete s.Commoncomorbidcon ditionssuch asn ephropathyor gas troin testinalcomplicationsrequ ir eatt ent ion.R enalimp airme ntn ecessitat esevalu ation ofth e par ath yroid-v itaminDaxisaswellasdoseadjust me ntofmedications. None ofth ecurr ent t her apiesfor osteopor osishavebee nclinicallystud ied inr enalfailure .Gastropar esis,malabsorption orspr ue, and diabet icdiar rheacan allcontr ibu tetoost eop orosisbyin terfe rin gwit hcalciumandvitaminDabsorption an drequ ir eseparate evaluation andt reat men t.Allpatient swith diabete swh oh ave exten siv e ne uropat hy,ampu tat ions,orth ost atichypote nsion ,or impairedvision are atincre asedriskforfalls. In add itiontotreatmentst ostr engt hen b on e,th esepatie ntsn eedcoun seling onpr even tion offalls, includingu seofwalke rs,nigh t-light s,muscle-stre ngth eningex ercises,andre movalofh azardsinthe home.
ENDOMETRIAL CANCER
Afin alpost men op ausalh ealth issu efor womenwithdiabe tesisthe risk ofen dometrialcancer. En dometr ialcancer isth efou rth mostcommon cance rin women, and d iabetesh aslon gbeen con side red ar iskfactor fore ndomet rialcance r.Aftercont rollin gforbodyweigh t,most(193,194, 195,196)butn ot all(197)stu die s P. 760 havesh ownt hat womenwithdiab etesofallt ypeshaveatle astdoubleth eriskofe ndomet rialc ance rin comparis ont oth enondiab eticpopu lation .Theriskdirect lyr elatedt odiabe tesiscon troversialbecause offr eque ntco-existen ceofoth erknownr iskfactor s,includingobesity,h ypert ension ,an dseden tar y lifest yle .Theconfoun din gofobesityinparticularh asbee nevalu ate din case-cont rolstud ies. Shoffand Newcomb(195),stu dyin gwomen inWisconsin,andSalazar-Mar tin ezet al.(198), studyingwomenin Mexico, foun dthatth eaddition alriskduet odiabe tesoverth eriskofb odysizealone wasmostlyin obese(BMI>29)womenwithdiab etes. Indepe nden tofwe igh t,ph ysicalactivit ygreatlydecreasesth e riskofe ndome trialcance r.Int heSwedishTwinRe gist ryofn ear ly12, 000women ,eve nligh texe rcise such aswalksorgardening decreasedth eriskbyhalf, and har dphysicaltrain in gredu cedth erelat ive risktoon eten th(199).Stur geonetal. (200)foundsimilarbe nefitsfrome ith erre creat ionalor nonr ecreation alactivityan dnotedth att hesub je ctswhowerelessact ive alsote nded t obe moreobese. Similarly,pat ie ntswithty pe2diabe teste ndtobemore obe sean dles sactive. Seve ralpot entialmechanismsforth eriskofen domet rialcancer have been postu lated. Oneofthe major recogn ize drisk factorsfor endome trialcanc erisu nopposedestr oge nexposur e(201).R ecognitionofthis inth e1970schan gedth eprescr ipt ionofestrogen replacemen tthe rapyt oinclude p roge sterone for women with au teru s,are gimen t hat hase liminatedt heincre asedinciden ceofe ndome trialcance rseen withest roge nalone. Ithasb eenpostu latedth atadditionale strogene xposu reinobesewome n,from per iph eralconver sioninth eincreasedbodyfat ,in duce sthecancer .Estr oge nlevelscor relate with per centageofide albodywe igh tin patien tswit hen dometr ialcancer, and womenwithdiabe teste ndtobe more obes ean dhave higher lev elsofestr oge nsthanwome nwit houtdiabe tes(202). Moredire ctly , Nyholmet al.(203)found t hat ,incomparisont oweight -matched cont rols,wome nwithdiabe teshad highe rle velsoftotalest rogens, although higherleve lsofsexhormon e-bindingglobulin keptth elevelsof free estrogen comparable.Becauseobesityandphy sicalinactivity ,aswellastype 2diabe tes,are associate dwith higher in sulin lev els, in vestigat orsh ave examinedth einfluen ceofinsu linleve lsin nondiab eticwomen. C-pept ide lev elscorre latedwithBMIan destrogen le vels,butafteradjustment for th esefact ors, nofurth erre lationsh ip wasseen betwee nC-pe ptidelevelsan dendome trialcan cer(204). Anothe rappr oachtothisissueistoc ompare ther iskinty pe1diabe tesve rsusth atinty pe2diab etes, but studiesev aluat in gthes evariab lesh ave alsoyieldedconflict in gresults(194,196, 205).Th e he terogen eityofpatients with diabetesandofthe in sulin lev elsindiab etesh aslike lyobscur edth ese epidemiologiccorrelations.Alon gduration ofdiabe tesalsowasnotsee ntocorr elatewith theriskof en dometr ialcancer(195),bu tin sulin le velsusuallydeclinewithpr olon geddu rationofd iabetes. Hyper glyce mia, whichmigh tberough lye stimat edov erth elong t ermbyin cid enceofdiabet ic complication s,hasnotbee nasse ssedin relat iontoend ometrialcan cer.
SUMMARY
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Diabetesh asdiverse effectsonre prod uctiveandpostme nopau salhealth .Aswit hother complicationsof diabet es,good g lu cosecont rolmayamelioratesome ofth eproble ms;othe rsrequ ir eappr oaches par ticulartodiabet es.Man yofth eissuesh aven otb eenspe cificallystudied, andge ner alization scan onlybemadefromst udiesofn on diabet icwomen .Anappreciat ionoftheu nique r eproduct ive consequ ence sofdiabe teswillimproveh ealthcareforthe sepat ie ntsbu talsoh igh light sthe n eedfor fur ther r esearch.
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115.Weet manAP. Au toimmu nitytosteroid-producingcellsand familialpolyendocrineautoimmun ity . Bailliere s Clin Endocrinol Met ab1995;9:157174. 116.WheatcroftNJ,SaltC ,Milford -WardA,e tal.Iden tificationofov arian ant ibodiesby immun ofluoresce nce,e nzyme-lin kedimmun osorbe ntass ayorimmu noblott in gin prematu reovarian failure .Hum Reprod1997;12:26172622. 117.Taylor R,Smith NM,An gusB,e tal.Re turn offer tilityafte rtwelveye arsofau toimmun eovarian failure .Clin End ocrinol (Oxf)1989;31:305308. 118.Kalan tar idouSN,DavisSR,NelsonLM.Pr ematur eov arian failur e.E ndocrin ol Metab Clin North Am1998;27:9891006. 119.Malacar aJM,Huer taR, RiveraB, etal.Men opauseinn or malan dun complicatedNIDDMwomen: ph ysicalandemotionalsy mptomsandh or monepr ofile .Matu rit as1997;28:3545. 120.RossRK,Paganini-HillA, MackTM, etal.Men opausaloestrogen ther apyandprotect ionfrom deathfr omisch aemicheartdisease .Lan cet1981;1:858860. 121.Bear dCM,KottkeTE ,Ann egersJF,et al.TheR och ester Cor on aryHe artDise aseProje ct:effect ofcigarett esmoking, h yper tension,diabe tes, andst eroidale strogenu seon cor on aryh eart dise ase among40-to59-year-oldwomen ,1960thr ou gh1982.Mayo Clin Proc1989;64:14711480. 122.Bush TL, Barre tt-Conn or E,Cowan LD, etal.C ardiovascu larmortalityandnoncont race ptiv euse ofestrogen in women:re sultsfromth eLipidR esearchClinicsProgramFollow-u pSt udy. C ir culation 1987;75:11021109. 123.Kan nelWB,McGeeDL.Diabe tesandcar diovascu lardisease .TheFramingh amstudy. JAMA 1979;241:20352038. 124.Kan nelWB,Wils onPW.Riskfactor sthatatt enu atet hefemalecoronar ydise aseadvan tage .Arch In tern Med 1995;155:5761. 125.Kaplan RC, Heckber tSR,WeissNS,etal. Postmenopau salestrogen sandr iskofmy ocardial infar ction indiabeticwomen. Diabet es Care1998;21:11171121. 126.MansonJE ,ColditzGA,Stampfe rMJ, etal.Aprospect ive studyofmatur ity -on setdiabe tes mellitusandriskofcoronaryhe art d iseaseandstrokeinwome n.Arch Inte rn Med1991;151:1141 1147. 127.BrussaardHE ,GeversLe uve nJA,FrolichM,etal. Short-ter moestrogen replace men tthe rapy impr ove sin sulin resistan ce,lipidsandfibrin olysisin post men op ausalwome nwithNIDDM. Diabetologia1997;40:843849. 128.Ander sson B, MattssonLA, Hahn L ,etal. Estrogen replacemen tthe rapyd ecreases hy perandrogen icityandimprovesglucoseh omeostasisan dplasmalipidsin post me nop ausalwome n withn on in sulin -depen dent diabetes mellitu s.J Clin En docr in ol Me tab1997;82:638643. 129.WalshBW, Sch iffI, R osn erB,e tal.Effec tsofpostmenopau salestrogen replace men tonthe concen trationsandmetabolismofplasmalipoprot eins.N En gl J Med1991;325:11961204. 130.Lop es-Vir ellaMF,Wohltmann HJ, LoadholtCB,et al.Plasmalipidsandlipoproteinsiny oun g insu lin-de pende ntdiabe ticpatient s:relation shipwit hcontrol.Diabe tologia1981;21:216223. 131.Robin son JG. HowHRTalter sthelipidpr ofile in womenwithdiabetes. Me dscape Womens Healt h 1996;1:4. 132.LilleySH,SpiveyJM,Vadlamu diS,e tal.Lipid andlipopr ote in responsest ooralcombined hormon erep laceme ntth erapyinnormolipe micob esewomen wit hcon trolledt ype2d iabetesmellitu s. J Clin Ph armacol1998;38:11071115.
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133.Fr idayKE, DongC, Fonte notRU. Conjugatedequ in eest roge nimproves g lyce miccon troland bloodlipoproteinsinpostmenopau salwomen with type2diabete s.J Clin End ocrinol Met ab 2001;86:4852. 134.Mann in gPJ,AllumA, Jon esS,etal. Theeffec tofh ormon ere placeme ntth erapyon cardiovascularriskfact or sint ype2d iabetes:aran domizedcontrolle dtrial.Arch In tern Me d 2001;161:17721776. 135.ThomM,Ch akr avar tiS, OramDH,e tal.Effe ctofh ormonere placementt herapyonglucose toleran ceinpostme nopau salwomen. Br J Obstet Gynaecol1977;84:776783. 136.Effects ofestr oge nor estrogen /progestinre gimensonh ear tdise aser iskfactor sin postmenopau salwomen. ThePostmen opausalEs trogen/ProgestinInt erve ntion s(PE PI)Trial.The WritingGroupforthe PEPITrial.JAMA1995;273: 199208. 137.Barr ett-C on norE,LaaksoM.Ische micheartdisease ris kin postmen opausalwomen .Effe ctsof est roge nuse on glu cose andinsu linleve ls. Ar terioscler osis1990;10:531534. 138.SpellacyWN,Buh iWC ,Bir kSA. Effectofestr oge ntreatment foroneye aroncarbohydrateand lipidmetabolisminwomen with normalandabnormalg lu coset olerancet estresu lt s.Glu cose, in sulin , growth h or mone, trigly cerides,andPremarin. Am J Obstet Gyn ecol1978;131:8790. 139.MansonJE ,RimmEB,C olditzGA, etal.Aprospect ive study ofpostme nopau salestrogen t her apy andsubse quen tincidence ofnon-insu lin-d epend entdiab etesmellitu s.Ann E pid emiol1992;2:665 673. 140.SamarasK,Hay wardCS, Su llivan D,e tal.Effe ctsofpostmenopau salhormon ereplace men t th erapyon cent ralabdominalfat,glycemiccon trol,lipidmetabolism, andv ascular factorsintype 2 diabe tes:apr ospe ctiv estud y.Diabe tes Care1999;22:14011407. 141.Fe rrar aA,Karter AJ, AckersonLM,et al.Hor moner eplacement ther apyisassociatedwith b ette r glycemiccont rolinwomen with type2diabete s:the North ern C aliforn iaKaiserPermane nte Diabet es Re gist ry.D iabetes C are 2001;24:11441150. 142.SzekacsB,VajoZ, Acs N, etal.Hormone replace men tthe rapy reduce sme an24-h ou rblood pre ssure anditsvariabilityinpostmenopau salwomenwith t reatedhy perte nsion .Me nopau se 2000;7:3135. 143.SzekacsB,VajoZ, VarbiroS, etal.Post men op ausalh or monere placement improvesproteinu ria andimpaire dcreatin in eclear ance in t ype2diabetesmellitu sand hyper tension.Br J Obst et Gynaecol 2000;107:10171021. 144.Ban gaJD, SixmaJJ. Diabet esme llitus, v ascular dise aseandth rombosis. Clin Haematol 1986;15:465492. 145.Hulle yS,Gr adyD,Bush T,etal. R an domiz edtrialofe strogenpluspr oge stin forse con dary pre vent ionofcoronaryh eart dise aseinpostmenopau salwomen. Hear tand E strogen /prog estin Re placementStu dy(HER S) R esearchGroup.JAMA1998;280:605613. 146.Heckber tSR,KaplanRC ,WeissNS,etal. Riskofre curre ntcoronar yeven tsin relationtouse andrece ntinitiationofpostmenopausalhormon ethe rapy .Arch In tern Med 2001;161:17091713. 147.Me yerHE ,TverdalA, Falch JA, etal.Fact orsassociat edwithmort alit yafter hipfractu re. Oste oporos Int2000;11:228232. 148.Me yerHE ,TverdalA, Falch JA. Riskfactorsfor hipfractu reinmidd le-agedNorwegian women andme n.Am J Epidemiol1993;137:12031211. 149.Forsen L,SogaardAJ,MeyerHE ,etal. Diabe tesmellitusandth ein cid enceofhipfract ure : re sultsfromth eNord -Tr on delagHealth Surve y.Diabe tologia1999;42:920925.
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150.NicodemusKK, FolsomAR.Type1an dtype2diabete sandinciden thipfract ure sin postmenopau salwomen. Diabet es Care2001;24:11921197. 151.Pagan in i-HillA,RossRK, Ger kin sVR,et al.Menopau salestrogen ther apyandhipfracture s.Ann In tern Med 1981;95:2831. 152.Schwar tzAV,Sellmeye rDE ,En srudKE ,etal. Olde rwomen with diabetesh ave anincr eased risk offractu re:aprosp ectivestu dy.J Clin En docr in ol Me tab2001;86:3238. 153.van Daele PL, St olkRP,Burge rH,et al.Bon eden sity in non -insulin-depe nden tdiabet esme llit us. The Rot terdamStu dy.An n Inte rn Med1995;122: 409414. 154.Hir anoY,KishimotoH,HaginoH,etal. Thech ange ofbonemineralde nsityinsecondary osteopor osisan dvert ebralfracture in cide nce. J Bone Mine r Me tab1999;17:119124. 155.Heat hH3rd ,Me lt on L J3rd, Chu CP. Diabet esme llitusandriskofsk ele talfract ure .N Engl J Med 1980;303:567570. 156.SeeleyDG, KelseyJ,Je rgasM,et al.Pre dict orsofan kle and footfract uresinolderwomen .The Stu dyofOst eoporoticFractur esRese arch Group .J Bon e Min er Res1996;11:13471355. 157.Wor ldHealt hOrganization.Asse ssmen toffr actu reriskan dit sapplication toscr eeningfor postmenopau salost eoporosis.ReportofaWHOStu dyGr ou p.World He alth Organ Tech Rep Ser 1994;843:1129. 158.LevinME, Boisseau VC,AvioliLV.Effect sofdiabe tesmellitusonbonemassinjuv enile and adult-on setdiabe tes. N E ngl J Med 1976;294:241245. 159.SelbyPL. Osteopeniaanddiabe tes.D iabet Med1988;5:423428. 160.RoeTF, MoraS, Cost in G, etal.Ver tebralbone densityininsu lin-de pende ntdiabe tic ch ildre n. Metabolism1991;40:967971. 161.Mu noz-Tor resM,JodarE ,Escobar -Jimene zF, etal.Bone minerald ensitymeasu redbydu alXrayabsorptiomet ryinSpan ish patien tswit hinsulin-depe nden tdiabet esme llit us.C alcif Tissue In t 1996;58:316319. 162.Barr ett-C on norE,Holb rookTL.Sex d iffere ncesinosteoporosisinolde radu ltswith n on -in sulindep ende ntdiabe tesmellitus. JAMA1992;268:33333337. 163.Kay ath MJ,DibSA, VieiaaJG. Pre valence and mag nitudeofosteopeniaassociat edwit hinsulindep ende ntdiabe tesmellitus. J D iabete s Comp1994;8:97104. 164.Mathias senB,NielsenS,DitzelJ,etal. Lon g-ter mbonelossininsu lin-d epen dentdiabetes mellitus. J Inte rn Med1990;227:325327. 165.RixM, Andreassen H, Eskild senP.Imp actofperipher alneu rop ath yon bon eden sity inp atient s withty pe1diabe tes. D iabete s Car e1999;22:827831. 166.ForstT, Pfut znerA, Kan nP, etal.Periphe ralost eop eniainad ultpatien tswit hinsulin-depe nden t diabe tesmellitus. Diabet Med1995;12:874879. 167.IversR Q,Cu mmin gRG,Mitch ellP,etal. Diabe tesan driskoffractur e:TheBlueMount ainsEy e Stu dy.Diab etes C are2001;24:11981203. 168.Rask in P,Ste vensonMR, BarillaDE,e tal.The hyper calciu riaofdiab etesmellitu s:its amelioration with in sulin .Clin En docrinol (Oxf)1978;9:329335. 169.Ge rtne rJM,Tambor laneWV,HorstRL ,etal. Miner almet abolismin d iabetesmellitu s:chan ges P. 763
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accompan yin gtreatmentwith aportablesu bcutaneousinsu lininfu sionsyst em. J Clin Endocrinol Metab1980;50:862866. 170.Thalass in osNC, Hadjiyann P,TzanelaM,et al.Calciumme tabolismin diabete smellitu s:effectof impr ove dbloodglu cose cont rol.D iabet Med1993;10:341344. 171.NagasakaS, Mu rakamiT,Uch ik awaT,e tal.Effe ctofglycemiccon troloncalciumand ph osph oru shandlin gand parathyr oidhormon ele velin patient swith non-insu lin-de pende ntdiabe tes mellitus. Endocrinol J1995;42:377383. 172.OkazakiR,TotsukiY,Haman oK, etal.Met abolicimprovement ofpoor lycont rollednoninsu lindep ende ntdiabe tesmellitusde crease sbon etu rnover. J Clin E ndocrinol Metab1997;82:29152920. 173.Krakaue rJC, McKe nnaMJ, Buder erNF, etal.Bone lossan dbon etur noverindiabe tes.D iabetes 1995;44:775782. 174.Chr ist ensen JO,Sven dsenOL .Bon emine ralinpre-andpostmenopau salwomenwith in sulin dep ende ntan dnon-insu lin-de pende ntdiabe tesmellitus. Osteopor os In t1999;10:307311. 175.Barr ett-C on norE,Kr itz -Silverst einD. Doeshyp erinsulinemiaprese rvebone?D iabetes C are 1996;19:13881392. 176.StolkRP,Van DaelePL, PolsHA,e tal.Hyper in sulin emiaandbone miner aldensityinanelderly populat ion:th eRotter damstudy. Bon e1996;18:545549. 177.Kwon DJ, KimJH,Ch un gKW,et al.Bon emine ralden sity ofth espineu sin gdualen ergyX-ray absorp tiometryinpatientswith n on -in sulin -depe nden tdiabet esme llit us.J Obst et Gynaecol Res 1996;22:157162. 178.Haffne rSM, Baue rRL.Th eassociation ofobesityan dglucosean din sulin con centr ation swit h bonede nsityinpre men opausalandpostme nopau salwomen. Me tabolism1993; 42:735738. 179.WeinstockRS,GolandRS, Sh an eE,e tal.Bonemin eralde nsityin women with typeIIdiabe tes mellitus. J Bon e Mine r Res1989;4:97101. 180.RosatoMT, Sc hne ider SH, Shapse sSA. Bon etur noverandinsulin-like growt hfact orIleve ls incre aseafterimpr ove dgly cemiccontrolin n on in sulin -depe nden tdiabet esme llit us.C alcif Tissue In t 1998;63:107111. 181.BjorgaasM,Hau gE,John senHJ. Th eur in arye xcretionofd eox ypyridin iu mcr oss-lin ksish ig her indiabe tict han in nondiabet icadolescen ts.C alcif Tissue In t1999;65:121124. 182.Lod erRT.Th ein flu ence ofdiabe tesmellitusonth ehe alin gofclose dfractu res. Clin Or thop 1988;232:210216. 183.Krakaue rJC, McKe nnaMJ, RaoDS, etal.Bonemineralde nsityindiabet es.D iabetes C are 1997;20:13391340. 184.Looker AC ,Wahne rHW,Du nn W L,etal. Proximalfemur b on emine ralle velsofUSadults. Oste oporos Int1995;5:389409. 185.Fink elst einJS,Klib ansk iA,Nee rRM.Alongitu din alevaluation ofbonemineralde nsityinad ult menwithh ist oriesofdelaye dpuber ty.J Clin En docr in ol Me tab1996;81:11521155. 186.Lun tH,FlorkowskiC M, Cun dyT,et al.Apopu lation -basedst udyofbon emin eralden sit yin women wit hlon gstan din gtype1(in sulin depen den t)diabete s.Diabe tes Re s Clin Pract1998;40:31 38. 187.En srudKE ,Lipschut zRC, Cau le yJA,etal. Bodysizeandh ipfractur eriskin olderwome n:a prospect ive study. StudyofOsteoporot icFract uresR esearchGroup.Am J Me d1997;103:274280.
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188.Me ie rCR, Sch lien gerRC ,et al. HMG-CoAredu ctase in hibitorsandth eriskoffractur es.JAMA 2000;283:32053210. 189.Pe dersen TR,Kjeksh usJ.Statindru gsan dther iskoffract ure. 4SStudy Group. JAMA 2000;284:19211922. 190.ReidIR,HagueW, EmbersonJ,e tal.Effe ctofpr avastatinonfre quen cyoffractur einthe LIPID stu dy:secondaryan alysisofar andomise dcon trolledtrial.Long -termin terv entionwithpravast atinin ischaemicdisease .Lan cet2001;357:509512. 191.AdamiS,Br agaV, GattiD.Association betwee nbonemineralde nsityan dseru mlipidsinmen. JAMA2001;286:791792. 192.NevittMC.E pide miologyofosteoporos is.R heu m D is Clin Nor th Am1994;20:535559. 193.BrintonLA,Be rmanML,Mort elR,et al. Repr odu ctiv e,menst rual,andmedicalriskfactorsfor en dometr ialcancer :resultsfromacase-c ont rolstu dy.Am J Obstet Gyne col1992;167:13171325. 194.LaVecch iaC,Neg riE ,Franc eschiS,etal. Acase-contr olstudy ofdiabet esme llitusandcan cer risk.Br J C an cer1994;70:950953. 195.ShoffSM,Newcomb PA.Diabetes ,bod ysize ,an driskofen dometr ialcancer .Am J E pide miol 1998;148:234240. 196.Parazz in iF,LaVe cchiaC, Ne griE,et al.Diabe tesanden dometr ialcancer:anItalian casecontr olstudy .Int J C ance r1999;81:539542. 197.KelseyJL, LiVolsiVA,HolfordTR,e tal.Acase -con trolstu dyofcancer ofth een dometrium.Am J Ep ide miol1982;116:333342. 198.Salazar-Martine zE,Lazcan o-PonceEC ,Lira-LiraGG,et al.Case-controlstudyofdiabete s, obesity,ph ysicalactivityan driskofen dometr ialcancer among Mex icanwomen .Cancer C au ses Cont rol2000;11:707711. 199.TerryP,Bar on JA,WeiderpassE,e tal.Lifestyleanden dometrialcancerr isk:acoh ort study fromt heSwedishTwinRe gistr y.Int J Can cer1999;82:3842. 200.Sturg eon SR,BrintonLA, BermanML,e tal.Pastandprese ntph ysicalactivityan dendometrial cancerr isk. Br J Can cer1993;68:584589. 201.Smith, DC ,Pre nticeR, ThompsonDJ,etal. Associationofe xoge nousest roge nan dend ometrial carcin oma. N E ngl J Me d1975; 293:11641167. 202.JuddHL, Dav idsonBJ, Fru marAM, etal.Ser umandr oge nsan destrogen sin post men opausal women wit han dwith ou ten dometr ialcancer. Am J Obste t Gy necol1980;136:859871. 203.NyholmH,Dju rsin gH,Hage nC, etal.An drog ensandestr oge nsinpostme nopausalinsu lin tr eate ddiabeticwomen .J Clin En docrinol Me tab1989;69:946949. 204.TroisiR,Potischman N,Hooeve rRN,et al.Insu linanden dometr ialcancer. Am J Epidemiol 1997;146:476482. 205.WeiderpassE,PerssonL, Ad amiHO,et al.Bod ysize in differ ent p eriodsoflife,d iabetes mellitus, hype rten sion, andriskofpost men opausale ndomet rialcance r(Swe den). Can cer C ause s Cont rol2000;11:185192.
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Pancreas and Islet Transplantation

Gordon C. Weir
THE PROBLEM
The d evast atingcomp licationsassociate dwith bot htype 1an dtype2diabete sare nowclearlylinke dto hy perglycemia(1, 2,3).The implicat ionofthe sefin din gsist hat normalizationofglu cose le velswith propert reat men tearly in thecour seofth edisease wou ldpre ven tthe d evelop men toft hemicr ovascular an dneu ropath iccomp licationsan dprobablymuchofthe macrovascular d isease.Th ecos tofth ese complication s,bothinpe rson aland financialter ms,isen ormous,andth ein cid enceofbothformsof diabet esisincr easing. Impr essiv eimprovemen tsin treatme nth aveb eenmade thankstoself-glu cose mon itoring, advancesininsu linth erapy,ne woralmedications,andh igh erstandardsofcare,bu tmost peoplewit hdiabet escon tinue tode velopdisablingcomp lications.Although progressisbeingmadeint he deve lopmentofappr oachest hat couldpre vent aut oimmun ediabet es,th eprospectsforpre vent in gtype2 diabet esseemslesspromising.Amechanical-celleq uivalent c ons istingofaglucosesen sor andan insulinpumpcouldprovide patien tswit hnormoglycemia,bu teffortstodevelopasat isfactor yglu cose sen sorh ave been fr ustratinginspiteofmanyingen iousapproach es(4, 5).Th emostobviou ssolutionis toprovide patien tswit hth e-cellsth eyaremissing, wh ich can bedonewithpancre as,isle t,or-cell transplan ts.Thisap pealingconcept e venwasteste dclinicallyasearlyas1893inBristol,E nglan d,when aph ysicianun successfu llytr ansplan tedpiece sofshe eppan creasin tot hesu bcutaneousspaceofa15year-oldboywithdiabe tes(6).Thiscon ceptu allysimple g oalcontinu estolook likeanat tract ive solution tothe prob lemofdiab etesbu thasturn edouttobee xtraordinarilydifficulttoaccomplish .
-CELL REPLACEMENT AS A TREATMENT FOR TYPE 1 AND TYPE 2 DIABETES

Whileit isge nerallyassumedthat-cell-replacemen tthe rapywillbeu sefulforpeople with type1 diabet es,man yfailtoapp reciate t hat itcouldbeaverye ffectivetre atment fort hosewit htype 2 diabet es,th in kingth atth emainproble minty pe2diabe tesisin sulin resistan ce,withadeficie ncyin insulinsecre tion mak in gon lyasmallcon tribut ion.Th ismisse sthe p ointt hat t ype2diabetes d evelop s onlywhen -cellsfailtocompensate P. 766 forin sulin resistan ce(7). Theinciden ceofty pe2diab etesh asskyrocket ed,lar gely becau seofour sede ntaryWeste rnlife style,withitsplent ifu lfood, whichleadstocen tralobesitywit hitscon comitan t insulinresistance. Howeve r,toun derstandth erole ofth e-cell,it must beapp reciate dthatmostpeople withinsulinre sistancen ever becomeh yperglyce micbecau seth eir -cellscompe nsat ewit hincreased insulinsecre tion :h en cethe keyrole of-cellfailu reinth edevelopme ntofdiabete s. Pe opleargue thataprohibitiv enu mber ofisle tswou ldbe requ ire dforpe oplewithty pe2diab etesand th atth ehyp erinsulinemiawou ldbe ath erogenic.In fact, manypeoplewit htype 2diabet eshaveinsulin req uirementst hat aren ot v erydifferen tfromth ose ofpeoplewithtyp e1diabe tes,inpartbec ause of th eresidualinsu linpr odu ctionint helatt er.Moreover, t here quirement foralargen umberofisletsforso manyp atient smaybesolve don cewaysarefoundt omake ins ulin -produ cingcellsr eadilyaccessible.Th e he althbe nefitsofsu chtr ansplan tswouldbeen ormou s.The microvascu laran dneu ropathiccomplication s ofd iabetessh ou ldbe preve nted ,an dther eare reason stoth in kth atth ecar diovascu lareve ntswouldbe lesscommon .Aftersu chat ran splant, anindividualwouldstillbeleftwithobesityan dinsulinresistance, withth eirhealt hconsequ ence s,but t hese wouldbeassociat edwithfar lessilln essth anwh endiabe tesis supe rimposed.Th erearemany approach esth atcouldhelpwithth eproblemoftype2diabet es,such as improvinginsu linsen sit ivitywith newdru gsan dreducing obesity, but-ce llreplace men talsocou ld providemajorbe nefits.Ifone followsthe sameargu me nts, - cellrep laceme ntcouldprev entt he hy perglycemia-relat edcomplication sforalmost allformsofdiabet es,su chasvariou sformsofmatu rityonsetdiabetesofthe you ng(MODY),mitoch on drialdiabete s,cysticfib rosis,anddiabet essecondaryto pan createctomy.Infact,th esen on -type1formsofd iabetesmayactuallybe e asiertarget sfor-cell rep laceme ntbe cause thet ran splante disletswouldbeen cou nte rin gon ly allograft rejection an dnot au toimmu nity.
PANCREAS TRANSPLANTATION
Pancre astr ansplan tswere first performe don ane xperime ntalbasisint he1960s,bu tthe procedure was notwidelyappliedun tilth emid-1980s(8, 9,10, 11).Byth eyear2000,moret han 1, 200transplan tswere beingpe rfor med y early, with manyofthese beingmadepossible b yanincr ease in accesstoinsurance coverage.The vastmajorityoft heset ran splantsh aveb eendone in theU nitedStatesandEu rop e. Improv eme ntsinoutcomehavebeen due t oadvan cesinor gan p reserv ation ,sur gicalt echn iqu es,and immun osup pressivedru gs.The mostcommon tran splant sandt hebest resultsh avebe enobtain edwit h simu ltaneousk idn ey/pancreas(SKP)t ran splantsgiven topatient swith type1diabete swhoh ave adv ance dneph ropath y.Much lesscommonar epan creastran splants d on eafte rakidne yallograft(PAK), whichu suallyrequ ir emoreimmun osu ppression.Decisionsabou tpan creastran splant softe nare drivenby
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th eavailab ilit yofakidn eyfromalivingre lateddonorbecauseofthe superiorou tcomes ofsuch transplan tscomparedwithdialysisand e vent ran splantation with acad aver ickidne y.Fewpatien ts rece ive apancreastransplant alon e(PTA),alt houghasin gle cent errece ntlyrep ort ed225ofthe secases (12).Ju stificat ionofPTA,withitsrisksofmortality,morbid ity ,an dimmu nosuppre ssion, requ ire sthat pat ie ntsh avese riouspr oblemswith the irdiabetes, whichmigh tin clu delife-t hre aten in gin sulin reaction s,instabilityofcont rol,andvariouspsy chologicalproblems.Afinal,e venlesscommon ,ap proach istheu seoft hedistalportion oft hepancreasprovid edbyalivin grelate ddon or .Ther econ tinue stobe debateabou tthe efficacyofu sin gon ly halfoft hepancre asan dthe r iskofdeve lopmentofeithe rglu cose intole ran ceor fran kdiabete sin t hedonors(13). The e xcelle ntre sultsob tainable b ysimultan eoustransplan tat ionofakidney andpancre as(SPK)are n ow beinge xperien cedbyan in creasin gnumber ofcen ters, with approximately85%ofth epan creases maintain in geuglycemiainthe recipie nt1yearafter tran splant ation an dapproximately50%fu nctioning wellafter5years.The e uglycemiame anst hat recipie ntsh aven ormalglucoselevelsaroun dthe clock, ar ewit houtincre asedriskofreactiv ehypoglycemia(14),havenormalgly coh emoglobinleve ls, andh ave nodietaryrestr ict ions,e venifthe yare taking medicat ionssu chascyclospor in eor tacrolimus(FK-506) an dglucocort icoids t hat caninh ibitinsu linsecr etion (15,16).Re sultsreporte dforPAKan dPTAhavenot bee nasgood,but they h ave been improvin gsteadily(10). Strategiesfordrainageoftran splant edpan creaseshaveevolved,with mostcent ersnowusinge nte ric drain agewith asid e-to-side anastomosisofthe don or d uodenu mandth erecipientileum(17)(Fig. 45.1).Alt hough t hisprocedure isassociat edwit hsomer iskofin fection ,itavoidsthepr oblemsthat plagu edthe useofbladderdr ainageviath edon or duodenu m:acidosis,deh ydrat ion, infe ction ,an da varie tyofoth erproblems(18). Bladderdrain age waswide ly u sedforabout 10ye ars, butman ypatien ts whoor iginallyhadbladder drainagewere laterconve rtedt oen tericdrain age. Theve nousdrain agefrom at ran splante dpancr easu suallygoe sdir ectlyin tothesy stemiccirculat ion, butsome cente rsare now employingt hesup eriormesen ter icve in t oallowdr ainag ein totheportalv ein ,whichismore phy siologically corr ectbut amore techn icallyde man dingprocedu re(19,20).
Figure 45.1.Combinedpancreasandkidneytransplant.Thedigestivejuicesofthepancreasaredrainedintothe intestineviaanentericanastomosisbetweenthedonorduodenumandtherecipientileum.Venousoutflowcanbe eitherintotheperipheralcirculationviatheiliacveinasshownorintotheportalvein.(DrawingcourtesyofDr.David Sutherland.)
The mostcommon lyu sedimmunosupp ressiveth erap yin thepasthasbeen triple the rapywith cyclosp orine ,azathioprin e,andpre dnison e,bu tcen tersarenowmore likelytousetacrolimu s(FK -506), mycoph enolate mofetil, andpr ednisone(21).An tibodiestoTcellsorth ein terleu kin -2(IL-2)rece ptor ar eusu allyu seddur in gthe ind uction phase.In g ener al,highe rdose sofimmun osu ppressivedr ugsar e req uiredforpatien tswhoreceivepancre astr ansplan tsth anforth osewh ore ceivekidney tran splant s alone, wh ich isworrisomebe cause ofth eincreasedrisksofin fection andmalignan cy(22).For SK P transplan ts,kidne yrejectionisusedasasur rogatemark erforrejectionoft hepancre as.Detect ionof problemswith t hepancre asismoredifficu lt forPAKand PTAprocedure s.Someh aveconsider edamylase outpu tau sefulmarkerforpatie ntswithblad derdrain age, butcu rren tappr oachesaremore likelytouse seru mleve lsofamylasean dlipasean dpan creasbiopsie s(23).Immun osu ppressionisnecessaryto controlnoton lyallograft r ejection butalsothe aut oimmun it ythator iginallycausedty pe1diab etesin th erecipients. Thepe rsist entautoimmunitymay b eespeciallyaggr essiv e,asind icatedbySKP transplan tsperformedbet weeniden ticaltwin swhowe renotgiven immu nosuppr essiv eme dication (24). Neithe rthe e xoc rin epan creasnorthe kidn eywasr ejected, butdiab etesre curre d,withimmun e dest ructionoft heisle tsdemon stratedbybiopsy.Re markably,t hisdestru ction occu rredinonlyamatt er ofwe eks,wh ich isfarmorerapidthanth enormalp rogr essionoftype 1diabet es,which t ypicallyt akes yearstoproduceh yperglycemia(25).
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Risk and Benefits of Pancreas Transplantation

De bate con tin ue sabouthowmuchpatientsbe nefitfrompancre astransplan ts(26).Thistransplan tat ion req uirescomplexsu rgeryandisaccompaniedbysignificant mortalityandmorbidity;patie ntsfre quen tly ar ehospitaliz edfor e xten dedper iodsan dreadmitte dforpr oblemssuchasin traabdominalinfec tionand vascularth rombosis(27). None the less, somestu die ssuggest th atsu rvivalisbe tterforpatie ntswithSKPtransplan tsthanforthosewithkidne ytransplan tsalon e (28,29), alt hough itisdifficulttofindstu die swith well-match edtre atment grou ps.The impact ofth ese transplan tson the complicationsofdiabete sseemstobemodest ,whichisnotsurpr isingconsiderin gthat somanyrecipient salreadyhav eadvance dabnormalit ie swh ent heyr eceiveth etransplan t.Var ious stu die shave fou ndsomest abilizationofretinopathyandimpr ove men tinner veconduct ionve locity,bu t th esechange sseemtoh ave littleclin icalimp act(30,31, 32).Arecen tstu dyfou ndth atsome histologic improvemen toft ran splante dkidn eyscantakeplaceafterpancre astransplan tation(33).Specifically, biopsiesofkid neysofpat ien tswithPTAth atwe reobtaine d5yearsaft erth epan creast ran splantsh owe d noben efit ,but biopsiesat10ye arssh owedimpressivere versalofhistologicabnormalit iest oward normal.Aprovocativestu dysugge stedth atpatient swith aut on omicn eur opathybe fore apan creas transplan thavebet tersu rvivalafte r7yearsth ant hosewit hfaile dgraft s(34);although encouragin g, th isfindingn eedstobeconfirmed.The mostobviousbe nefitofp ancr eastr ansp lantsisthatpat ien ts considerth eirqualityoflifeimproved ,par ticu larlybecau seoftheirfre edomfrominsu lininjections, hy poglycemice pisodes, and foodrestr ictions.Itmust beremembered t hatqualityoflifeisadifficu lt par ameter toe valuate(8, 26).Fore xample ,ithasb eendifficulttos how, usingstandardpar ameterssu ch aswh eth erpat ie ntsar emore activeorperformbette ratwork, t hat theirliv esare improved. Non eth eless,th emoststr ikingfinding ,an dofun den iable impor tan ce,isthatpat ien tsar every happy to befre eoft heirdiabet es. De bate scon tinue aboutth erisk-to-bene fit r atioofpan creastran splant ation ,particularlywit hacostof app rox imate ly$100,000perpatient(26). Nowth atmore in surancepr ogramsh ave agree dtocove rthe costsoft hisp roce dure ,the demandh asincre ased. Th ere isnoprospectfordoin glargecontr olledtrials ofp ancr eastr ansplantation, butn ewknowle dgeab ou tit sv aluewillcontinu etoeme rgefromsmaller stu die s.Un tilamajoradvanceoccur sin islettr ansp lantationorinth edeve lopme ntofsomekindof improved ins ulin d eliver ysystem,itsee mslike lyt hat pancr east ran splantationwillcontinu e.Th euseof halfofapancreasmight maketh isformof-cellr eplacement ther apyavailabletomorepatie nts. Th e possibilit yofdoin gmorePTAsmayreceivemor escrut in y,particularlyasaprocedur eforpatient swith early prot einur ia,wit hitspoorprognosis.Asren alfailu reworsensinth eseindividuals, theirriskof macrovascu lardisease andmortalityismar kedlyin creased.Th eDiabe tesCont rolan dComplicationsTrial (DCCT)hasprovent hat improvedglycemiccont rolisst ron glyprotectiveagainstt hedev elopment of kidney dise ase(1);thu s,pan creastran splant ation cou ldpr ove valuable forpatie ntsh eade dtowardre nal failure. Thispossibilitybecomeseve nmoreattractivebecauseofrece ntev ide nceth att heprogre ssionof diabet icn ephr opathymightbep artiallyreve rsibleinpatientswith p ancr eastr ansp lants(33). P. 767
ISLET TRANSPLANTATION
The firstsu ccessfulisle ttransplant s,performedinrodent sin thee arly1970s(35,36),wer emade possiblebyt hede velopment ofamet hod ofisolating isletsfromp ancr eases with collagen ase(37), leadingt oth eexpe ctat ionth atsu chtransplan tswou ld soonbeavailabletoevery on ewit htype 1 diabet es.Atth ebeginn in goft he21stce ntu ry,th efailuretomeetth esee xpectation shasbe en he artb reak in gforcoun tle sspatien ts,th eirfriendsandfamilies,andth einvest igatorsstrug glingt o progressasrapidlyaspossible .Inde ed,th ereh asbee nmuchde bate abouth owscience shouldproce ed whe nthe rearesoman yopin ionsabou thowtob alance applie dversu sbasicresearch(38). Thesimple explanat ionforwhyth eproblemofislet t ran splantation hasn ot b eensolvedisthat,desp ite the concept ualsimplicityofthe task, it hastu rne dou ttobeext raordinar ilydifficu lt. None the less, despite th efrust rationsan dmisstep s,substant ialprogre ssh asbe enmadet hat shouldprov ide afou ndation for eve ntu alsuccess.
Two Major Barriers to Successful Islet Transplantation

Fort hesakeofsimplicity,onecanconsolidat eth eproble mofislettr ansp lantationint otwomajor bar riers:howtoprov ide anadequatesu pply ofinsulin-producing ce llsan dhowtopr even tthe processes oft ran splantr ejection andautoimmunityfr omdestroyingth esece llson cetransplan ted.
Human Islet Allografts

Muchworkwithsmallandlar gean imalmodelswasn ecessarybeforeth efir stserioushu manislet allogr aftscouldbeprovidedinth elate1980stoimmunosuppr essedpatientswith k idn eytransplan ts (39,40,41, 42,43).The seearly t ran splantsinitially usedisletsobtaine dfromasman yasfivedonor pan creases,withsomeofth eseisletsbeingcr yopr eserv ed.The isletswer ein jectedint oth eportalvein, usingadir ectapproachwithdissect ionalongth eumbilicalvein;mor erecen tly,howeve r,at ran shepatic an giographicprocedur ehasgainedfavor (Fig.45.2).The seislet sbecomewe dgedinth epor tal
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tribut ariesanden graft, presu mablyr eceivingmostofthe irv ascular supplyfromhostve sselsg rowing intothe islets(44). Portalhyp erten sion, hemorrhage,orth rombosiscanoccur, b utsuch complication s havebee nrare(45).Th erewer eafewearlysuccess es,withsome recipie ntsbeing in sulin -fr eeformore th an2years,but then it becameappare ntth atmost ofth esetr ansplantswere failu res.Th ein it ial resu lt sweredisapp ointing. Datafromt heIn tern ational P. 768 IsletTransplant ationRegistry showt hat betwee n1990an d1998, on ly33(12%)oft he267r ecipie ntsof isle tallograftsremained insu lin- fr eeformoret han 1wee kandonly8%maintain edth atst atu sforover1 year(45,46).Th elong estper iodofinde pende ncefromins ulin was70month s.About35%ofth ese allogr aftshadcon tinuing g raftfu nction (C-pep tide greaterth an 0.5ng/mL)afte r1ye ar. Howeve r,ab ou t 30%ofth epat ien tshadamarke dredu ctioninC -peptideleve lswithin1month ,aph en omenoncalled primaryn on fu nction.Be cause sucharapidlossisrar ely seenwith allograft sin t heabsence of au toimmu nity,autoimmune destru ction isth ou ghtt obelar gelyresponsible.
Figure 45.2.Islettransplantationinhumansusuallyisdonestartingwithacadaverpancreasthatisdigestedwitha collagenase/proteasemixture.Theisolatedisletsarethenintroducedintotheportalveineitherbytranshepatic angiographyorvialaparoscopy.Theisletsthenarecarrieddownstreamandwedgeintheportaltributaries, whereupontheyarevascularizedbyvesselsfromtherecipient.
The p oorresu lt sobtain eddu rin gthe 1990swe rever ydish ear ten in ganddiscouragedth eexpansion of clin icaltr ials. Fortu nat ely,the fewcent ersth atpe rsist edwit htransplan tsmadeadvan cesthatproduce d importantinsight s(40, 45,46,47,48, 49,50).Although veryfe wr ecipien tswere freedofthe irinsu lin req uirements, it b ecameapp aren tth atth efun ctionofthe graft edislet spersistedinsome ofth em, as eviden cedbymeasu rab leC -peptidepr odu ction. Asisth ecase with the e arlystagesoft ype1diabetes, residu alin sulin s ecretiongre atlyimprovedglyce miccon trolev enth ou ghinsu lintr eatmen twasstill req uired.Th us,inabou t20%t o30%ofcarefullyperformed,well-docu men tedislettransplan ts,C pept ide secret iondidpersistandapp eare dtoleadtoimprovedglycoh emoglobin lev elsandfe we rseve re insulinreaction s(47).
The Complexities of Islet Allografts

Asin vestigator sbecamemore rig orousabou tdetails,r esultsbegantoimprove, although the ycon tinue d tobedisappointing. Be tter resultscouldbeobtaine difth ecoldische miatimeofth ecad aver p ancr ease s waslimitedtolessthan8hoursbeforeisletisolat ionandifmoreth an6,000isletequ iv alents p er kilogramwer etransplant ed(45,46). Be tter t echn iqu esforisletisolation h ave evolve d.Somefindth at th enewst andardizedcollag enasepreparat ion, L ibe rase, giv esbett eran dmoreconsisten tislet yie lds (51),andeffortsh avebe enmade t omin imizeth eamou ntofendotoxininthe reagents .Thepe riod immediate lyafterth etransplan tmaybecr itical.Th ephen omen on ofprimaryn on fu nction,withr apid disappe aranceofmeasurableC-pep tid e,islikelycau sedbyautoimmunity, becau sesuch rapidfailure virtu allyn ever occu rswith au tot ran splants. Other comple xeven tsdur in gthe e arlyimplan tat ionph ase mustleadt oconsiderable lossofisletmass.Forexample,th ere must besomeobligatorylossofcellsto localh ypox iain n on vascu larizedclumpsofisle ttissue(52, 53).Inaddit ion,anonspec ificin flammatory resp on se(54)and p ossiblylocalizedclott in g(55)mayenh ance the immu neprocesse sofre jec tionand au toimmu nityan dact ivateth einnateimmun esystem(56).Hype rglycemiamay prod uceincre ased oxygen con sumptionby -cells,wh ich wou ldfur the rdepriveth emofoxygen in theirlocale nvironment, soevery effort shouldbemadetomaintain e uglycemiawit haggr essiveinsulinthe rapy .Acasemaybe madeforusingint rave nousinsulindur in gthefirst10daysafte rthe tran splantwh ilen ewvesselsfrom th ehosten terth eisle tgraft s(44). Theh yperglycemice nvironmentappearstohav ean adver se influen ceon the out comeofislettr ansp lants(57).Th erewasevidence thatthe useofant i-th ymocyt e globu lindu ringth ein duct ionper iodwasben eficial(45, 50).Someth ou ghtth euse ofnicotinamide, ver apamil, pentoxifylline, an dvit amin E wasvalu able(45),bu tthe efficacyoft heseagen tsremainsto bee stablished. De spit ethe separ tialsu ccesses, the resultswer efarinfer iortothoseofpan creast ran splantation ,which resu lt sin theimmediateach ie vementofnormoglycemiain85%ofrecipient sandinth eremaining 15%
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foratleastayear.Th isindicat esthatth eisletscont ainedinonep ancr eassh ou ldbe e nough andt hat bothtr ansp lantre je ctionandautoimmu nitycanbecontr olle dbyconven tion alimmu nosuppre ssion. Someh ow, t heisletscontain edinthe irn or malh omeinthe pan creasmust b ele ssvulner abletoimmu ne injuryand/orth etoxice ffe ctsoft heimmun osu ppressiveagent s.Itisalsopossible thatthe abilityofthe pan creastog ener ate n ewisle tsfromduct smaybehe lpfu l(58).Moreover, thepr esen ceofdr aining lymph nodescontain edinthe wholepancre assee mstoprovideapr ote ctiv eeffectagainst autoimmun ity (59,60). Apuzz lingfindingisthatth eme ant imereq uiredforthe d evelop men tofinsu lininde pend enceint he33 rep ort edsucce ssfu lallograft r ecipie ntswas17924days(45).On eexplan ationisthatin sulin indepe nden ceten dedtocoin cide with theloweringofthedosesofimmu nosuppr essiveme dication ssuch aspr ednisone, wh ich are diabetogen ic, b utth eact ualreason maybemuchmor ecomplex.On emigh tnot expe ct-cellmasst ohaveincre asedd uringth ist ime,bu tprecu rsorductce llscarr ie dalon gwith the isle ts(61,62)might hav ebeen the sou rceofsomenewislets.Although hostvesse lsgr owinto transplan tedisle tsinon ly 7to10days(44),we have noide ahowlongittakesth evesse lstobefu lly establish ed.In theirn ormallocationinth epancreas,isle tshaveaspe cializedvasculat ure;arter iole s bre akintocapillarie swith in the core ofth e-cellsandth ene xit t hrough the isletman tle thatcon tains glucagon -secret in g-cells(63,64). When tran splant edislet sarer evascu larized,t hen ormalrelat ionsh ip bet we en-andnon--c ellsmaynotbe r eestablish ed,possib lyleadin gtoalt ered-ce llfun ction(65). In add ition,re in ner vation(66)an dtopographicremod elingofth eisletmicro-organsmaytakealongtime . The rear eot herre asonsforbeingconcer nedt hat t ran splante disletsmay n ot funct ionase fficient lyas normalisletsint hepancreas.Ith asbee nfoundt hat theoxyge nten sionofislet g raftssituatedu nde r th ekidneycapsuleofrode ntsiscon siderab lylowe rthanth atforisle tsin thep ancr eas(67),afactorth at couldresultinareduc tioninglucose-indu cedinsulinsecre tion . Although we nowr ealizeth atincre asingth emassofisletstransplan tedishelpful,t hiswasnotclearin th e1990s.Isletsfromasmanyas fivedonorsoften failed, while isletsfromasin gle pan creaswe re somet imessufficient. Another comple xvar iable isisle tpurity;man yoft hesuc cessfultransplant shav e use disletpr epar ation sthathadapu rit yofmor ethan80%,an dot hersh adapurityof50%orle ss, raisingqu estion saboutt heinfluen ce P. 769 ofn on -islet ele men tssuch asdu ctcells. Th eben efitsofimmun ologicmatch in gofdonorandrecipient haven otbe encarefullystudied, butmost successfu ltr ansp lantshavebe enmatch edonlyforbloodt ype an dnotfor histocompatibilityantigen s(45).Me asu rementofislet autoantibodiespr iortotransplant ation isusuallyoflittlehe lpbe cau sethe tit ersar etypicallylow,bu tsomehavefoun dthatthe p resen ceof au toant ibodiesmaybeassociat edwit haworseoutcome(68,69).An approach thatmaybeworth pur suingisthe measure men tofge nee xpressionofvariou simmu nemediatorsincirculat in glymph ocyte s dur in gthe cour seoft ran splantation ,asth ish asbee nfoundt ocorrelat ewit hkidney allograft rejection (70).
The Edmonton Protocol

Frustr ate dbythe mediocrere sultsofearlie rtrials,agr ou pofinve stigatorsin Edmon ton,Albert a, Canada,tr ie dane wapproach in 1999(71). Th eyth ou ghtt hat rapamycin(sirolimus)migh tbeben eficial an dthatglucocort icoidsweretoxictoislets. Th eyalsodid e veryt hingpossib let oimpr ove t hequ alit yof th eir isletpr epar ation sand reasone dthatmoreisletswouldberequ ir edth anwaspreviouslycon side red ne cessar y.They recru ite dpatien tswit htype 1diabet eswhohadseriou sproblemswithhy poglycemia, whichjust ifiedth euse ofpotent iallydangerousimmu nosuppre ssive agen ts.In con trast toth eprocedu re forear liertr ansplants,t heisle tswere u sedimmediate ly aftert heirisolat ionrathe rthanbeing maintain edintissuecu lt ure. Th eimmun osu ppression regime nincluded r apamycin(sirolimu s)an d tacrolimu s(FK-506)butn opr ednisone. Forin duct ion,antibodytotheIL -2rece ptor(dacliz umab)was use d.Isletswere in troducedint oth elive rthr ou ghth epor talveinviat ran shepaticangiograph y.Islets frommor ethanonecadave rdon or werere quired, with twosu fficingformostofthe patient s. Nor mogly cemiawasnev erat tained after t hefirsttr ansplantbu tdidoccur imme diatelyafte rthe second orthirdtr ansplant.Atotalofabout11, 000islet equivalen ts(IE)pe rkilogramwere used. At thet imeof th iswriting, 17patient shave been rende redinsu lin-fre ewit hglycoh emoglobin lev elsint hen ormalor ne arn ormalrange. Mostoft hepatientsh ave g lu coseint olerance, andt heirstimu latedC -peptidere le ase isapproximatelyon eth ird ofnormal,whichsu ggestst hat t heir-cellmassismarginalorth atth e grafted-cellsarelesse fficient t han pan creatic-ce lls.Someofth epatien tshavemaintain ednormal glycoh emoglobin lev elswith ou tin sulin foralmost2ye ars. The r esultsoftheE dmont on g rou pare spectacularlybett erth ananypr eviou sresults, butth is en thu siasmmustbe tempered b yther ealitythatpat ie ntsmustre ceivedan gerousimmun osu ppressive th erap yand t hat twoormore cadaverpancreasesar erequ ir ed,wh ich meansth atve ryfewpat ie ntswill betr eat ed.Noneth eless,th isisat rueadvan ceth atsh ou ldprovideafoun dationforfutu reimprove men ts withdifferen tprotocols.Tobrin got herg rou psuptothe samelevel,th eImmun eToler ance Ne twor k fun dedbyth eNationalInst it utesofHealth ,wit hhe lpfromtheJu ven ileDiabetesFoundation ,isfu nding 10cen terstoperform40tran splants t otr ytor eproduce t heE dmontonr esults.Aswitht heEd monton trial,t hemulticente rtrialwillenrollpatientswithout kidn eytr ansplantswhohaveth reateninge pisodes
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ofh ypogly cemia;h owe ver,patient swith sever ein stabilit yofth eircon trolandadvan cin gcomplications willalsobe con side red.
Allografts in the Absence of Autoimmunity

Insight in tot hepossible p roblemscau sedbyautoimmu nityh avebe enprovidedbyclust eroperationsfor abd omin alcan cerinwhichth elive r,pancreas,an dot her organswer eremove dfromth epat ien t,wh o th enre ceivedacadave rliver in towh ich isletsisolatedfromt hesamecadave rdon or wereplace d, providin gapu reallogr aftsituation(46). Theseisletallogr aftsmore ofte nproduce dnormoglycemiathan didisletsg ive ntopatien tswit htype 1diabet es;pat ien tsbecame in sulin -in depen dent 60%ofthet ime, an don epat ie ntwasinsu lin-fr eefor5ye ars.Alth ou ghtransplan tationofthelivermayh aveh adsome ben eficialinfluen ceonthe immu nesy stem,the absen ceofaut oimmun ity issu spectedt obe amajor reason for t hesu ccess.In addition ,the serecipient saret ypicallyu nhe althy, soth eymayre quirelesscellmasst oaccommodat ethe ir r educe dnut rit ionalintakeandweight .
Islet Autografts
Tran splant ation ofisletsth atdonotfaceimmu neattack prov ide simpor tan tle sson sabouth owwellislets can performin t heliver.Wh enpancre asesarere movedbe cause ofpain fulp ancr eatitisor someother reason ,itisoften pos sibletoisolate theisletsan dtransplan tthe mintothe liverv iatheportalv ein . The sedig estedpancre aticpreparat ionsh avet ypicallybe enre lativ elyimpure ,contain in gnon-isle t pan creaticele me nts,including ductcellsthathaveth ecapacit yforn eogene sis.Th esepatie ntsdo remar kablywell, with about70%beinginsu lin-inde pend entat1ye arifthe yreceivemoreth an300,000 IE(46). Sometime ssu ccesscanbeachievedwithe venfe werth an200,000isletsconsider ablyfewer th ant heus ualrequ ir eme ntforsucce ssfulallograft s(72,73).The mostob viousex planationforsucce ssis th atth erearen oproblemswith eit her allorejectionoraut oimmun it y;it must alsobe remembe red, howeve r,th atth eremovalofglucagon bythe pan creat ectomyandth ete nden cyofth esepatientst obe th in cou ldmake themrelat ive lyinsu lin-se nsitiv e.
EFFORTS TO CONTROL TRANSPLANT REJECTION AND AUTOIMMUNITY

Cu rren tor gan tran splantsaresu ccessfulbecauseofimmu nosuppr ession, whichalth ou ghmore effective th ane ver,cont in uestobeassociat edwit hnotable r isk, the main t hreatsbeing su sceptibilityt oinfect ion an dthe developmen tofmalignancy(22).Th ereisgreatreluct ance tou sesuch dan gerousdru gsin peoplewit htype 1diabet eswhoseprognosismightoth erwisebegood. Fortu nately,considerable progressisbeingmade in thequ estforsafe rand moreeffect ive immu nosuppr essiv edrug s.Aswele arn more aboutth edifferen cesbetwe enre je ction andautoimmunity, wecan expectd iffere ntapproache sto beu sedfor each process.Ev endifferen tdru gsare likelytoberequ ir edfor xenograftrejection.
Induction of Tolerance
Amajorgoalfor thet ran splantation fieldistobe abletoin ducet olerance, thatis, treatme ntgiven on ly at thet imeoft ran splantation willsome howtrickthe recipie nt'simmu nesys temint oaccepting transplan tedforeigntissue ashisorher own. Manydiffere ntapproache sc urre ntlybeingstu diedcou ld leadt ofulloroperation altoler ance (Table45.1). Tolerancet otransplan tedtissu ehasb eenindu cedbya varie tyoft echn iqu esinan umberofexper iment almodels(74),but man yscientificandsafetyh urdles mustbeover comebeforesu chapp roachescanbeu sedinhu mans.On ehopefu lex ample wasthe islet transplan tsbetwe endiffere ntspeciesofnonh umanprimate sinwh ich an ti-C D3immu notoxin , cyclosp orine ,an dsteroidsweregiven on lydu ringth eperitransplan tperiod,wit hnormoglycemia per sistingformore than100daysinthe absen ceoffu rth erimmun osu ppression (75). TABLE 45.1. Approaches to the Induction of Tolerance Induction
Graft-based tolerance induction MHCknockouts(classIorIIMHCantigens) Removedonorantigen-presentingcells(passengerlymphocytes) MaskingofclassIMHCantigensbyantibodies Privilegedsites(brain,testes,thymus,anteriorchamber,other) Genetransfertoislets(eg,CTLA4Ig,IL-4,TGF-) Centraltolerance
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Clonaldeletion:thymicinjectionofantigen Clonalinactivation:thymicirradiation Peripheraltolerance Anergy Immunedeviation:fromTh1toTh2 Inhibitionofco-stimulation(CTLA4Ig,Anti-CD40ligand) Peptide-basedtherapy(parenteralororalforautoimmunity) Immunosuppression Donor-specifictransfusion(DST) Peripheralcellsuppression(CD4subsets) ClonaldeletionofperipheralTcells Chimerism ClonalTcellsthathometoisletsandinhibitimmunedestruction AdaptedfromRossiniAA,GreinerDL,MordesJP.Inductionofimmunologictolerancefortransplantation.Physiol Rev1999;79:99141.
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Immunosuppression and Immune Modulation

Impressivesu ccesswit hislet allograft sin nonhu manprimatesh asbee nfoundby b lockingco-stimulat ion withantibodiest oCD40ligand(CD154)onTcells, whichresu lt sin in hibitionofT-ce llactivationby an tigen-pr esen tin gcells. Th isn ewage nth asproduce dexcellentr esultsinexpe rimen tswit hmon keys an dbaboons,withn or malizat ionofglu cose leve lsandsee minglymin imaltoxicity(76, 77).Unfortu nately, trialsofthisagen tinpersonswith lu pusne phritishad t obe stopp edbecauseofthromboe mbolic phe nome na. Alth ou ghtre atmen twith an ti-C D40lig andcont rolledallograftreject ion,itisnotclearif blockadeofco-st imulationwillprotectagainstautoimmunity(78). Anothe rnewagen tusedwith somesucce ssin n on hu manprimateisle tallograftshasbeen CTLA4Ig, whichalsoblocksco-stimu lation (79) .Tcellscan beinhibitedby antibodie sin variousother ways.An age ntinclin ic alislettr ansplanttrialsisanonmitoge nichuman iz ed,Fcrecep tor -nonbindingOKT3 an tibody ,whichinhibitsT-cellactivation(80).Avarie tyofoth erexpe rimen talage ntscouldtur noutto beu seful.FTY720isanagentt hat displace slymphocyte sfromth eperiphe ralcir culation an diseffe ctiv e invar ioustr ansp lantationmodels (81). Monoclon alant ibodiestothet ran smembraneprote in t yrosin e kinasephosphatase CD45h aveb eenfoun dtoinh ib itt here je ctionofislet allograft s(82) .Thesolu ble complement r ecept or1(sCR1)TP10mayinhibitthe in flammationar ou ndne wlytr ansp lanted isletsand mayhe lpcont rolprimarynonfu nction(55).Blockadeofthe IL -15r eceptorwithmutatedIL -15/Fccan inhibitT-cellex pan sionan dprotectislettr ansplan ts(83).In oth erex perime nts,IL- 10/Fcprolon gedislet xen ogr afts, p ossiblybyin hibitin gmacrophag efunct ion(84).Th esearejustafewexamplesofagen ts th atarebeingde velope d.Pr eviou sexper ien ceshowsth atcombination ther apyu suallyprovide sthe b est resu lt s,soitwillbech alle ngingtodete rmine howthese newdru gswillin teract. Immu nologist salsoarelear ningmore aboutimmun oprivilegedsitessu chast hete stes,br ain,t hymus, an dthe ant eriorch amberofthe eye, k nowled gethatmayprovideinsightsintopossiblen ewstrategies (85).C otr ansplan tat ionofisletswith Se rtolicellsh asbee nfoundt oprovidesomep rot ection against reject ion(86).Th isorigin ally wasassu med t obe cause dbythe expre ssionofFasligan don Sertolicells, but recen texpe rimen tssugge stthatth eprotectionisc ause dbysecre tionoftransforminggr owth factor(TGF-)(87).
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THE SHORTAGE OF INSULIN-PRODUCING TISSUE

Atpre sentt heonlysourcesofislet sfortr ansplantationintohu mansarecadaverpancre ases, whichar e inver yshortsupp ly. Itiscu rren tlynotpos sibletouselivin gdonorsbecau senoten ou ghisle tscan be reliablyobtained fr omadonatedportion ofapancr eas. Inth eUnite dSt ate s,it willbe amajorch alle nge toobt ain3, 000u sablecadaverpancre asespe ryear,yet theinciden ceoft ype1diabetesisab out 30,000 case sperye ar(88),andtyp e2diabe tesdev elopsinmore than10timesasmanype ople.Th esucce ssof th eEdmon tonprotocoldepen dedonth euse oftwoormorecad aver p ancr ease s.There hav ebeen some succe sseswit hisle tsisolated fr omon ly one pan creas, butitmayben ecessaryforthe don orpancre asto havealargeisle tmassand forth erecipient tobe smallan din sulin -sensitive.An oth erpr oblemis compe tit ionforpan creaseswit hthosedoingwhole-pan creastran splants, part icu larlybecau sewholepan creastransplant sarepr esen tly moreoftencover edbyhe althinsu ran ce.Thiscompe tit ionislikelyto cau seproblemsu ntilislettr ansp lantsh avebe enproven toprov ide s uperiorresu lts. There hasbe en muchdiscussionabout thepossibilityofu singhu manfetalt issu e,bu tdespitesome advances, thisis provingtobead ifficultroute(89, 90).Manyt ran splantsofhu manfetalpancre ashavebee nper formed ar ou ndth ewor ld, b utnoclear b enefith asbee ndemon strated(45).Atpr esen t,noon ehasfou ndaway toexploitth egrowthpote ntialoffet alpan crease s;moreover, manyet hicalandp racticalissuesclou dthe fut ureofthisapp roach.
Expansion of Human -Cells from Stem Cells, Other Precursor Cells, and Cell Lines
Itisnowappre ciatedth atn ew-cellsarege neratedth rough out adu ltlife ,bothfromr eplicationof pre existin g-cellsandth rought heformation ofne w-cellsfrompr ecursorcellscon taine din pancr eat ic duct s(91).Inth epre senceofhyp erglycemiaand insu linr esistan ce,-cellhyper trophyalsocan contribut etothe incr ease in -cellmass(92,93).Tomain tain-ce llmass,birth ofne w-cellsis balancedbyde ath of-cells,mainlythrough apoptosis. There isincre asingex cite men tab out the possibilit yofexp anding -c ellnu mbe rbyexploiting thede velopmen talcapacit yofpre cursorcells.This couldbeaccomplishe dwith stemcellsorot her p recur sorce llsbyfindingne wwaystostimu lateth e rep licationofe xist in g-cellsorbycre atingausefu l-cellline .
Stem Cells
The d efin it ionofstemcellshasbecome verycomp lex .There are true s temc ells,su chash ematopoiet ic orin testinalce lls,th ath ave thecapacityofunlimitede xpan sionandar ecapable ofgen eratingvarious cellt ypes.Th ereareembryonicstemcellsfoun din blastocyststh atarecap ableofde velopingint oany specializedcelltype. Th ent here arefacultat ive orfu nction alstemcellst hat arediffere ntiate dcells cap ableofge neratingn ewcells. Th esecanincludediffere ntiate dpan creat icdu ctcellst hat ,wit hth e properst imulus,canch ange theirdiffere ntiationan dbecome activat edtoformnewisletan dacinarcells (94).Ith as P. 771 rece ntlybecomeapparen tthatstemcellsh ave amu chwidercapacityfordiffe rent iation t han has pre viouslybee napp reciated ,wit hth erebe in gexamplesofh ematopoiet icste mcellsdiffer ent iatin gin to live r,ne rve, andmusclecells(95).Itmayalsobepossiblefordifferen tiatedce llstoturn in toc ellswith charact eristicsofembryonicstemcells(96). Rec entadvan ceshavegen eratedoptimismt hat stemcellsmigh tbeu sedtomakene w-ce llsan dthu s solve thepr oblemoflimited-cellsupply.For example,ithasrecen tlybeen shownth atdu ctcells obtaine dfromadu lt h uman cadav erpancreasescan beexp ande din vit roandth atwh enth esepr ecursor cells(fu nctionalste mcells)arest imulate dwith growthfact ors andmatr ix, the yformduct c ystsfrom whichspr ou tisletst hat con tain-cellsand t heothe rislet celltype s,th esebeingcalledcu lt ivatedh uman isle tbuds(C HIBs)(58). Atprese nt,n ot e nough CHIBscan b egene rat edtobeuse fu lforclin ical transplan ts,bu tthe resee mstobepoten tialforfu rthe rexpansion .Alt houghadultpan creaticductcells haveth iscapacityforis let regen eration, itse emst hat the p roce ssisn ormallysuppre ssedin vivot o accommodate the n eedforalowrate ofne oge nesis.Witht heproper in v itr oorin vivostimulus,t hese rest raint scanbe remove d,ash asbee nshowntooccuraft erpartialpancr eat ectomyinrats(97,98). The sestudiesrais ethe hop ethatasinglepancre ascouldprov ide enough isletstosupp ly-ce llsfor more thanon ere cipient .Inaddition, itmightbep ossible toobtain pan creat ictissu efromape rson wit h diabet esan dthe ncultivat enewislets,wh ich canbe retu rned int heformofatr ans plant. Fortype 1 diabet es,th iswouldmean t hatalloreject ionwouldnotbeap roblem,bu tau toimmun it ywou ldst illn eed tobecontrolle d.Forty pe2diab etes, thet ant alizingpossibilityexiststh atC HIBscou ldbe p rov ided asan au totran splant with noimmu nere je ction. Othe rwork ershaveobtaine dcon side rablee xpan sionofcells obtaine dfromhu manislet s,whichu nfor tun ate lyse emt ocontain littleinsu lin(99,100).Effortscontinu e tomaketh esecellsdiffer ent iateintoa-cellphen oty peuse fulfortr ansplan tat ion. The p ossibilityofusingembryonicstemcellsh asbecomemoreattractivewithth edemon strationt hat mou seembryonicstemcellscan begrowntoforminsu lin-containingcellscapableofcuringdiab etesin micewith c hemicallyindu ceddiabet es(101). Th iswasaccomplishedbymeansofaselection process employingantibioticres istancege nesdr ive nbyth einsulinpromoter .Specializ edtissuecu lt ure
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tech nique sthen wereappliedt hat prod ucedaggregatesofcellscontain in gnear-normalamou ntsof insulinan dhavin gthe capacityt osecr eteinsu lininre spon setoglu cose le velsin theph ysiologicrange. Thissucce ssr aisesth epossibilityt hat human embr yon icst emce llsmigh tbedeve lopedinasimilar mann ertogen erat ean unlimitedsu pply of-cells.
Production of Insulin-Producing Cell Lines

Advancesinmolecu larand cellbiologyhav emadeitthe or eticallypossible toman ipu latet he differen tiation ofcellsbygen eticengine eringsothatthe ycou ldbe usedfortransplan tat ion.It hasbe en possibletotransformmur in ein sulin -producingce llswith the SV40Tantigen, expandth esecells,an d th entu rnoffthe oncogen ewithat etracyclin eresponse ele men t,withr esultantre differ entiat ion(102). Although s uchmodifiedmurinece llscou ldconce ivablybeuse dfort ran splantsintohu mansifthece lls were somehowprotecte dfromimmun edestru ction ,hu mancellswouldbeaprefer ablesource. Un fort unately,ithasproven d ifficulttocreateacomp arable h uman celllin e.Anoth erapp roachwouldbe tocreatea-ce llequ ivale ntbyaddinggen esorin hibit in gthee xpressionofe xist in ggene s(103,104). Fore xample ,th eproin sulin gene canbe expres sedin cellsth atn or mallydonotmakeinsulin,witht he resu lt in gcellscapablenotonlyofmaking p roinsu linandcleav in gitt oinsu linbu talsoofstoringan d secre tinginsulininresponse toavar iet yofstimuli. By addingaddit ionalgen esth atinfluen ceglucose metab olism,itiseven possibletomanipulate t hese cellssothatthe irinsu linse cretionispartially reg ulated b yglu cose .Anothe rapproac hhasbeen toe nginee rcellsfromt heinte rme diatelobe ofth e pituitarytomakeinsulin(105). Th esece llsare ofinte restbe cause despiteth eirproduction ofsignificant quantitiesofin sulin ,the yare notsubjectt oautoimmune attack.Although the sepreliminaryresu lts are en cou raging, itisbecomin gclearth atn ormal-cellsarere markablycomplicate d,whichmean sit maybe difficu ltt ocre ate n ear -normal-ce llsbyalte rin gafewge nes. Onthe oth erh and, asmore islearned about themast erswitchest hat con trolth edifferen tiation ofcells,more p romisin gresultsmaye mer ge. Human in sulin -producingcelllinesh ave b eende rivedfrom-ce llsfrompat ie ntswithpe rsist ent hy perinsulinemich ypogly cemiaofin fan cy(106).Alth oug hthe secellscanbe e xpan dedintissue culture , th eydonotcon tainmuch in sulin andh ave n ot yetbe enen gin eer edtosecret ein sulin properlyin resp on setophysiologicleve lsofglu cose .Inconsideringt hepoten tialuseofin sulin -secret in gcellsfor transplan tat ion,t hequ estion remainsofwheth erth enon--ce llsoft heisle tor someequ ivale ntsh ou ld becontainedinth etransplan tedcellaggre gate s.Itsee msth atn on --cellsareprobablyn otre quired, as sugg estedby experiments inwh ich relativelypu re-cellp opu lationsp repar edbyflowcyt ometry fun ction edreason ablywellwh entr ansplantedint odiabe ticr ode nts(107).
Xenotransplantation
De spit eincreasedoptimismabou tth eprospectsfordeve lopingne wsour cesofh uman-ce lls, invest igatorsare stillexploring thepossibilityofu sin gtissuefromoth erspeciesasxenotransplan ts (Table45.2).The listofspeciesthatar epot entiallyuse fu linclud epigs ,cows, rabbits, r ode nts, ande ven fish.Pigsh ave h adparticularappealbe cause piginsu linh asbee nuse din thepastfortreatingpeople withdiabe tes,pigshaveglucoselevelssimilartothoseinhu mans, p igsarepartoft hefoodch ain,and peopleseemtobecomfortab leabou tth eprospectofusingth issourc e.Un fort unately,pigisle ttissueis noteasytowork with .Itcontinu estobedifficu ltt ogen eratehigh -qualityisle tsfromadu lt pigs (108, 109).Much wor kisn owbeingdone tod evelopwaysofu sin geithe rfetalorneonatalisle ttissue, whichareat tractiv esou rcesbe cause ofth eir growt hpoten tial(110,111, 112,113,114).Oneofth e problemswith t histiss ueisthe immaturityofthe cells,wh ich me ansth at itcantakeweek sormon thst o normaliz e P. 772 glucoselevelsin transplant recipie nts. An ot herpote ntialproble misthatporcin etissuecont ainsporcine en doge nousret rov iru ses,wh ich canbe tran sferre dtoh uman cellsintissuecu lt ure(115,116).Ther eis considerable u nce rtainlyab ou twheth erth isr eprese ntsahealt hthr eat ,butint heUn it edStat es, transplan tat ionofporcine tissueforthe treatme ntofneu rologic d iseasehasbeen allowedtoproceed withcaution .Thu sfar,n oh umanr ecip ien tsofp orcine tissu ehavebee nrep ort edtocarry porcine ret rov iru ses(117). TABLE 45.2. Potential Sources of Insulin-Producing Cells for Islet Transplantation
Human sources Livedonors(probablynotanoption) Cadaverpancreata Fetalpancreata
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Expansionofexistinghuman-cellsin vitroorin vivo Cultivationofnewisletsfromprecursorductcellsin vitroorin vivo Stemcellsembryonicandadult Celllines Xenograft sources Pigs,cows,rodents,rabbits,fish,other Celllines Transgenicpigs(orotherspecies)
Immune Attack on Xenogeneic Islets

Reject ionofxen ograftsisacomplexandeffect ive proce ss(118,119,120) .There isanearly attackcalled hy peracu tere je ction mediat edbyantibod iesandcomplemen tthatcan leadtodestru ction oftransplan ted organ with in minu tes.Th esepre formedIgMan tibodiesre cogn iz eaglycoprot eincalledthe Gal-(1,3)Gal epitope(Galepitop e)thatisstronglyexpre ssedonth esurfaceofe ndothe lialcells. Th isisaparticular problemfororgan tran splant sbecau sethe att ackonen dot helialce llsproducesische miath atleadsto rapidde ath ofth eorgan .Celltran splant smay notbeasv ulnerable tot hisproce ss.Fore xample ,it see msth atisle tcellsfr omadultpigshavelit tle ofth isGalepitope(121). Howev er,e venth ou ghislet cellsmighte scapeh yperacute rejection ,th eywillbesub je ctedtoTcell-mediate ddamage, whichseems tobesimilartoallore jec tion, andt oothe rin sults,su chasinfiltrat ionwitheosinophilsandmacrophages (118, 122).Su rprisin gly ,xen ogr aftedt issu emayalsobesuscep tiblet oau toimmu neattack,whichdoes notsee mtobespe cies- specific(123).
IMMUNOBARRIER TECHNOLOGY
Semipe rme ablemembr ane sthatcreateanimmunobar riercan preve ntdest ruct ive lymphocyte sfr om killingtransplan tedislettissue(124,125,126). Th esemembran eshaveopeningslar geen ou ghfor glucose,oxygen ,an dnu trient store ach t hee ncapsu latedisletsan dfor in sulin tobe release dtoe nter th ebloodstream. Yet,th eholesare smallen oug htokeepwh ite bloodcellsfrompe net ratingt he membr ane and r each in gthe isletce lls.Import ant quest ionsre main aboutjust h owpe rme ableth e membr ane snee dtobe .Rece ntly,itwasfoun dthatme relymaintain in gadistan cebetwe enlymphocytes an dislet c ellsmaybee nought opre vent aut oimmun edestr uctionan dalloreject ion(127,128). Protection ofx enotransplan tsseemstobemoredifficultbecausesmalle rope ningsmigh tben ecessarytolimit leakageofshedantigen sandt opre ven tent ryofpoten tiallyt oxiccytokines. Itish ope dthat immun obarriers,ifsucce ssful,willmak ethe useofimmu nosuppr essiv eme dication comple tely un nece ssary. Alth ou ghsafedrug t reatme ntsth atwillprotect tran splant edislet ce llsmaybeavailablein th efutu re,t here maybeape rioddu rin gwhichmemb ran eprotectioncouldbeclinicallyuse fu l. Thetwo majorapproach esare macroe ncap sulation an dmicroencapsulation.
Macroencapsulation
Macroen capsulat ionu sesdevicessu chash ollowfibersorpar allelflatsh eetssealedatt heed gesin which manyisletsarecontain edwit hinasinglede vice (125,129,130, 131).Largege lbe adsoreven slabsmade ofe it heragaroseoralginatecan alsobe con side redformacroencapsulation(132). Oneofthemajor adv ant agesofsuch anapproachisth epos sibilityofimplan tin gthe devicesinavarietyoflocat ionsbu t ofst illbein gabletoret rie veorreloadth em. Th emainproblemwitht hisapproach has b eent hedifficu lt y ach ie vin gapracticaldensity, whichmean sthattoogre atasurfaceare awou ld berequ ir edtosupport th eencapsulat edis let cells(130). Moreover ,que stionspe rsistaboutwh eth erth ereleaseofinsu linwill berapidenough ,par ticu larlyfromlarge gelb eads, tocont rolbloodglucosele velsadequ ate ly .Itis hopedt hat advancesintissue engine eringwillimproveth epoten tialofmacrodevices.
Microencapsulation
Micr oen capsu lation isan appr oachinwhichsingleisle ts,asmallnumberofis let s,or aggre gate sofcells ar econ taine dwith in amembran eThemost commonlyuse dme thodusesalg in ateobtain edfrom seaweed, wh ich can formagelaft erexposur etocalciu morbar iu minsolu tion (133,134,135, 136,137) (Fig. 45.3). Th us, isletscanbecaptur edin asmallge lbe ad(lessthatamillimete rin diame ter)t hat can becoat edwit hamate rialsuchaspoly-L-lysineth atcanprovideper mselect ivity. Becau sepoly-L-lysine
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can gene rat ean inflammatorytissue react ion, anoute rlayerofalginat eusu allyisadd edtomakethe cap sulesmorebiocompat ible.R ecent studiesindicat ethatsimplebariu malginatemicr ocapsuleswit hout apoly-L-lysin ecoatingcansucce ssfullypr ote ctagain stau toimmu nityan dallore je ctioninmice (128). Agar oseh asalsobeen usedformicrocap sules(138), ashasalgin ate mixedwithothe rpolymers, suchas cellulosesu lfate(139).Anothe rapproach ist ou seapoly ethy len eglycolwithph otopolymer ization t o formacoatin g(140). Forah umant ran splant, probablymoreth an 300,000isletswillne edtobe en capsu latedan dplacedint oth eperitonealcavity,bu tthatcan beaccommodat ed,assuggest edbya pilotstu dyperformedinhu mans(135).
Figure 45.3.Alginatecapsulescontainingporcineneonatalpancreaticcellclusters.Isletcellsoraggregatesofcells areprotectedfromimmunedestructionbyasemipermeablemembrane.Acommonapproachistousesmallbeads ofalginatecoveredwithpoly-L-lysine.Insomesituationsthepoly-L-lysineisnotused.Themembranewillprevent penetrationbycellsandlimittheentranceofantibodies.Themembranemustbepermeableenoughtoallowthe passageofglucose,nutrients,andoxygentotheisletsandofinsulinouttodiffuseintosmallvessels.(Photograph courtesyofDr.AbdulkadirOmer.)
Although s omesucce sseswit himmunobarrierapp roachesinboth s malland largean imalmodelshave bee nreporte d(126,133,141),the feasibilityandrep rodu cibilit yofth ismeth odologyh ave stillnotbeen establish ed.Man yaspe ctsofth ist echn olog ycou ldbe explore dtoimproveth eprospectsforsucce ss. Cooperat ionbe tween scien tistswor kin gwit hpolymerch emistr y,bioe nginee rin g,an dislet cellbiology ne edstobepromoted .Thefieldnowfacessome fundame ntalqu estion s:howcanbio- incompatibilit yofth emate rialsbe minimized;h owt hick,den se,andstrongsh ou ldt hemembran esbe; whatist heidealconfiguration ofad eviceor capsule;sh ou ldth edev icebe retr iev able;an dwhat isth e idealimplan tationsite?Somepossib ilit iesareth eintraperitonealsp ace, t heome ntalpouch ,th e pan creas,asu bmu cosalsp aceinth egut ,an dasubcu tan eoussite. P. 773
GENE-TRANSFER TECHNOLOGY TO PROTECT ISLETS

Pr ospe ctsare improvin gfor find in gclinicallyusefu lve ctor sthatcan e fficien tly t ran sfergen esintocells (142, 143,144),mean in gthatitwillb epossibletoexpre ssgene sin isletcellswith resu ltant overprodu ctionorun derpr odu ction ofdesignatedpr ote in s.Poten tialvectorsforgene tran sferinclude viruse s,lipidcarr ie rs,orelectroporation.An impor tan tgoalwouldbetotransfer gene ss oth atth ey wouldbeperman ent lye xpresse din alloftheinsu lin-p rodu cin gcellsofan islet. Ade novir alvectorsth at can transferge nesintoisle tson atemporary basisare n owavailable;un fort unately,h owev er,t heir expr ession cann ot b eexpec tedtolastlon gerth an80days.Noneth eless,th eycanbeu sedfor short-ter m proof-of-principleexpe rimen tstolearnwh ich gene smightbe helpfulfor prot ectingtr ansplantedislets. Anothe rcan didateisthe gut less aden oviru s,whichh ashadsomuch ofitsade novir usstru cture removedth atitshouldnotgen erateanimmune responset oth einfecte dcells(145).Anothe rvectorth at holdsattr activepr omise fore fficient g enet ran sferisthelen tiv iru s,ar etrovirusth atcantransdu ce gen esintothe g enome ofnondividingcells( 143,146,147). Per man en ttran sduct ioncanalsob eobt ained withadeno-associated v iru svectors(148).Itispossiblethatsomewaywillbefou ndtouse synth etic lipidcar rie rseffectively. Ye tan oth erpossibilit yist omaket ran sgenicpigstoint rod ucegen esinto porcine-cellsusingan in sulin -promoterconst ruct. The rear emanywaysbywhichisle tsmight beprotecte dfromeithe rtransplan trejectionoraut oimmun e at tack. Forexample, someoft hepr ote in son theout sideoface ll,such asclassImajor histocompatibilit y(MHC )ant igen s,migh tbede let edorchan gedsothatth e-cellswouldescape recogn itionbyth eimmune system(149).An ot herapproachistoin troduce p rot ein sthatmigh tbe secre tedbyt ran splante disletsandser veasmissilestodis ablein vading lymphocyte s.Ithasalready bee nshownth atisletsen gin eere dtosecrete the smallproteinCTLA4Igare moreresistantt otransplan t reject ion(150,151, 152).Production ofanan tibody thatwou ldbindt oCD40ligand(CD154)migh texe rt asimilare ffe ct.Anu mbe rofcy tokine s,such asIL-4,vIL-10,orTGF-, mighte xertdiffere ntkindsof inhibitoryin flu ence son attackinglymph ocy tes.Th ecombinat ionofIL-4andIL-10hasbeen ableto
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pre vent t hede velopmen tofdiabe tesinNODmice ,pre sumablybytilt in gtheimmu nityawayfromth e dest ructiveTh 1pattern ofimmun eat tack(153).Un fort unately,adenoviralexpr ession ofIL-10in transplan tedisle tshasnotslowedre je ction ofratisletst ran splante din tomice(154). Ar ecent report sugg estsisle tproduction ofIL-4wasn oth elpfulin p reven tingallogr aftre je ction(155)butth at lentivirus-mediat edtransdu ctionofis let swith IL-4couldprotectt ran splante disletsfromin sulitis(156). TGF-canmodulatelymph ocy tereaction sfromaTh1toaTh2patt ern(157,158), buth igh dose scan cau sefibrosis,wh ich probablywou ldleadtog raftfailure .Inh ibition ofIL-12withadominan t-ne gative mutantmayalsohavevalue forislettransplan tat ion(159).Othe rpotent iallyvalu ablepeptidest hat migh tbesecr etedby tran splante disletsareth eIL-1recept orantagon ist prot ein(IRAP)andsolubletype 1TNFrecept or s(144).Workisalsobe in gcarriedout with in doleamine2,3-dioxyge nase (IDO),a try ptop han e-cat abolizingen zymeexpr essedbyt hetroph oblast t hat helpsinhibitfetalre je ction(160). Anothe rwayt oimpr ove su rvivalmigh tbetobolste rthe in tern aldefens eme chan ismsof-ce lls.Var ious proteinscanprotect cellsag ainstoxidant in ju ryan dapoptosis. Thus, on ecou ldint rodu ceag enet omake -cellsover expre sscatalaseormanganesesu peroxidedismu tase ,glu tat hion eperoxidase ,or hemeoxygen ase, wh ic hare enzy mest hat prot ectag ainstoxidant in ju ry.Altern atively, g enesforth ean tiapoptoticproteinsA20,Bcl2, Bcl-xL, FLIPs,orMyd88cou ldbe used(161,162, 163).Stillothe rgen es couldprovide prot ection again stin juryfromacombinedattackbyan tib odyandcomplemen t,which occursinth eearly st agesofxen ogr aftre je ctionofor gans, butmayn ot beaproblemwith islets. Itmigh teve nbepossible t ode liverge nest oisle tsin viv o,wh ich cou ldbe usefu lforprev enting au toimmu nityortransplant rejection.On eappr oachist ode velopge neticallymodified lymphocyte sthat couldhomet oisle tsthr ou ghth erecognition ofisle tan tigens. AT-ce llclone thathasb eenfoun din mice can home t oth eisle tsofNODmicebyre cogn izinginsu lin, subdu in gthe autoimmun ereactionint he isle ts,an dthe rebypr even tin gdiabet es(157).Th ismod ulation ofautoimmunityse emst obee xerte dby secre tion ofTGF-byth eTcells. Thedev elopment ofTcellst hat p rodu ceothe rcytokin es,su chasIL -4, migh talsobe anattractivestr ategy .Withtime ,other approach esth atcoulddeliv ergen estoisletsin vivoarelik ely tobe developed.
PREDICTING THE FUTURE

Atte mptst opre dict thefu ture ofisle ttransplan tationhaveprovedh azardous.U nexpe ctedobstacle sh ave plagu edthisdifficu ltfieldfor decade s,an don eisnotsafepr edic tin gan ythingdiffere ntforthe futu re. Howe ver, with the e xtraord in aryadvan cesoccurringinbiomed icalscience ,th eremigh tbeamajor bre akth rou ghinth ene arfu ture ;ont heothe rhand,pr ogre ssmight bemadeinsmallincre men ts.Th e resu lt sobt ainedwithh umanallograft ssh ou ld c ont in uetoimpr ove asnewmeth odsfor immun osup pression and immu nomodulat ionar edeve lopedth atmake it p ossibleformorepeoplewit hout kidney tran splant st ore ceiveislet s.Ther eare reason st obe optimisticab ou tthe p ossibilityofexpan sion ofh uman -cellssothatcellsu pply willn olon gerbe alimit in gfactor.Newapproache stopr ote ction fromimmun edest ructionare beingpu rsuedonman yfron ts.E vent hought oleranceisthe majorgoal,it willbene cessar ytok eepworkingonother approach es,su chasbe tter immu nosuppre ssive med ications, immun obarriertech nology, andge net rans fe rappr oaches. Recen tly,th efie ldofislett ran splantation h as bee ninfuse dwith newen ergyandre sou rcesth atsh ou ldaccelerateth ejour neyt osuc cess.
ADDENDUM
Sinceth einitialwritingofthischapter ,bymid-2004th eEdmon tongroupt rans planted isletstomore th an70patients, usingvariouspr otocols, andh ascontinu edtoobt aininsulinindepe nden ceinth evast majorityofsubject s,althoug his let sfromtwoormor epan creasesare stillusuallyre quired. O ther cen tersinth eUn it edStat esan dEur ope h ave been lessactive,bu tprogressisbeingmade .Twogroup s haven owrep ort edsucce ssinobtain in gin sulin in depen den cefromsingle-donortransplan ts(164,165). Although e ncouragin gthatsingle-donorislet t ran splantscansu cceed,t hisusuallyh appen son lywh enth e recipient hasve rylowinsu linre quirement sandt heisle tpreparat ionwasofexce llen tquality.It seems like lyt hat the-ce ll massrequ ir edtonormalize g lu coseleve lsispropor tionalt oth einsulinrequ ir eme ntsofthe recipie nt. The MiamiandBay lorgroupsh aveb eensu ccessfulincoordinatingisle ttransplant sbetwee ncitie s,with pan creasesflownfr omHou ston toMiamiandisolat edislet sflownbacktoHoust on forimplan tat ion (166). Thisworkandth atofot herssh owt hat isletsn eednotbe t ran splante dimme diatelyaft erisolation, but canbe placedincultu rean dtransplan ted1t o2dayslate r.Toanswe rthe quest ionofwh eth erisle ts transplan tedtoindivid ualswit hkidne ytran splant sc oulddoaswellasthe islets-alone Edmon ton app roach,se veralgr ou pshav ehadsuccesswithavariet yofre gimens(167,168,169). Agr ou pin Zurich hashadcomparablesuccesswith simultan eousislet kidn eytr ansp lants(170). Not ableprogressh asbee nmadeinde velopingimmun ologicst rate gie stocr eate tolerance andblock au toimmu nede struct ion. Th isworkh asbee ncarr ie dou tin mice,pigs, andn on human primates (171, 172,173,174). Forfu rthe rupdatesonpancre asan dislett ran splantation ,readersarerefe rredt oseve ralexce llent rece ntre vie ws(175,176,177, 178). P. 774
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94.Zangen DH,MillerC P,Smit hFE,et al.Incr eased isletandduct alin sulin promoter-1/id x-1 ex pression in pancr eat icre gene ration.D iabetologia1995;38[suppl.1]:45A. 95.VogelG. Can oldcellslearnn ewtricks?Scien ce2000;287:14181419. 96.Kond oT,RaffM. Oligodendr ocyt eprecu rsor cellsre progr ammed tobe comemultipote ntialCNS ste mcells.Scie nce2000;289:17541757. 97.Bonn er-WeirS,Tre ntDF, Weir GC .Partialpan createctomy int heratan dsubse quen tdefect in glucose-indu cedinsulinrelease.J Clin Inv est1983;71:15441553. 98.Sh armaA,Zangen DH,R eit zP, e tal.The homeodomain proteinIDX-1in creasesaft eran early bu rstofp rolife rat iondu rin gpan creaticr egen erat ion. D iabete s1999;48:507513. 99.R amiyaVK,Marrais tM, Ar forsK E,et al.Rev ersalofinsu linde pend entdiab etesu sin gislets gen eratedinvitrofrompancreaticstemcells. Nat Med2000;6:278282. 100.Beat tie GM,Itk in -Ansar iP,CirulliV,e tal.Sust ainedprolife rationofPDX-1+cellsde rive dfrom hu manisle ts.D iabetes1999;48:10131019. 101.SoriaB, Roc heE, BernaG, etal.In sulin -secre tin gcellsde rivedfromembryonicstemcells normalizeglycemiain s treptozotocin -in ducedd iabeticmice.D iabete s2000;49:157162. 102.EfratS,Fusco-DeMan eD,LembergH, e tal.Cond itionaltransformation ofapancr eatic-cellline der ive dfromtransge nicmiceexpr essin gate tracycline -regu latedoncogene .Pr oc Nat l Acad Sci U S A 1995;92:35763580. 103.ClarkSA, Qu aadeC, Con stan dyH,et al.Nove linsu linomacelllinesprodu cedbyiterative en gin eer in gofGLUT2, glu cok in ase, andh umaninsu line xpression.D iabetes1997;46:958967. 104.Hoh meier HE ,BeltrandelRioH, ClarkSA,e tal.Re gulation ofinsu linse cretion fromnovel en gin eer edin sulin omace llline s.Diabe tes1997;46:968977. 105.Lip esMA, Cooper EM,Skelly R,et al. Insu lin-secr etingn on -isletcellsare resistan tto autoimmu ned estru ction. Proc Natl Acad Sci U S A1996;93: 85968600. 106.MacFarlan eWM, Oapos;BrienRE ,Bar nesPD,e tal.Sulfonylure arece ptor1an dKir6. 2exp ression inth enovelhu manin sulin-secre tin gcelllineNES2Y.Diabe tes2000;49:953960. 107.Pipeleer sDG,Pipeleer s-MarichalM,Han nae rtJC, etal.Transplan tat ionofpurifie disletce llsin diabe ticr ats. I. Stan dardizationofislet cellgrafts.Diab etes1991;40:908919. 108.DavalliAM,OgawaY,ScagliaL,et al.Fu nction,mass, andr eplicationofpor cin ean drat islets tr ansplan tedint odiabe ticn udemice.Diabetes1995;44:104111. 109.Bran dhorstH,Brandh or stD, He rin gBJ,et al.Sign ifican tprogressinporcineisletmassisolation ut ilizin gLib erase HIforen zymaticlow-te mper atu repancreasdigestion .Tran splant ation 1999;68:355361. 110.Mande lTE, Kou lman daM,Kovar ikJ, etal.Transplan tat ionoforgancu ltu redfet alpigp ancr eas innon-obese diabetic(NOD)mice andpr imate s(Macaca fascicularis).Xen ot ran splantation 1996;2:128132. 111.Korsgren O,Ander sson A,Sand ler S. Pre treatme ntoffetalporcinepancre asincultu rewith nicotinamideacce ler ate sr ever salofdiabet esafte rtransplan tationtonud emice. Su rgery 1993;113:205214. 112.TuchBE ,SimpsonAM,Smith MSR, etal.Basicbiologyofpigfet alpancr easanditsuse asan allogr aft. In :Pe tersonC M,Jovanovic-Pete rson L,eds. Fe tal islet t ran splantation .NewYork :Plenu m Press,1995:51.
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113.Korbutt GS,E lliott JF, AoZ,et al.Lar gescaleisolat ion,gr owth ,an dfun ctionofneonatalporcine isle ts.J Clin Inv est1996;97:21192129. 114.YoonK-H, QuickelRR,Tatark iewiczK, e tal.Differ ent iationandex pansionofb etace llmassin porcinen eon atalp ancr eaticcellclus terstr ansplan tedint onu demice .Cell Tran splant1999;8:673 689. 115.Patie nceC ,Take uchiY,WeissRA.In fection ofh umance llsbyan endogen ou sretr ovirusofpigs. Nat Med 1997;3:282286. 116.van derLeanLJ, Locke yC,Griffeth BC ,et al.Infect ionbyporcinee ndogenousr etrovirusafter isle txen otr ansplantationinSCIDmice. Natur e2000;407:9094. 117.ParadisK,LangfordG,LongZ,e tal.Searchforcross-speciestransmission ofporcine en dog enousre trovir usin pat ien tstre ate dwith livingpigtissue. Scien ce1999;285:12361241. 118.Bach FH,Winkler H, Fe rran C,e tal.De layedxe nograftr ejection .Immun ol Tod ay1996;17:379 384. 119.Dorlin gA,Riesbeck K ,War rensA, e tal.Clinicalxen otr ansplan tat ionofsolidorgans. Lance t 1997;349:867871. 120.Sode rlu ndJ, W enn bergL, C astanos-VelezE, etal.Fetalporcine islet-lik ecellclust ers tr ansplan tedt ocyn omolgus monkey s.Tran splantation1999;67:784791. 121.McK enzieIFC, K ou lman daM,San drinMS, etal.E xpressionofgal(1,3)galbyporcineisletcells anditsrelevancetoxen ot ran splantation .Xenotransplan tat ion1996;2:139142. 122.Platt JL,Nagayasu T.Cur ren tstat usofx enotransplant ation.C lin Ex p Pharmacol Physiol 1999;12:10261032. 123.HaskinsK, Wegmann D. Diabet oge nicT-ce llclone s.Diabe tes1996;45:12991305. 124.Colt on C K.Implant ablebioh ybridartificialorgans.Ce ll Tran splant 1995;4:415436. 125.LacyPE, He greOD,Gerasimidi-Vaze ou A, etal.Main tenanceofnormoglycemiaindiabeticmice bysu bcutaneousx enograft sofen capsu latedisle ts.Science 1991;254:17821784. 126.Lan zaRP,Jackson R,SullivanA,e tal.Xen otr ansp lantationofcellsu sin gbiodegr adable micr ocapsules.Transplan tation1999;67:11051111. 127.Lou dovarisT,JacobsS,Young S, etal.C orr ection ofdiabe ticNODmicewithinsu linomas implan tedwithinBaxter immu noisolation devices.J Mol Biol1999;77:219222. 128.Du viv ier -KaliVF,OmerA,Pare ntRJ, etal.C ompletepr ote ctionofislet sagain stalloreject ionand autoimmu nitybyasimplebarium-alginatememb rane .Diabe tes2001;50:16981705. 129.Brau kerJ, MartinsonLA,Young SK ,etal. L ocalinflammator yresponse around diffus ion ch amb erscontain in gxenografts.Transplan tation1996;61:16711677. 130.Suzu kiK, Bon ner- Weir S, Triv ediN, etal.Fun ctionandsu rvivalofmacroen capsu latedsyn gene ic isle tstransplan tedintostrep toz ocin-diabe ticmice.Transplan tation1998;66:2128. 131.Tatarkiewicz K,Hollist er-LockJ,Qu icke lRR ,etal. Reve rsalofh yperglycemiainmiceafter su bcutaneoustr ansp lantationofmacroencapsulate dislets. Tran splantation1999;67:665671. 132.JainK, AsinaSK,Pate lSG,etal. Lon g-termpres ervationofislet sofLan gerh an sinh ydrophilic macrobeads.Tran splant ation1996;61:532536. P. 776
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133.SunY, MaX, ZhouD, etal.Normalization ofdiabet esinspontaneouslydiabet iccyn omolgu s mon keysbyxe nograft sofmicroen capsu latedporcineisle tswit houtimmun osu ppression.J C lin Inv est 1996;98:14171422. 134.De VosP, DeHaanBJ, Wolter sGHJ,e tal.Improvedbiocomp atibilitybu tlimite dgraftsu rvival aft erpu rificat ionofalgin ate formicr oen capsu lation ofpancreaticislets. Diabet ologia1997;40:262 270. 135.Soon-Sh iongP,HeintzR E,Meridet hN,etal. Insulinindepe nden ceinat ype1diab eticpatien t aft eren capsu latedisle ttransplan tation.Lancet 1994;343:950951. 136.Lan zaRP,Ch ick WL.Tran splant ation ofen capsu latedce llsan dtissu es.Su rgery1997;121:19. 137.CalafioreR. Per spectivesinpancreaticandisletcelltran splant ation fort heth erapyofIDDM. Diabetes C are1997;20:889895. 138.IwataH,TakagiT, Amemiy aH,et al.Agaroseforabioartificialpancreas.J Biomed Mat er Res 1992;26:967977. 139.Wan gT,LacikI,BrissovaM,et al.Anen capsu lationsy stemforth eimmun oisolat ionof pancreaticislets. Nat Biote chn ol1997;15:358362. 140.Cru ise GM,Hegr eOD, LambertiFV, etal.In vit roandinvivoperformance ofporcineisle ts en capsu latedininte rfacially photop olyme rizedpoly(e thylen eglycol)diacrylat eme mbr ane s.Cell Transplant 1999;8:293306. 141.Soon-Sh iongP,Feldman E,NelsonR, etal.Long-t ermrever salofdiabe tesbyth einjection of immun opr ote ctedisle ts.Proc Natl Acad Sci U S A1993;90:58435847. 142.Saldeen J,Cu rie lDT,Eizirik DL,e tal.Efficientge net ran sfe rtodispe rsedh umanpancre aticislet cellsin vit rou sin gaden ov iru s-polylysine/DNAcomple xesorpolycationicliposomes. Diabet es 1996;45:1197-1203. 143.LeibowitzG,BeattieGM, KafriT,et al.Ge netr ansfe rtohuman pan creat icen docrin ecellsu sin g viralvect ors .Diabet es1999;48:745753. 144.Gian noukakisN, Rude rtWA,RobbinsPD,e tal.Targ etingau toimmu nediab eteswithge ne th erapy.Diab etes1999;48:21072121. 145.Che nHH.Persisten cein mu scle ofan ade noviralv ectorthatlacksallviralgene s.Pr oc Nat l Acad Sci U S A1997;94:16451650. 146.Naldin iL, Blome rU,GallayP,etal. Invivoge nede liver yandst abletransdu ctionofnondividin g cellsbyalent iviralve ctor .Scie nce1996;272:263267. 147.BlomerUL, Nald in iL, K afriT,etal. High lye fficient andsu staine dgene tran sferinad ultneu rons withalen tivir usvect or. J Virol1997;71:66416649. 148.Fishe rKJ,Joos sK ,Alst on J,etal. Recombinantadeno-associate dvir usfor mu scledire ctedgen e th erapy.Nat Med1997;3:306312. 149.EfratS,FejerG,BrownleeM,etal. Prolon gedsurv ivalofpan creaticisletallogr aftsmediate dby adenovirusimmun ore gulatoryt ran sgene s.Proc Natl Acad Sci U S A1995;92:69476951. 150.Steu rerW,NickersonPW,Ste ele AW,etal. Exvivocoat in gofisle tcellallograftswith mur in e CTLA4/Fcpr omot esgraft toler ance .J Immun ol1995;155:11651174. 151.Gain erAL, K orb uttGS,Rajotte RV,et al.Expr essionofCTLA4-Igbybiolist icallytransfect ed mou seislet spromotesisle tallograftsurv ival. Tr ansp lantation1997;63:10171021.
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152.Fe ngS,Qu icke lRR ,Hollist er-LockJ,et al.Prolon gedxen og raftsu rvivalofisle tsinfecte dwith smalldosesofaden ov iru scon tainingC TLA4Ig.Transplan tat ion1999;67:16071613. 153.Rab in ovitchA, Su are z-Pinz onWL ,Sor ensen O,etal. Combine dther apywithint erleukin-4an d inte rle ukin-10inhibitsau toimmu nediab etesre curre nceinsyn gen eicislet-tr ansplan tedn on obe se diabe ticmice.Transplant ation1995;60:368374. 154.De ngS,Ke tchu mRJ, Kuche rT,etal. IL-10an dTGF-betagene tran sferforxen oge neicislet tr ansplan tat ion:comp arison ofeffe ctin con cord ant vsdiscordantcombination .Tran splant Proc 1997;29:22042205. 155.Davie sJD, Mue llerR ,Min son S, etal.In terleu kin -4se cretion byth eallograftfailst oaffe ctthe allogr aft-spe cificin terleu kin -4re spon seinvitro.Tran splant ation1999;67:15831589. 156.GallichanWS,KafriT,K rah lT,e tal.Len tivir us-mediatedt ran sductionofisletgraftswit h inte rle ukin4resultsinsu stained g enee xpressionan dprotectionfrominsu litis.Hum Ge ne The r 1998;18:27172726. 157.Zekze rD,Wong FS,We nL,et al.Inh ibition ofdiabe tesbyaninsulin-re activeC D4T-ce llclone in th enonobesed iabeticmouse .Diabet es1997;46:11241132. 158.KingC, Dav ies J, Mu elle rR,et al.TGF-bet alaltersAPCprefe rence ,polariz in gisletantigen re spon sestowardaTh 2ph enotype .Immu nity1998;8:601613. 159.Yasud aH,NagataM,ArisawaK,et al.Localexpressionofimmu noregu lator yIL-12p40gene prolon gedsyn geneicisle tgraft survivalindiabet icNODmice.J C lin Inv est1998;102:18071814. 160.Me llorAL,Munn DH.Try ptop han catabolismandT-cellt olerance:immun osu ppressionby starvation?Immu nol Today1999;20:469473. 161.ChaoDT,Linet teGP,BoiseLH,et al.Bcl-XLandBcl-2re pressacommonpathwayofce lldeat h. J Ex p Me d1995;182:821828. 162.SarmaV,LinZ, ClarkL, etal.Activationofthe B-cellsur facere ceptorCD40in ducesA20, a nove lzincfinger prot einthatinhibitsapoptosis.J Biol Che m1995;270:1234312346. 163.Rab in ovitchL Y, Suar ez-Pinz on W ,Mu hke rjeeB,et al.Expr ession ofth ebcl-2gen efroma defe ctiveHSV-1ampliconve ctor protectspancre aticbeta-cellsfromapoptosis.Hu m Gene Ther 1996;7:17191726. 164.HeringBJ,K andaswamyR,HarmonJV, etal.Transplan tat ionofculture disletsfromtwo-lay er pre serve dpancr ease sin t ype1diabetes with ant i-C D3antibody.Am J Tr ansp lant2004;4: 390401. 165.Markman nJF,De ngS,HuangX,e tal.Ins ulin ind epen dence followin gisolate dislet tr ansplan tat ionandsingleislet in fusion s.Ann Su rg2003;237:749750. 166.GossJA,SchockAP,Brun icardiFC ,etal. Ach ie vement ofinsulinindepe nden ceinthr ee consecu tivetype -1diabe ticpatient sviapan creat icisle ttransplan tationusingisletsisolat edat a re moteisle tisolationcen ter. Tr ansplan tat ion2002;74:17611766. 167.KesslerL, Buche rP, Milliat-GuittardL,e tal.Influe nceofislett ran sport ationon pan creaticislet allot ran splantation int ype1d iabeticpatien tswit hinth eSwiss-Fren chGRAGILnetwork. Transplant ation2004;77:13011304. 168.Fiorin aP,FolliF,Bertu zziF, etal.Long-t ermbene ficialeffectofislet tran splantation on diabetic macro-microan giopathyinty pe1diabe tick idn ey-tr ansplan tedpatient s.Diabe tes Care2003;26:1129 1136. 169.CaglieroE,C handrakerA,DeaA, etal.Isletce lltransplan tationintype 1diabet icpatients re cipien tofre nalallogr afts.D iabete s2004;53:{Suppl2]A452.
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170.Lehman nR, Weber M,Be rtholdP,e tal.Succe ssfulsimultan eousislet -kid neyt ran splantation us in gaster oid-free immu nosuppre ssion:two-yearfollow-u p.Am J Transplan t2004;4:11171123. 171.Zhen gXX,San chez-Fue yoA, Sh oM,et al.Favorablytippingth ebalan cebet weency topathican d re gulatoryTcellst ocre ate tran splantation toler ance .Immun it y2003;19:503514. 172.NikolicB,Takeuch iY, LeykinI,e tal.Mix edhemat opoieticchimer ismallowscur eofautoimmune diabe testh rou ghallog eneictole ran cean dreve rsalofautoimmunity. Diabet es2004;53:376383. 173.Contre rasJL, Jenk in sS, Eckh offDE ,et al. Stablealph a-an dbeta-islet cellfun ction after toleran ceinduc tiontopancreaticisletallograftsindiabe ticprimat es.Am J Tr ansplant2003;3:128 138. 174.Kaman oC ,VagefiPA, KumagaiN,e tal.Vascu larizedth ymiclobet ran splantation in miniatu re swine:t hymopoiesisandtoleran ceindu ctionacrossfu llyMHC-mismat chedbarriers. Proc Natl Acad Sci U S A2004;101:38273832. 175.Suth erlan dDE, Gru essn erA,Hering BJ. Beta-cellre placeme ntth erapy(pan creasand islet tr ansplan tat ion)fortre atment ofdiabe tesmellitus:aninteg rate dapproach .En docr in ol Metab C lin North Am2004;33:135148. 176.Oberh olzer J, ShapiroAM, Lake yJR,et al.Cu rren tstat usofisletcelltran splant ation .Adv Sur g 2003;37:253282. 177.Shap iroAM, NanjiSA, Lake yJR.C linicalislet t ran splant:cu rren tan dfutu redirectionstowards toleran ce.Immunol R ev2003;196:219236. 178.RobertsonR P.Islett ran splantation asatr eatmen tfor diabetes aworkinprogress. N E ngl J Med2004;350:694705.
Chapter46 Diabetes and the Healthcare System: Economic and Social Costs
Jam es L. Rosenz we ig Int heUn it edStates,th emedicalcostsofdiabet esare substantial.Asth eprototypeofthe ch ronic disease in volvingmultiple organsyste ms, diabete sh aspre sent edagr eatch alle nget oth ehe althcare syste matatime oftr ansition fromtraditionalfe e-for -servicereimburse men ttomanag edcare and cap itation .Inth eUn it edStat es,asign ifican tproport ionofthe ind ividualswith diabetesh ave un diagnoseddisease(1). Ar eviewofalloft hecu rren tly accept edperformance measure sand in dicator s ofq ualityofcare forpatien tswit hdiabet esshowsthatgoalsforcarear enotbeingmetint heUn it edStat esan din the worldatlarge (2,3). Inr eviewin gthe manage me ntofdiabetesmellitu s,onemustbe awar eofcer tainge neralpr in ciples. First ofall,diabetesisacomplex ,chronicdisord er.U nlike someother chronicdisorde rs,such asas thmaan d osteoart hritis,it in volvesmultiple systems.Diabetes isnotjust anen doc rin edisease ,an dcon trolof glycemia,alth ou ghimportant, isnotth eonlyaimofthe rapy. Pre vent ionandtre atment ofth elon g-term complication softh edisease compriseamajorpart ofth eov erallcare ofdiabet es.Man yofth eeffortsof tre atment in volvemeasurest hat hav ein crement aleffectsandresu lt in chan gesinpatie ntbeh aviorthat haven oper ceiv ableben efittot hepatientatth etimeofin terv entionbut mayhavesig nificanteffe cts manyy earslat er.In accomplishingth esegoals,th eprimarycaregivermustbe abletowork in ateam withspecialistsan deduc ators. P. 778
PREVALENCE OF DIABETES IN THE UNITED STATES AND IN THE WORLD

Diabetesison eofthemostcommonch ronicdiseasesaffe ctingpeoplein the UnitedSt ates. Itis
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estimate dthatcurr ently18.2million Amer icanshavediabe tes,r eprese nting6.3%ofthepopu lation. This figureinclud es13million in dividu alswith diagnoseddiabe tesan dan estimated5.3millionpe oplewho ar ecurr entlyu ndiagnosedandu ntre ate d.Itisestimatedth atapproximat ely798,000newcasesof diabet esare diagnosedeachye ar(4).Thepr evalen ceofdiabetesinth eUn it edStat esin creased progressivelydu rin gthe secondhalfofthe 20t hcen tury ,wit han approximately40%in crease recorded sinceth elate 1970s. Itisclearthatth eov erallburde nofdiabeteswillincre asesu bstan tiallyworldwide inth enex t20year s. Seve ralfactorshavecontr ibu tedtoth ein creasin gburde nofd iabetesint heUn it edStatesan d worldwide. Th eseinclude aspecificin crease in ther iskfactor sfort ype2diab etes, suchasin creasin g obesity(5, 6)andlackofadequ ate physicalactivity(7),bothofwhichhavebee nshowntoincreaseth e like lihood ofdeve lopingdiabe tes(8, 9). Th eincreasedagin gofth epopulationwor ldwide(10)is contribut in gtot hepr evalen ceofadise aseassociat edwit hag in g.Inaddit ion, t heU nitedStateshasseen ar apidand proportionat elygreatergr owth ofth ose minorit ypop ulation satt hegre ate striskfort ype2 diabet esan dit sassociatedcomplication s(11),aswe llasofpopu lation sthrough ou tth ewor ldwith increasedrisk(12).An oth erfactor con tributingtoth eapparen tin creaseinthe prevale nceofdiabete s hasbeen the improveme ntinsu rveillancesyst emsfordiabet es,which h asallowe dbette rasse ssmen tof th etru eburd enofdiabete s(13). Many addition alnewcas esprobablystillgoundiag nosed.Datafromthe Nation alHealthIn ter vie wSu rvey indicate thatapproximately93%ofallpeople with diabete shave char acte rist icsoftype2diabete s(14). The p revalen ceofboth diagnosedandun diagnoseddiabe tesincre asespr ogre ssiv ely with age from app rox imate ly1.6%ofin dividu als20t o39yearsofagetoapp rox imate ly20%ofindividuals60ye arsof age and older. Th egre atmajor ity ofindivid ualsolder thanage 40year sh ave type2diabete s(even a majorityofthoseyoun gert han 40have type2diabete s). Bothdiagn ose dandu ndiagn ose ddiabete saree speciallypr evalen tin minorityet hnicpopulations.Wh en th eprevalenceisstandar diz edfor ageandsex, diabete sis1.6t imesmore prevalen tamongnon-Hispan ic AfricanAmerican sand 1.9timesmor eprev alentamongHispan icAmerican sthanamongnon-Hispan ic whites(15). Impaire dfastingglucoseleve ls, acon ditiont hat isth ou ghttobeaprecu rsor to, andt o pre disposeindividualsto,ty pe2diabe tes,issignificantlymore prevale ntinHispanic-Americans t han amongnon-Hispan icwh it esan dtend st ooccuratearlier agesinth ise thn icpopulat ion.Th ein cid ence an dsever it yofth emajorse con darycomplicat ionsofdiabete sarealsogreater int hese p opu lationst han inth egene ralpopulation. Although t heinciden ceofdiab eteswillcontinu etoin crease substantiallyin the U nitedStatesandothe r deve lopedn ations,th erateofin crease willbe mu chmore r apidin deve lopin gcou ntr ie s,whichar emu ch lessabletohandleth efin an cialbu rden impose dbyeithe rcon vent ionalorinten sivetre atment of diabet es.The WorldHealt hOrganizationestimates t hat then umberofpeople in t heworldwith diabete s mayne arlydoublebyth eyear2030,ap proaching360million people(16). Enormou sin creasesin diabet esare proje ctedforSou theastAsia,th eweste rnPacific, thee aste rnMediterr ane an, and the Ame ricas.The actu alcaus eofth isincr easingworldwide epidemicisnotent ire lyclear,bu tit islik ely relat edtodecre asedph ysicalactivityan dchan gesindietre latedtoth ein dustr ializationinth esere gions (Fig. 46.1).
Figure 46.1.Numberofpersonswithdiabetesmellitusintheworld,bygeographicregion,intheyear2000, comparedwithprojectedestimatesbytheWorldHealthOrganization(WHO)fortheyear2030.(Adaptedfromdata fromWHO.Availableat:http://www.who.int/ncd/dia/databases4.htm.AccessedMarch4,2004.)
IMPACT OF THE COMPLICATIONS OF DIABETES

Diabetesh asamajorimpacton theh ealth ofth eU. S. popu lation .Itisthe leadingcau seofn ew blin dness, end-st ager enaldisease(ESRD),an dnon-tr auma-r elated amp utationsinadults.C arefor diabet esan dit scomplicat ionsconsu mesapproximately15%of P. 779 th etotalhealt hcar eexpe nditur esin the coun try. That figu reisout ofproportion tot he6%pr evalen ceof
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diabet es,re flect in gthe excessmor bidityofan dmedicalcarerequ ir edbypatie ntswithdiab etes. Diabetesisassociated with asubst ant iallyincre asedmor talit yriskin bot hme nan dwomen .Riskof deathisin creasedth reefoldtofivefold forper son sage45to64an dtwofoldtot hree foldfor thoseage 65to74.There lativeriskdeclin eswithadvan cedage asmort ality duetoother dise aseincre ases. In eachage group,wome nwithdiabe teshaveag reat errelative mortalityriskth an d omenwithdiab etes. Int heUn it edStates,approximat ely 18%to20%ofthosepe rson swhodie betwee nthe agesof45to74 yearshavediabe tes(17). Pe oplewithdiab etesaretwotofour timesmor elikelytoexpe rie nceh ear tatt ackorstroketh an are peoplewit houtdiabe tes(4).Pe oplewithdiabe tesyoun gerth anage45yearsare 11.5t imesmore likely tohavecar diovascu lardisease thanar epeople with ou tdiabet es.The relativeriskofhav in g car diovas culardisease ,aswe llasothe rcomor bidities, wh ich decre aseswithincr easingage,stillre main s subst ant iallyelevatedforpeoplewit hdiabet esolder thanage 65y ears(4). The mostcommon cause ofdeathinpe oplewithty pe1ortype 2diabet esiscardiov ascular dise ase, whichisthe cause ofmor ethan50%ofdeaths. Theacutecomplicat ionsofdiabete s,such as ket oacidosis,hype rosmolarcoma, an dhypogly cemia, are then extmost commoncauseofdeath, rep resen tin gabout 13%.Asindividualswithdiabe tesage,th erelat ive con tributionofcardiovascular disease tomortalityincreasesan dthe con tributionofacute complicationsde creases(18).Int heMultiple RiskFactorInt erven tion Tr ial, theabsolut eriskofde ath relate dtocardiovasculard iseaseinmenwith diabet eswassu bstan tiallyincr eased c ompare dwith thatinme nwithoutdiabe tesforeve ryage grou p, eth nicbackg rou nd,andn umberofaddition alcardiov ascular risk factors(19).The mortalityratesfor menwithdiabe tesincre asedst eeplyasth enu mbe rofr iskfactor sin crease d.Wh enpatie ntswith diabet esare followedu pfor6yearsafte ramyocardialin farction(MI),th eir mortalityriskisin creased by40%,comparedwithth eriskfollowingMIinpat ie ntswithoutdiab etes(20). Th eincreasedriskof post-MImortalityiseven morepr onoun cedinwomen wit hdiabet esthaninmenwithdiabe tes. Alth ou gh th ereh asbee nasu bstan tialdeclin ein mortalitydu etocoronaryh eart dise aseinth eUn ite dStat esove r th epast 30ye ars, thishasnotbeen seen inpatient swith diabete s.Infact,ag e-adjust edmortality d ue toheartdiseasehasin crease d23%forwomen with diabete s(21).Itisthough tthatth egene ral decr easeincardiovascular mortalityinth egene ralU. S. popu lation isdu etoared uction in car diovas cularriskfact orsandimpr ove dmet hodsoftr eatmen tofcoronaryart erydisease.The se measu reshavebe enlesseffect ive forpatientswith d iabetes, especiallywomen. The morbidity associatedwithth echr on iccomplicationsofdiab etesalsorepr esen tsasignificantpu blic he althproblem.Diabe tesisthe leadingcau seofn ewblin dnessinadultsag ed20to74ye ars(4), accoun tingfor20%ofalln ewcase sofblin dnessinpe rsonsage d45to85ye arscausedinlarge part by diabet icre tinopath y(22).Itisestimatedth at approximately90%ofthe secase scanbe preve ntedwith improved g lyce miccon trol, ann ualophth almologicexamination s,an dtheu seoflasertre atment if ne cessar y.Thepr evalen ceofcataractsistwofoldtofou rfoldhighe rin patien tswit htype 2diabet esth an inth epopu lation with ou tdiabet es.C ataractsareacommoncauseofvisu alimpairmen t,but not per manen tblindn ess,inolderindividuals. Diabetesisalsot heleadin gcaus eofE SR D(4),accoun tingfor 43%ofnewcasessu bstan tiallymore th ane ith erh yperte nsion orglome rulon ephr itis.In the U nitedStates, then umberofnewcasesofE SRD due todiabetesincr eased fivefoldtosixfoldbe tween 1984and2001(23),andth eper centageofall case sofESR Ddu etodiabetesh asincre asedfrom28%to43%(24). Ah ig hperce ntageoft hese cases couldbeprev ente dor su bstantially delayedwith measure saimedatimprovingglycemiccon trol,more agg ressivetre atmen tofh yperte nsion ,an dear lyt reat men tofmicroalbumin uriawithangiot ensinconver tin genz yme in hibitors. The r iskforamput ationinin dividu alswit hdiabet esissu bstan tiallyg reat erth ant hat inp eoplewithout diabet es;diabet esaccoun tsfor g reat erth an60%ofn on traumaticlower-limbampu tationsinth eUnite d States(25).Thisisdueinlarg epart toe ith erpe riph eralvasculardiseaseorperiphe ralneu ropath y, whichoccursinapproximately50%ofin div idu alswhohave had d iabetes20ye arsorlon ger(26).Man y oft hese casescouldbepre vent edbyre gularfoot examinat ionsandtre atment ,appr opr iateedu cationin footse lf-care,imp rove dcon trolofbloodglu cose and c holest erol, andsmokin gcessat ion. Int heUn it edStates,diabe tescostsar emoret han $132b illionan nu ally, with $92billion r elated t o directmedicalcost s.In1992th ecostwas$85billion,andth enu mber sareincr easinge achye ar(27). The reisc urre ntlynohealt hcar epolicyage ndafocuse don arre stingth ein creaseoft hischronicdise ase, whichinvolves18millionAme ricansandisthese con dmostexpe nsivediseasein the U nitedStates. In th iscoun try,diab etesisthe le adingcau seofblindn ess,ampu tat ions,E SRD, kid neydialysis,an dkidney transplan tat ion(18).Th emortalitydu etotype1diabete sis30%highe rin theU nitedStatesth an in Eu rope,andinthe United St ate sse riou srenaldiseaseinallt ypesofdiabete sismore thanquadru plet he rateinEu rop e(28,29).
GLYCEMIC CONTROL AND MORBIDITY

Poorglycemiccontrolisamajorreasonfor theh igh in cide nceofmicrovascu larcomplication sin volving th eeyes, kid neys, and n erve sofpeoplewithdiabe tes.Th eDiabe tesCont rolan dComplication sTrial
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(DCCT)clear lyde monstr ated t hebe nefitsofimprovedglycemiccontr olin redu cin gbot hth ein cide nce an dthe prog ression ofre tin opathy andn ephr opathyinpe oplewitht ype1diab etes(30). Su bstan tial clin icalandepidemiologiceviden ce,e speciallyfromtheU nitedKingd omProspect ive Diabet esStudy ( 31), th eKumamot oStu dy(32),andth eWisconsinE pid emiologicalSt udy(33),indicatesth atth esame principleappliestopatien tswit htype 2diabet es. The d iagnosisofdiabeticket oacidosisin volvedapproximat ely100,000hospit alization sin theU nited Statesbet we en1989and1991an drepre sente dalmost5%ofallpatientswith d iabetesadmitte dto hospitals.Mos tofth eseadmission sarepr even table. Se vereh ypoglyc emiaisalsoamajorcauseof increasedemerg encyde part men tvisit sandh ospitalizat ions.
DISABILITY, ABSENTEEISM, AND EMPLOYMENT ISSUES ASSOCIATED WITH DIABETES

Disabilityaffect smanyper son swith diabete sint heU nitedStates,with e stimatesrangingfrom20%to 50%ofth ediabeticpopulation.In div idu alswith diabete sreportratesofdisabilityth ataresub stan tially highe rthanth ose reportedb ythege ner alU.S.population. Reported activitylimitation sweretwoto th reetimeshighe ramon gpersonswithdiabe testh an among t hosewit houtdiabe tes(34).Patien tswit h type 1diabe tesfromth eCh ildren 'sHospitalofPit tsburgh IDDM(insu lin- depen dent d iabetesmellitu s) reg istr ywerese ventimesmore likelytoreportworkdisabilityt han wereth eirnondiabe ticsiblin gs. Impairme ntsforpersonswith eit hert ype1orty pe2diabe tesincre asewithage.Disabilityismore common in minoritygroups. Disabilityispropor tionatelymore commoninpe rson swit htype 2diabet es th anamongt hos ewith type 1diabet es(63.5%ve rsus42.9%r eportact ivitylimitat ions),possibly becauseofthe olderaverageag eofpatientswith t ype2diabetes. Themajor deter minantfordisability app earst obet hepr esence ofth elatecomplicat ionsofdiabete s. The e ffectsofdisabilityonthe popu lation ofper son swith diabete sarev eryext ensive. Pat ie ntswithty pe 1diabeteswh oaredisabledhavedr amatically lowerratesofemployme ntth an doindividualswith diabet eswhoare notdisabled(49%n ot workingv ersus12%)an dhigher rate sofabsent eeism(13.8 day speryearver sus3. 0pe ryear ).Disab led ind ividualswith diabetesu sehe althcareser vice smore frequ ent ly, wit hgreatert han twic ethe hos pitalizationr ates andaveragenu mbe rofph ysicianvisit sand ade creasedqualityoflife. Ratesofabsen teeismamon gemployeeswithd iabetesarere port edase lev ate din s omestud iesbu tnot other s(35,36,37).Although the reiscon troversyr egard in gtheimport ance ofabsent eeisminper son s withdiabe tes,itiscle arth atsignificant rate sofab sente eismte ndtobelimit edtoasmallsu bsetofthe populationofind ividualswith d iabetesnotmore t han30%. Mostemploye eswit hdiabet eshavenormal workatt endancer ecor ds.The reisasugge stion t hat manyofthepe rson swhohav ehighratesof abs ente eismmaybedisabled (34). Disabledpe oplewithdiabe teste ndtobeab sentmor efrequ ent lyand havelon gerabsence sthandopeop lewith diabeteswh oarenotdisabled. Ifthe impact ofdisabilityinpe rsonswit hdiabet esis similar t oth atint hegen eralpopulat ion, disability willhavesignificanteffe ctson the ire mploy ability. Alowerpropor tionofpersonswith diabetest han per son swith ou tdiabete sare cu rre ntlyemployed, even afte radjustmen tsare madefor age(Fig.46.2), but thepr oportionoft hosenotemployed wh oaredisabledissimilartothatin the gene ralpopu lation (34). P. 780
Figure 46.2.Theemploymentstatusofindividualswithtype2diabetes,withtype1diabetes,andwithoutdiabetes. (FromSongerTJ.Disabilityindiabetes.In:HarrisMI,CowieCC,SternMP,etal,eds.Diabetes in America,2nded. Bethesda,MD:NationalInstituteofDiabetesandDigestiveandKidneyDiseases,1995:259278.NIDDKDpublication no.95-1468.)
Withahigherde gree ofun employmentandabsent eeism, ther eisconce rnth atpe rson swit hdiabet es mayface discr imin ationinthe work place.Thishasbeen reporte din se veralst udies(38,39).Th e1990
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Ame ricanswithDisabilitiesAct,h owe ver,e xpan dedth eopp ort unitiesofdisable dpersonswithdiabe tes. Thisle gislat ionpr ovidesstandardsinemployee hirin gan dallowsfor work-r ulean dwork- environment change st omeet t hen eedsofin div idu alswith disabilities.Itappliest oallemployer swith atleast 15 employe es,an ddiabet esisspe cificallylisted asadisability unde rthe Ac t.Theconce ptth atdiabe tesis inan dofitselfadisabilit yisacon troversialon e,bu tthe le gislat ionmakesitillegalt odiscriminate againstan in dividu alju stbecauseh eorsheh asdiabe tes. Never the less, the rear especificareasofemployment where emp loyme ntofpersonswithdiab etes continu estoberest rict ed.Personswithdiabe testakin gin sulinhavebee nrest rict edfrombein gairline pilots,dr ive rsin in terst ate comme rce,dr ive rsoflocalmasst ran sit, and ,un tilrece ntly,air -traffic controlle rs.Themajorcon cern hasbe ent heriskofdevelop in ghypoglycemiad uringsituation sin wh ic h alte rationsinjudgment orconsciou snes scouldpu tthe pilot ordr ive rin dan geroratr iskt oothe rs.The av ailabilityofse lf-mon it oringofbloodglucose,alongwithagreatervarietyofin sulin regime nsin rece nt years,th eab ilit ytoadjustdoses, andcoun tcarb oh ydrat es,hasamelioratedth ispr oblemsomewhat,bu t th eDC CTestablishe dthatin ten sifiedinsu lintr eatmen tcan beassociated with anincr eased r iskfor seve rehy poglycemia(30).Since1984,t heAmerican Diabet esAssociat ionh astakenth eposit ionth at Any personwithdiabe tes,wh ethe rin sulindepe nden tor non -insulindepe nden t,shouldbee ligible for an yemployment forwh ich h e/sh eisoth erwisequalifie d(40).Itisun derstood,however ,th atasmall min orityofpatien tswit hdiabet eslackorare unable tor ecognizeth ewarn in gsign sofh ypog lyce miaand ar eatgr eat erriskfor alterationsinmen talfunct ionth atmightleadtoconfu sionoralter ation in consciou sness. Th ose in dividu alswhoh ave recur rent episode sofseve rehy poglycemiashouldbe individ uallyevalu atedand, in s omesituations, beconsideredformodification ofth eiremployment resp on sibilities.
OTHER SOCIAL ISSUES IN DIABETES Driving

Ith aslon gbeen claimedth atdiabe tesisassociatedwithanincre asedriskofaut omob ileacciden tsan d crashes. Th ree st udies,ofdriversinC alifornia, Oklahoma,an dWash in gtonstate,iden tifiedincre ased ratesofcrash esin driverswithdiabe tes(41,42, 43).Howe ver,itisposs ibleth atth edriver swith diabet esinthe sestu dies we reselecte dbecau seth eyhadmorese vere d isease.In addition ,selection biasmayh aveplay edarolein someofthese studiesbe cause thedr ive rswit hchr on icdiseasewere un derre vie wfordr ivingoffense s.Anothe rstud y(44)linke dthed iagnosisofdiabete stoanincre ased riskofh ospitalizationfordriving-re latedroadt rau ma,butonlyamongyoun gerdriver s. P. 781 Astud yoftr uck-per mitholdersan dcommercialdriversinQue becfoundanincre asedre lativeriskof crashesfordriverswith n on -in sulin -tre ated d iabeteswith ou tcomplicationsbu tnotforthosetr eat edwit h insulinorwith complication s(45). Othe rstudies, howe ver, hav efaile dtofindanas sociationbet we en drivingac ciden tsan ddiabet es(46,47,48,49). Dr iving r equirescomple xpsychomotorskills,pr oces sin gofinformation ,an daccur ate ju dgme nt.It is impaire dbyacu teh ypoglyce mia.R epeatedepisodesofmildh ypoglyce miacanbeassociat edwit ha decr eased abilitytorecognize itssymptomsandanincreasedriskofcogn itive impairment. Ast udyofthe per forman ceofindividualswithdiab etesinadriv in gsimulatordu rin ginduce depisode sofmildan d moder ate hypogly cemiash owe dthatdrivin gperformanc ecan b esign ifican tlydis rupte dduringr elatively mildhypoglycemia,an dmanyindividualsfailtotake corr ectiveact iontotre atth ehyp oglycemia(50). Anothe rstud y,howeve r,rep ort edthatmostdr ive rswit hhypoglycemiawhowerecognitivelyimpaire d recogn ize dthisan dreportedt hepe rceptionthatth eycouldnotdrivesafe lyathyp oglycemicleve ls, but menandmiddle-agedpat ie ntswer emorelikelythanwomen and men unde r25yearsofagetoju dge th atitwassafefor themtodrivedur in ghypogly cemia(51). Itisimport ant fort hosewit hdiabet esto haveedu cat ionalre in force men tofsafedrivinghabitsan dtobe encouragedtoche ckglu cose le vels beforedr iving. Per son swh ose glu cose lev elsarebe low70mg/dLsh ou ldbe treatedbe fore driv in g.Blood glucoseawaren esstrain in g(BGAT),an8-we ektrain in gprogramth atu sesbehavioralt echn iqu esto increaseawaren essoffluct uat ionsinbloodglucoselevels,h asbeen associatedwith fe weran dle ss ext remehypoglycemice vent s(52) andinfollow-upstu die shasbe enfound tobe associatedwitha red uction in motorveh iclecrashesandviolat ions(53). Becauseh ypog lyce miamaybe afactorinmotorve hicle accidents, mostre gulatoryauth oritiesput rest ric tionsonapplican tswhohaveinsulin-tre ate ddiabete s,whet hert heyh ave type1ort ype2 diabet es.However ,on ly ind ividualswith t ype1diabetes appeartobeat g reat erriskfor drivin gmishaps (54).For manyyears,t heU. S.FederalHighwayAdministration proh ibite din dividu alsusinginsulinfrom obtainingcommer cialve hicledr iving license s.Howe ver, ith adte mporar ilypermittedwaiv ersfor some insulin-using d riv ers(55)but iscur rent lyn ot givingt hem.Man ystat esare allowin gsomeindividuals withinsulin-tr eate ddiabete stodr ive comme rcialv ehicle swith in stat eboundaries.The Amer ican DiabetesAssociation hasargue dforr epealoffederalr estriction son comme rciald rive rswit hinsulintre ate ddiabete sb ecau seoft heclaimt hat itisdiscriminat ory andcont raryt oth eAme ric answith Disabilitie sAct (56).Thisremainsacomple xand c ont ent iousissue, in whichthe ju stified advocacyfor
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th erightsofpeople with diabete smu stbebalancedwithcarefulan alysisofth eriskstopublicsafety.
Travel
The su ccessfulmanagement ofdiabet esrequ ir escare fulatte ntiontothesy nchr on ization ofinsulinor oralhypoglycemicagent stomealsandphy sicalactiv ity .Thech an gesin me als,act ivity, andt imezones th atoccurwithair flightcancre ate u nique p roblemsfor in dividualswith diabete s,especiallythose injectinginsu linorusingsu bcutane ous insu lininfu sionpu mps. Inad dition,t rave ler stodistantcoun tries havetocar rysyringe sandvialsofin sulin ,an dtheincr ease dsecurityn eedsofairtravelpose special problems. Thish asbe comeacu telyeviden tsinceth eeve ntsofSeptember11, 2001. Manyairlinesand count rie snowr equireair -trav elp assen gerstocar rywritten docu men tat ionofthe irmedicalcon ditionand th enee dtocarrysy rin ges,n eedles, andvialsofin sulin forinjection.Despiteth eseinconve nience s, th ereisnoreason wh ymostindividualswithdiab etes, wh eth erornotth eyrequ ir ein sulin,sh ou ldn otbe ablet otravelexte nsivelybyairacrosslongdistan cesortimez on es.Travelerswithdiabe tesshould observe t hefollowin gguidelin es,wh ich aremod ifiedfromth epre viouse ditionofthistext ( 57). 1. Thep atient shouldreviewtravelplanswithh isorhe rcare prov ide ran dadjustt hetimin gofmeals an din sulin dosagestoth eschedu le oftr avel.Howthisis accomplish edishighlyin dividu aliz edfor eachpat ie ntandtravelplan. Goodcommun ic ation betwee npatie ntandcar eprovid erise ssent ial. 2. Thep atient shouldbesuppliedwithan ot efromth ephysician out liningt hediagn osis,list in gthe gen erican dprop rie tary namesofmedications, giving t heph ysician'sn amean dteleph on enu mber , an d,ifpossible,list in gphysiciansatthe destinationwh ocanbeconsu lt edin an eme rgen cy.Most count rie shav ediabete sassociation sthatcan assistin tern ationaltravelers. Ift hepatientcarries syringe s,lance ts,orne edle sforinject ion,t hen ote shoulddocu me ntth eme dicaln ecessityforth eir use . 3. Thep atient shouldcarry adequ ate supplie sofmedication san dmaterialstotreathypoglycemia.He orshesh ou ldn ot d epen duponth elocalav ailabilityoft hesemat erials.Thes esuppliesshouldnev er bech eckedinbaggage thatisn ot accessibleor thatmight reach adifferen tdest in ation .Onsome trips,itmaybe appropriate tocarrye xtrap rescription sforinsu lin, syringes, andoth eresse ntial supp liesincase oflossorth eft. 4. Itisimportan tforthe insu lin-r equiringpatientt oh aveonh isorhe rpersoneasyidentificationof diabet esincase ofemerge ncy.Th eseindividualsshouldwearme dical-ale rtbraceletsorneck laces whe ther orn ott heyaretr aveling,bu titise speciallyimport ant forth emtowe arth emd uringtr avel todist ant placesorfore ign cou ntr ies. 5. Thep atient shouldcon ductfre quen tglucosemonitoringth rou ghoutt hetr ip, especially wh en travelin gacrosstime zon esan dwhen me alschedu le sarealt ered. 6. Thep atient shouldtake specialprecaution stoavoidmot ionsickne ssort rave ler s'diarr hea,bothof whichmaycont ribu tetohy poglycemia,de hydration ,or ketoacidosis,andmustbe especiallycare fu l tohavethe properimmun ization swh ent rave lingabroad.
COSTS OF MEDICAL CARE OF DIABETES

The e con omic costsofdiabete swerere por tedas$11.6billionindirectmedicalcost sin 1986forpeople withtyp e2diabe tes(58)an d$45.2billionindirec tmed icalcostsin1992forallpeoplewit hadiag nosis ofd iabetes(59). Ast udycomparingth ecostsoftr eatmen tofpatient swith andwith ou tdiabete sin 1992 showedth at, on aver age, theann ualpercapitah ealthe xpend itu resforpat ien tswithdiabe teswere app rox imate lyt hree andahalftime sthecostsforpat ie ntswithoutdiab etes. Fromthisit couldbe calculat edth atth ecostsofcareofpatien tswith diabete srepre sent edalmost15%oftotalh ealth care expe nditur esin the UnitedSt ates. The American Diabe tesAssociationpu blish edmoree xten sive analysesoft heeconomiccostsofd iabetes, calculat in gthatdirectmedicalan din dire ctexpe nditur esatt ribu tablet odiabe testotaled$98billionin 1997(60)an d$132billionin 2002(61).Direct costsareth ose associatedwithh ospitalizat ion, ambulat ory care, and medicat ion. Indirectcostsre presen tlostpr odu ctiv ity duetomorbidityan d pre mature mortality.Tothismu st alsobeadde din tan gib lecosts, su chasreduc edlifeex pectancyan dqualityoflife, forwhich t he assign men tofamone taryv alueisdifficult(62,63). Theper capitameancost sforpe rson swit hdiabet es, $13, 243per year ,werefoun dtob efive timesth ose forpe rsonswit houtdiabe tes,bu tth isratio overstatesth eimpactofdiabetesbe cause the sepatien tsten dtobeolder ,on ave rage (61). Theratioof per capitaex penditu resbet weenpe oplewithandwithoutdiabeteswassubstantiallygreaterfornonwh ite pat ie nts(4.5:1)thanforwhitepatients(3.6:1).E xpen dit uresforoutpatientmedicationswere 3.2times gre ater forpatientswith d iabetes. Theratioofexpen dit ures b etween personswithdiab etesandper son s withoutdiabe teswasn early iden ticalin patien tswhowereyoun gerth an 45y earsofage (3.2:1)andin th ose45to64yearsofage(3.3:1).Thisratiodroppedto1. 6:1forpatient s65y earsofage andolder, P. 782
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ast heincre asedmedicalcos tsforn on diabeticelderlypatie ntsn arrowedth egap. Dire ctme dicale xpenditu resassociate dwith diabete stotaled$91. 8billion ,ofwh ich $23.2billionwas relat edtocon trolofdiabete sand bloodg lu cose, $24.6billiontoexce ssprevale nceofthe chronic complication sofdiabe tes,and$44.1billiontoexcesspr evalen ceofge neralmedicalcondition s.As expe cted, thelar gestproportion ofex penditu resat tributable todiab eteswasforinpatientcare(43.9%), th enfornu rsin g-home care ( 15. 1%),andth enforou tpatie ntcare(10.9%). Twoth irds ofth ecost sfor medicalcarefordiabet esar eduet ocareoft hee lder ly. Indirectcostsre latedtodiabet eswere calculat edtobe$39. 8billion ,ofwh ich $7.5billionwasattribut edtodisability. The p ayment formedicalservicesfordiabete sisinsignificant flux .In1987,15%ofpatient swe reselfpay in g,whe reasin1991,t hen umberincre asedto20%.In1991,h ealth maint enanceorganizations (HMOs)becameas ign ifican tpaye rgroup,accou ntingfor12%ofpayme ntsforpat ien tswithdiabe tes nation ally. Thisn umberisnowin creasin gsteadily.ForsomeHMOs,diabet esaccoun tsfor 15%to20%of th eme dicalcosts,alt hough p atient swith diabete saccount foronly2%oft hepe rson scare dfor. All pat ie ntswithdiabe tesareacu telyawareth atth ere islesssupp ort forth isdisease,withr egard to edu cation,su pplies, andh ealth care access. In1992, t hedirect costsofhospitaliz ation srelate dtodiabeteswe re$37billion.The rehasbeen a decr easeint heabsolut enumber ofadmissionsofpatien tswit hdiabet espr obably approximately15% dur in gthe d ecade of1980to1990an dadecr ease int heprimarydiag nosesofdiabe tesby38% bet we en1983and1990(64).Thes edatareflectmor estringe ntcriter iaforh ospitaladmissions. Alth ou gh th eabsoluten umberofadmissionsofpatient swith diabete shasde creas ed,th eperce ntageofd iagnoses ofd iabetesamongalldischar gedpatie ntsincre asedby 27%bet ween1983and1990.The sedat areflect ar elativeen rich me ntofin patien tcase sofindivid ualswithdiabe tes,e xplain in gthe in creas esin hospitalizationcosts.Diabetesaccou nte dfor8.4%ofallh ospitaladmissionsd uring1989th rou gh1991, an dfemalepat ien tsrepr esen ted57%ofth eseadmission s.Patientswithd iabetesareh ospitalized2.4t o 3t imesmore freque ntlyth anareindividualswithoutdiab etes. Inaddition,th edur ation oft heirhospital stayis30%long eronave rage ,exce edingth atofpatien tswit hou tdiabet esby1.7days(65,66). Diseasesofthecircu lator ysystemwere t hemost freque ntlyliste dprimarydiagn osis:33%ofcases. The proportion ofcase sin whichdiabet eswaslist edasth eprimarydiagn osisdeclinedsignificant lyfrom29% in1980to15%in1990,ast reatme ntofhyper gly cemiah assh ifte dfromthe in patien ttotheout patient sett in gund ermanagedcareinthe United St ate s.That tren dshouldbeexpe ctedtocontinu e.Although hospitalizationsfor con trolofgly cemiah ave d ecreased,t heag e-adjust ednu mbe rofh ospitalizat ionspe r 100pe oplewithdiabe tesincre ased11. 7%during1980th rough1990(64).It hasbe enes timat edthat costsassociatedwith theh ospitalizat ionofin div idu alswith diabete sin theU nitedStateswer e$37billion in1992an dthatbetwee n64%and80%ofd ire ctexpe nditure sforpe oplewithconfirmeddiabet eswere incur redinth ein pat ien tsett in g(34,67)(Fig.46. 3).
Figure 46.3.Annualhealthcareexpendituresforpatientswithdiabetesin1992.Amountsarein$billions.DME, durablemedicalequipment.(DatafromRubinRJ,AltmanWM,MendelsonDN.Healthcareexpendituresforpeople withdiabetesmellitus,1992.J Clin Endocrinol Metab1994;78:809A809F.)
Diabetesisassociated with in crease dme dicalcarecostsinthe manag edcare setting. Acomparisonof 85,209patien ts withdiabe tesinth eKaiserPerman ent eSystemwit hage -andse x-matche dnondiabe ticcont rolsubject s showedex cessexpe nditure sof$3,494perpe rson ,withper -personex penditu resforpatien tswit h diabet es2. 4time sthoseforcon trolpatient s(68). Thelarge stpar tofth etotalexce sscost wasfor inpat ie nth ospitalcar ewit hinth eHMO, repre senting 38. 5%oft hetotal.C ost srelated topr imary carein th eou tpat ie ntset tin grepr esent edonly6.8%ofth etotal,withspe cialty ou tpatien tcar eon ly7.2%. (Fig. 46.4).Asmight beexpe cted, t helar gestproportion ofth etotalexce ssc harg eswerer elatedt oth e P. 783
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tre atment oflon g-ter mcomplication sofdiabe tes,pr in cipallyather oscleroticheartdisease,stroke, an d chr on icre nalfailure.
Figure 46.4.CalculationofdistributionofexcessmedicalcarecostsattributabletodiabetesintheKaiser PermanenteHealthCareSystem(DatafromSelbyJV,ZhangD,RayGT,etal.Excesscostsofmedicalcarefor patientswithdiabetesinmanagedcarepopulation.Diabetes Care1997;20:13961402.)
The incr ease dcostofme dicalcareforpat ie ntswithdiabe tesisevident fromthe timeofdiagnosis.In onestu dyofp atient swith type2diabete sin anHMOsett in g,me dicalcarecostsforthe first y earafter diagn osiswere2.1timesh igh erth anformatch edpat ie ntswithoutdiab etes(69). Forthe next 8years aft erdiagn osis,th ediabet es-relat edin crement alyear lyinpatient ,ou tpatie nt, andph armacymedical costsremained relativelyconstant, averaging$2,257.Alt hought heincre men talcostswere r elativelyflat dur in gthe cour seoft hestu dy,th eydidapp eart oriseinth elast2y ears ,an ditwasassumedt hat t hey wouldin crease greatly aspersonswith diabetesde velope dmajorch ron iccomplicationswithlon ger dur ationofdisease. Fromth eperspe ctiv eoft heemploye r,diabe tesimposesasu bstantialeconomicburde n,with r espect t o bothmedicalcare andpr odu ctivit y.Inarecen tstu dyofth eimpactofdiab etesonth ewor kfor ceofa large corporation, the incr ementalcostswer esubstantial(70).Th ein crement alcostofdiabet esamon g employe esran gedfrom$4, 671inthe group18to35y earsofage to$4, 369inindividu als56to64ye ars ofage. Alth ou ghth elargest proportionoftheincr eme ntalcostswere relate dtomedicalin pat ien tcar e,a subst ant ialamoun twasre latedtome dicallyre latedworkloss. It isinte restingt hat thecostsre latedto medicallyre latedworklosswer ehighe rin the y ou nger g rou pofe mploy ees,possiblyb ecau seafte ra cert ainag e,th esick estindividualswithdiabe tesmaybedr oppingout ofth ewor kforce . Datah ave been accumulat in gthatifman agedcareplan sdon ot improvethe ove rallg lyce miccon trolof th eir patien tswit hdiabet es,th ey,orth ehealthcaresyste mingen eral, willbe facinghighe rme dicalcare costsin the longte rmasthe excesscostsofcaredu etocomplicationsandcomorbiditie sbecome manifest. Inonestu dyofp atient sfromHealth Partne rsin Minn esota, 3-yearmedicalcarecostswere close lycorrelatedwithbaselin ehemoglobinA 1 c (HbA 1 c )leve lsatthe start ofth eme asu rementpe riod (71).In creas esin HbA 1 c of1%were associatedwitha7%in creasein cost s.Theincr eme ntalincre asesin costswit hrisin gHbA 1 c we reev engre ate rfort hosepatien tswit hhy perte nsion ,lipiddisorde rs,and car diovas culardisease . Rec entst udieshaveindicate dthateffortstoimproveglycemiccont rol,alth ou ghcostlyin the mselves (72),willhavelon g-termben efits,notonlyin redu cin gcomplication sb utalsoin redu cin gcosts. An an alysisofth eDC CTin dicated t hat ,ifsu bstantialaddition alresource swereinve stedeachye arin pat ie ntswithty pe1diab etes, t heincr eased t reatme ntwouldbehighlycosteffect ive ,wit han incremen talcost of$28,661pe ryear oflife g ained. Ift hisisadju stedforimpr ove dqualityoflife,th e incremen talcost perqu ality -of-life year gainedis$19, 998(73).Mark edredu ction sin costwouldbe ach ie vedbyde creasin gESRDandlowe r-ext remity amp utation. Fu rthe rimprovemen tsin cost, life expe ctan cy,andqualityoflifeareachievedifthe econ omicsofinte nsivecontrolaree xtrap olate dove ra pat ie nt'slifetime (73).Economicmodelingofthecostsandben efitsofinte nsivecontrolbased ont he DC CThasbeen performe dan dapplie dtot hepopulat ionofpatien tswit htype 2diabet esin the United States(64).Itcalcu latedt hat t helife timecostsforgen eralan ddiabete s-relate dcare usinginten sified tre atment fort ype2diabeteswouldbeapproximate lyt wicet hat forst andardcar e.The redu ctionin lifet imemedicalcostsofcomplication s,however ,wou ld largelyoffse tthe d iffer ence(Table 46.1, refe rence 74).Alt houghint ensiveth erapyfor type1andt ype2d iabetesismore expen sive than conven tion alther apyinth eshortru n, itslong-ter mcost-effect ive nessiscomparabletothatof
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pharmacologictreatme ntofhype rten sionandelevatedch oleste rol.Thismean sthatfromth eperspe ctive ofp ublich ealthandth ehe althcaresyst em, prog ramstoh elpphysiciansachieveint ensiveman agemen t oft heirpatie ntswithdiab eteswouldbeaworth while long-te rmfinancialin vestmen t(75). TABLE 46.1. Cost of Treatment, Effectiveness, and Incremental Cost-effectiveness under Standard and Comprehensive Care for Type 2 Diabetes
Generalmedicalcareanddiabetes costs Eyediseasecost Renaldiseasecost Neuropathy,LEAcosts Coronaryarterydisease Total costs QALY(undiscounted) QALY(discounted3%) Lifeyears(undiscounted) Incremental cost/QALY gained
Standard care $32,365
Comprehensive care $58,312
Difference $25,947
$3,128 $9,437 $4,381 $13,458 $62,769 16.04 11.43 17.05
$1,536 $960 $1,469 $14,414 $76,922 18.03 12.30 18.37
($1,592) ($8,477) ($2,912) $956 $13,922 1.99 0.87 1.32 $16,002
LEA,lower-extremityamputation;QALY,quality-adjustedlife-years. DatafromEastmanRC,JavittJC,HermanWH,etal.ModelofcomplicationsofNIDDM:analysisofthehealth benefitsandcost-effectivenessoftreatingNIDDMwiththegoalofnormoglycemia.Diabetes Care1997;20:735 744.
More modestint erven tion sin improvin gdiabete scare h ave alsobe ensh ownt oimpr ove glyce miccon trol an dredu celon g-termcost sformedicalcare (76,77,78).C ost analysisofthecareofpatien tswit htype 2 diabet esfollowed in t heU nitedKingdomProspectiveDiabete sStudyh asalsoshownsubst ant ialsavin gs incostswit hin ter vent ionstocon trolglu cose(79, 80)andbloodpr essure (81).Alt houghint ensive glucosecontrolint hestu dyincreasedtr ialtr eat men tcos tsby695perpatie nt, itr educe dthecostof complication sby957compar edwit hconven tion altreatme nt. Howeve r,ifstan dard-pr acticevisit pat tern sweret obeassumedrather thantrialconditions, the per-patie ntye arlycostswou ldbe lower, at 478.The costpe reven t-fre eyearofinte nsivebloodglucosecon trolwascalculate dtob eabout1166, indicatingt hat thisformoft herapyinper son swith type2diabete sish igh lycosteffe ctiv ean d supp ort ableeconomically.Similareconomicadv ant ageswer efou ndinmode lingth ere sultstocostsin th eSwissh ealthc aresys tem( 82). Inad dition,imp rov edglycemiccontrolmayalsoleadtoamore product ive workforce, redu cethe econ omicburde ndue tomedicallyrelate dwork loss,an dimprove qualityoflife(83). P. 784
DIABETES, MANAGED CARE, AND DISEASE MANAGEMENT

The b urgeoning d isease-management con ceptisrapidlyestablishing itse lfasasig nificantandpowerful en tit yin the health care in dustr yforman agingch ron icdiseases.Duringt hepastfewyears,agrowing nu mbe rofdiseasemanagementv endorshaveofferedawide variety ofprogramswithmultiple ince ntives forqualityimpr ove men tan din creasedcost-effectiven ess.Th eback grou ndsandth eir motivationfor providin gdise aseman agemen ttohealth care provide rscan behighlyvariable.Progr amshave been deve lopedandarebeingmark etedandimplemen tedbyinde pende ntdisease-managementv endors, pharmaceu ticalcorporations, manag edcare compan ie s,specializedconsultants, p atient education al serv ice scompan ies, homeh ealth care compan ies, an dhigh-tec hnologydataman agemen tan dsoftware companiesinwhatisbe comin gan excee din glycompetitiveen vir on men t.Man yofth esecompaniesare
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joiningforceswithclinicalorg anizationsorothe rbusinesse stocombin eproducts, skills,an dstrategies more effectivelyinthe marketp lace.
WHAT IS DISEASE MANAGEMENT?

Diseasemanagement isacomple tean dcompre hen sive met hodofprovidin ghealt hcareth atfocuseson management ofcar eacrossth econ tinuu mforpopulationsofpatient swith chronicdise ases. Disease management isacomprehe nsiveinte grat edappr oachtocare andr eimbur seme ntbasedfun dament allyon th enaturalcour seofth edisease ,withtre atmen tdesigned t oaddressth eillne sswith maximum effect ive nessandefficie ncy(84). Disease man age men tcan beth ou ghtofasan appr oachtocare t hat ident ifiesth eopt imalprocessesforcar eofapatien twith aspe cificcon dit ionandimplement st hose processeswh ilemeasu ringth eou tcomet odemonstrateimp rov eme nteconomically,h umanistically,an d clin ically(85).Dise aseman agemen tisorient edtowardwellnessandpre vent ion. Th egoalsofdisease management aretoext endt heper iodsofwe llness t hat patien tsexpe rie nce, t oimp rove the over all qualityofth eir lives,t opre ven toccu rren ceorexac erbat ionofcomplicationsoracutee pisodes, todirec t ut iliz ation ofse rvicesan dresourcesappropriate ly, andt omeasu reoutcomescon sist ent ly. Inpractice , disease manage me ntisbeingimplement edasawaytocon taincostswh ilemaximizingth eov erallquality ofcareacrossaninsu ran cecompanyoremployer'spopulation (86,87).Th erefore, d iseasemanagement isbeingimplement edmostwidelyin patien tswit hconditionsforwhichcostsavin gsare mostsubst ant ial.
WHY IS DISEASE MANAGEMENT NECESSARY?

Atleast 90millionAmerican sare d iagnosedwithonech ron icilln ess;asman yas39millionar e diagn osed with moreth an one chronicillness(88). R esearchde monstr atest hat approximately20%of th epop ulation wit hdiabet esin cur80%ofh ealth carecosts(89).Th isdisproportion ateu tilizat ionisvery significantandhasthe pot entialtoworse nwithth eaging ofth epop ulation (88).Traditionalhe althcare directse fforts atreactingtoth eacu teepisode.The reisofte nalackofcontinu ity ofcar ebecauseofthe existe nceofahe althcaresyste mth atpr ovidesfragmente dand u ncoor din ate dcare .Clin icaland bud getaryprioritiesareconcen trat edinconflictingpositions ,wit hlitt lecommonun derst anding or integ ration.Dise aseman agemen tprovide sares pon sive ,coordinatedh ealth caresy stemthatin tegrates th eactivitiesan dprioritiesofallparticipantsint hedeliveryofcar e. Diabetesison eofthemostcomplexan dsign ifican tchr on icdiseasesin healt hcar e.Itse mer gence asa majorcause ofclin ical P. 785 morbidityan dincreasin ghealt hcarecostswasamplydiscussede arlie rin thischapter. Thediseasein manyp eopleisdiagnosedonlyup ont heirdev elopingser iousandlife-t hreaten in gcomplication srelated tothe unde rly in gdiabete s.Inev aluat ionsofthe impactofdiabete son theh ealth care systemand the effect ith asonapopu lation, thefactsgiveaconv in cin gpict ureofdiabete sasan appr opriat etargetfor disease manage me nt.Accordingtoth eresu ltsofthe DC CT,maintain in gbloodglu cose lev elsascloseto normalaspossib leslowst heonse tand p rogr ession ofeye ,kidney ,an dnerv ecomplication sr elated t o diabet es(31).The DCC Tshowe dthatsust ainedlowe redbloodglucoselevelshadpositiveeffe cts,ev enin th osepatient swh oh adpr iorhistoriesofpoorcon trol. Tight ercontrolalsocontr ibu tedtoalowernu mbe r ofg lyce miceven tsth atledtohospitaliz ation s.Achievingandmaintain in gsuch con siste ntbloodglucose controlisex tremelychalleng in gboth for p eoplewithdiabeteswh oareat temptingtobalan cebusylives withmanagement ofth isdiseasean dfort heircar eprovid ers.Dise aseman agemen toffer san infrastruct ureforinte grating allth ekeymembersofthe health care teamwithth epat ien tsan dthe ir significantothe rs,incombination with proactiveandcompre hen sive servicestoimprovet hequ ality and cost-effective nessofdiabete scare. Not ablechallen gesinthe healt hcar esystemaffe ctthe abilityofclinicianst omanagediabe tes succe ssfullyandsu ppor tthe necessityfordisease manag eme ntasacon ceptandasapractice .Those challen gesinclude Thelack ofstandardiz edcar ethr ou ghoutth econtinu umofcare thathascon tribute dtoh igh variabilityinphy sician pract iceandinre sultan tpatien toutcome s
Thelack ofacc essib leandimmediat ely availablescre ening, t reatme nt,p reven tion ,an d pharmacologicutilizationgu ide line sandpr ot ocolsforclin ician sin activepracticesett in gs
Lac kofre sou rcesan dsystemsth atprovideconsisten teducation and r einfor ceme ntforprofession al car eprovid ers
Inappropriate u tilizationofservicesandre sou rces,includingh ospitalizationsandemerge ncy department visitssecond arytooftenpr even tableglycemicoccur ren cesan deven tsrelate dtoacut e an d/or chroniccomplication sofdiabet es
Lac kofconsisten tsystemsth atcanassistclin ician stoiden tifyhigh-riskpatie nts, toinst itu te compre hen siv epreve ntiveandedu cationprograms,andtocoordinateappropriateu tilizat ionof serv ice s
Absen ceofsys tems,for mats,an dresource sforpe rfor manceandoutcome measure me nt;data
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collectionan danalysis;t rendanalysis;pat ie ntident ificationan driskstratificat ion;tr ackingand mon itoringofpatien ts;an dreportingandfee dbackmechanismst hat have strongpoten tialt o influen ceeffectiveh ealth care d eliver y
Inadequ ater esou rcesandsyst emst oprovidecompre hen siv epatien tedu cation an dsupportinlon gter mself-management Inadequ atesy stemsforcoordin atingt hecarean dprior itiesofmu lt ipleparticipants the patient , primarycarephy sician ,specialists,cas emanag ers,n urse s,an doth ercareproviders in afocu sed, concert ed,inte grat edteamapproach
Diabetesisadiseasewit hmultiplest akeh olderswh oh aveaveste din tere stin improvedsyst emsand outcome s,i.e., patien ts,providers, employers, commu nityage ncies,h ealth p lans,h ealth facilitiesan d age ncies,andph armaceu ticaland oth erven dors.Asadiseasestat e,diabe tespre sentsacombinat ionof highv ariability inpr acticeandcost,high p revalen ceofworkorsch ooldayslost, andsign ifican t difficu ltiesinman agemen t.Howe ver, ther eisarealisticabilityt oalte rthe cou rseoft hediseaseacross th econ tinuu mofcare through impleme ntation ofadisease-management p rogr amthatprovide sa focusedandspecificsetofg oalsandinter vent ions, aswellasaconsisten tevalu ativeprocess.
ESTABLISHING A DIABETES DISEASE-MANAGEMENT PROGRAM

Seve ralcomponen tsare nece ssaryforth edevelopme ntandimplement ation ofasuccessfu ldiseasemanagement p rogr am.Thepu rposeoft hedisease-manageme ntpr ogramistoprovide toolsand processest opatie ntsandcareprovidersth atinte grat ethe patien tasar esponsible ande mpowere d par tne rofth ehe althcarete am. The objectivesofthe diabete sdisease-man agemen tprogramshouldencompassclin icalst andardsan d expe ctat ions, u tilizationman agemen t,patie ntself-management issu es,patie ntqu alit yoflife ,staff sat isfaction, an dthee stablishmentofevalu ativepr ocesse sand t ools . The firstobjectiveistoimproveclin icaloutcomesbystandardiz in gcare andpr ovidinggu idelinest hat haveinte grat edbestpr acticewithaccreditat ioncriter iaforqu alit yan dbyproviding systemsthaten able clin ician sand p atient stoadhe retothe e xpecte dstan dard s.Evalu ationofimprov eme ntisme asur edby th esuccess fu lloweringofHb A 1 c leve lsacrosst hepatie ntpopulat ion. Processimpr ove men tsalsoin clu de th eperce ntageofpatient sreceivingfoote xamin ationsyearly,bloodpressu remeasu remen tstwice a year,comp rehe nsiveeye examinat ionsannu ally ,lipidprofilesonceayear ,an durine protein/microalbu minu riascree ningsonceayear. The se con dobject ive istoimprover esou rceu tilizationbypromoting b ette rcon troloverdiab etes management aseviden cedbyre ducedn umberofhospitalization soremerg encyde part men tvisit s, red uceddu rationofstayre latedtohy poglycemicorh yperglycemiceven ts,andredu cedcardiovascular an dlower-e xtre mitycomplication s. The t hirdob je ctiv eist oimpr ove patient self- man age men tbeh avior sand sk ills b yprov idingpatient swith acce ssibleandconsisten teducation alprogramsan dbehavioralsu ppor t.Improvementisme asu redbyth e increaseinth enu mbe rofpatie ntswh oself-mon itorbloodglucoselevelsdaily,che ckthe irfe etdaily, un derst andh owtomanagehy poglycemia,andhaveasick-daymanagementplan. Afou rth objectiveistocon tribute toahigher qualityoflifefor peop lewith diabetesby prov iding edu cationalan dpsychologicalsupport d uringth eprocessoftheirachievingmaster yofse lf-management an dthr ou ghoutth eongoin gexper ien ceoflivingwithach ronicilln ess.E valuatingdepr essionmeasure s an dsurv eyingsat isfactionleve lsre gard in gavailabilityofedu cationalan dsupportmechanisms, accesst o car e,andclin icaloutcomesare impor tan tcomponen tsofu nder stan din gwhatle arn in gandps ychosocial supp ort saren eede d.Appropriate s upportmechanismsaredesigne dtob eeffectiveandtohavea posit ive impactont hequ ality oflife. Refer ralguidelin esar edesigne dforindividualinte rven tionand follow-u pwit hcert ifieddiabet esedu catorsorme ntalh ealthpr ofessionalsas n eede d. Afift hob je ctiv eofth edisease -manag eme ntprogramistoprov ide evaluativeprocessesandtoolsfor measu rin g,document in g,an alyzing,andre por tin gpat ien ts'complian ceratesan dresponse sto tre atment ,pat ie ntoutcome s,tre nds,andoverallprogrameffect ive ness. Included areth edev elopment of riskstratification;t rackingandmon it oringofclin ical, e con omic,an dquality-of-lifeoutcome s;and measu rementofkeyind icator s. Asix thobjectiveistoimprov ecliniciansatisfactionbyinteg ratingp atient andcareproviderpr ioritie s intothe ove rallpr ogr amst ructu reandbypr ovidingongoin gsupportandfeed back.
P. 786
RECOMMENDED ELEMENTS FOR A DIABETES DISEASEMANAGEMENT PROGRAM

Adiabet esdise ase-man age men tprogramshouldbede sign edtoaddr essthe ove ralln eedsofthe gene ral pat ie ntpopulat ionth ath asbee nidentified,aswellast otarget sp ecificact ivitiesforpatien tswhohave bee nidentifiedasathighriskforcomplication s.Thee le men tsthathavebe enident ifiedascore
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componen tsforan e ffectivediabe tesdisease -manag eme ntprogramfollow: Est ablish me ntofacollaborat ive work t eam De velopmen tofanasse ssme ntprocess Imple men tat ionofarisk-managementp roce ss Ph ysicianedu cationprogramsan dprocesses Imple men tat ionofclinicalguidelines Edu cationalprogramsandsupp ort mech anismsforpr ofessionalan dofficestaff Pr ogr amsandt oolsforpat ie ntself-management Dataman age men tan dtech nologicalsupport Int egrationint oqu ality improvement Management ofcar ecoordination andu tilizat ion Ongoingsup port mech an isms
ESTABLISHMENT OF A COLLABORATIVE WORK TEAM

Est ablish me ntofacollaborat ive work teamisakeycompon entint heprocessofproviding t he foundation fordiabe tesdiseasemanageme ntth atpr omot esan dsupportsth einteg rationan d coordination ofinte rdisciplinary member sashealthcareteamsformanagement ofpat ie ntcare.The disease -manag eme ntconcep trelie son amu lt idisciplinarymethodologyforpreve ntingfr agmentation and forbuilding acare in frastr uctu reth atmaximallysu ppor tsthe need softh epat ien t.Th echargeoft he workteamistotailorth ecoredisease -manag eme ntprogramtomeetth ene edsoft hepatientandcare providersandtoguideth edeve lopme nt, imple me ntation, and e valuation p roce sses.The work t eamis accoun tab lefordev elopingandmaintain in gacollaborat ive processfor comple tin galln ecessaryste ps towardachievingasuccessfu lprogramfordiabet esdisease man age men t.Th eresponsibilitiesoft hework teaminclude the followin g: Assessingth eorgan ization alpract ice sandre sou rces, includ in gstaffingpatter nsan dskillmix; av ailabilityan daccessibilityofdat abase s;data-manageme ntcapacity;man agement systems;an d per tin ent relation shipswit hpatie nts, familie s,paye rs,andrefe rralsources, Assessingth ecur rent baselineclin ic alp racticesandoutcome s Clar ifyingt hegoalsan dobjective sandiden tificat ionoftar getar easforimprovemen t Modifyingth ecomponen tsoft hedisease-managementpr ogr amasrequ ir edtoaddre ssthespe cific ne edsoft heorgan iz ation De terminingth efor ums, sched ules,an dmaterialsre quiredforade quat ephysician andst aff edu cationalprocesses De veloping andimp lemen tin gpat ien tedu cationaltoolsan dprocessesth atareappropriateforth e gen eralpopulat ionan dfor thosemore in tense measure sthatare specified forh igh -risk patien ts Planninganddev elopingth estep s,con ditions, andt oolsforth eimplementation phase Actingaschampion sandadvisorsdu ringth eimplementation phas e Pr ovidinggu idanceinth eevaluat ive p hase ;ide ntifyin gthe mosteffect ive and appropriate utilization oft heoutcomesdat aan dan alysis;anddirect in gtheinformationtobeuse din quality-improvemen t act ivities
ASSESSMENT
The assessment proce ssiscondu ctedtodet ermin ecurr entbaselin eclin icalandorgan ization alpract ice s. Evaluat ionoftheclinicalpract icesinclud esdete rminingh owwellthecour seofth edisease is un derst ood,whatth ebestpr acticestandardsare ,whet her majorob staclestoach ie vin gbestpractice existandwhatth osebarriersare,wh atth ecompositionofthe patien tpopu lation with diabete sis, and whatthe specificinfluen cesuponcomplian cean dpreve ntionare .Theassessment oforgan ization al practicein clu desdet ermin ationoft heavailable work force r esourcesforimplement ation ,aswe llas tech nologicalavailabilit yand r equiremen ts.
PATIENT IDENTIFICATION
Acrucialelement in t hediabe tesdisease-managementpr ogramisth eability t oiden tifyallpatie nts withinth epractice orfacilitysett in gwhomee tcriteriaforen rollmen tintothe progr am.Anypatientwith adiag nosisofdiabete sshouldbecon sid eredasapar ticipantinth eoverallprogram.The prog ramshould
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bede sign edtome etth enee dsan dtopr ovidese rvic estoallpatie ntswithdiab etes. Inadditiontoa bas icprogram, oth ercompone ntsaredesigne dtot arge tpatien tswhorequ ire in ten sifiedserv ice s, edu cation,andsup port .Patientscanbeiden tified t hrough avarie tyofsour ces,i.e. ,claimsdata, emerge ncydep artmen tdata,inpatie ntadmission d ata,home careadmission data,ph armaceu ticalclaims dat a,ph ysicianrefe rrals,andothe rrefer rals(e.g. ,case -manag eme ntre ferrals, self-r eferrals) . Int hecasethatth eenr ollmen tisbasedonar eferralsy stemversu sin clu sionofallpatientsina population,re ferralscanber etrieved fr ommu lt ipleav enu es:primarycar ephysician s;nurse practitione rs;an dstaffnu rsesfromavar ie tyofacute in patient ,ambulat ory ,office, orh omecar e sett in gs. The r oleofthepr imary careph ysicianisveryimp ort ant t oth edisease -manag eme ntprocess. Onceth e pat ie nth asbeen id entified,th eprimarycarephy sician iscontactedtoprovidear eviewand approvalan d toin it iateth ein vitationprocesstothe patien t.Wh ethe rthe enrollment processisautomaticin clu sion, criteriab ased, orr elian tonrefe rral,oncet hepatienth asbee nident ified,h eorshebe comesan active par ticipantinth eprogram.
RISK STRATIFICATION
Adiabet esdise ase-man age men tprogramisdesignedtoimprovet hequ alit yand cost-e ffe ctivene ssfor th eent ire patien tpop ulation thathasbeen ide ntifie d.Howe ver, with in thatlarger p opu lationt here isa groupofpatien tswhoare con side redtobehigh r iskforcomplication san dwhoaccountforasign ifican t proportion ofresour ceutilization and medicalcosts.Thissubse tofpatient sr eprese ntscandidat esfor inten sifiedt herapyan din terv ention. Riskstratificationisacr iticalprocessindiseas emanag eme ntbe cause itpr ovidesadetailedpatie nt profileandident ifiesth ose p atient swhoareatriskfor d evelop in gsevere chroniccomplication s( 90, 91). The r isk-st rat ificationinfor mationisuse dasagu id eforcarepr oviderst oen ableth emt oachievetwo obje ctives.The first objective isth edeve lopme ntofprograms, syste ms, p roce sses,andtoolstargete dtot heh igh -riskpatien tgroup.Patien tedu cation altoolsan d processes, care coordinat ion, andcase-management activitie s,refe rralstocertifieddiabet eseduc ators orspecialist s,an dfollow-up r egimen sare dire ctedbyt heinformation thatis p rovided b yrisk stratification. Thesecond objectiveisindivid ualizationofcarebasedonscientificin formationth at descr ibe st hepatient'scircumstan ces. The g oalsforin tegr atingarisk s trat ificationcomponen tintothe diabetesd isease-management prog ram include(a)preve ntion or delayofonse tofch roniccomplicat ionsoracu teev ents;(b )d ecreaseinthe seve rit yofcomp licationsth atdooccu r;(c)ext ension ofth epatie nt'slife,(d)improv eme ntinth e pat ie nt'squalityoflife;(e)dec rease in preven tab leh ospitalizations, eme rgen cydepartmentvisits,or inapp ropr iateut ilizationofr esou rces;and(f)improvemen tin patien tan dcare prov ide rsatisfact ion. P. 787
PROFESSIONAL AND OFFICE-STAFF EDUCATIONAL COMPONENT

The comple xit iesandcomp licationsinhe rent in thecareandtre atment ofdiabe teshaveincre asedt he deman dson care p rov ider stor emain curr entandcompe ten tin theman age men toft hisdise ase. Th e profession aland officestaffe ducat ionalcomp one ntisdesigne dtomaximize thek nowledg ebase ,to increaseth elevelsofpr acticalskills,andtoexpandth ele velofconfidence ofcareprovidersinth e management ofdiabet escare .Thee ducationalpr ogr amsarepr epare dwit hfle xib leformatsand cur ricu lu mst oad dressth esche dulin gnee dsofcareproviders.Programsshouldbede veloped thatcan resp on dtomultiple le arning needs atvariousleve lsofin ten sity .Thefollowin garesu ggeste dtypesof programsforin clu sionint hecur ric ulum. Int rodu ctoryCont in uingMedicalEducation (CME)programstoreviewth ediabet esdiseasemanagement p rogr amandint rodu ceguidelinesorprotocols Pr ofessionalstaff(certifie deducation alunit;C EU)ed ucat ionalprogramsfornu rsesandallied health profession als.The seprogramsin clu deth efollowing: Int rodu ction tot hedisease-managementpr ogr amandclinicalguidelin esan dprot ocols Ongoingedu cationalser iesabou tdiabet es,includingpathophy siology, screen in gand treatme nt methodologies,medicationmanagement, patien tself-manage me ntandedu cationaltech niques, psych osocialissu es,management ofacu tecomplications,andpre vent ionandmanagementof chr on iccomplications Edu cationalsessionsfor officestaffr egar din gtheadministr ativecompone ntsofthe d iseasemanagement p rogr am:formalan din formal Session sfort rainingth etrainer The g oalofthediabetesdisease-management p rofe ssionalandstaffe ducationalcompon entistoprovide
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consisten tand cont in uouslear ningopport unitiesth atareaccessib leandmean in gful.
PATIENT SELF-MANAGEMENT
Edu cationinself-manageme ntofdiabete sisacrit icale lemen tin providing p atient swith the mech an isms ne cessar yforman agingth edisease anditssu bseque nteffe ctson the irlives.E mpoweringpatients and he lpingt hemacqu ire thesk illsforeffe ctiv eself-manage me ntar ethe fou ndat ionofthe e ducational processforthe patien twit hdiabet es. Forpe oplewithdiab etes, man age men toft heirdisease relie son con tin ualtr eatmen tan dcon stan t balancingoft heinte gralpar tsoft heirlive severy d ay.E ffectivemanagement ofdiabe tesrequ ir es vigilanceandcommit men ton a24-hour -a-daybasisan dsign ifican tlifest yle modificat ions. E ducation and self-managementplay vit alrolesingu idingth epatie nttowar din depen dent andcompeten tmanagement ofd iabetes. Thegoalofth epatie nted ucat ionalcompone ntofdise aseman agemen tist ofacilit atet he pat ie nt'sandt hefamily 'sabilit ytoincr ease t heirdiabe tesknowledgebaseforself-manage men t,t o increaseth eircon fide nceinapply in gthekn owledge topr acticalsituations, and t osh are e xperien ceswit h other peoplewith diabetes. Theeffe ctiv ediabete sdise ase-man agemen tprogramincorpor ates multiple individ ualan dgroupformats,withanemphasisoninte ract ive participation.Th ehealt hcar eteamis providedwithstandardizedpat ie ntedu cationalmater ialssothatth epat ien tisreceivingconsisten t information .Techn ologyhase nab led carepr oviderst opre sent education almat erialtop atient sin awide rangeofcreativ eways, in clu din gan dnotlimite dtocallcen ters, vide os, e-mail,int eract ive Websites, an din teractivesoftware (88).Cu rriculumsc anfocusonmean in gfultop icsrangingfroms urvivalskills,to mealplann in g,toin ten semonitoringofblood g lu cose, tomorein-dept hself-managementt echn iqu esan d information .Incen tivesformain tainingatten dan cean dcompliancewithe ducationalpr ogramsmay b ea he lpfu ltoolforsupporting t hepatient. Itisimpor tan tfort heed ucat ionalprogramstoadd ressan d integ rate psychosocialne edsan dthe enormou semotion alan dpsychologicaltollexactedbylivin gwith diabet es.E ngag in gthepatient andfamily asact ive partn ersinth ehe althcarete amandaddressing edu cationalne edsacr ossth econ tinuu mareimportantattribu tesfor success.
CLINICAL GUIDELINES
Clinicalguidelin esprovid eabasisforscree ning,t reat men t,e valuation, and p har mac ologicmanagement processesint hedeliveryofcar etop atient swith diabete s.They mus tbelin kedtocommonlyre cogn iz ed measu resofclinicianpe rforman ce(92).Part ofeve rydisease -manage me ntprogramen tailsthe deve lopment, impleme ntation ,an devaluation ofdisease -specificclinicalpath ways,wh ich canalso en compasscarealgorithmsor p rot ocols. Thegu ide linesmust in corporatecur rent knowle dgean d refe rence reliableresource s.HEDIS(He althPlanE mploy erDataandIn format ionSet)(93)andAmerican DiabetesAssociation Clin icalPract iceR ecommendation s(3)can beuse dasimportantr eferen ceelement s forthe d evelop men tofgu id eline s.Consisten trev iewsforne cessar yupdatin gan dmodifications contribut etothe cr edibilityoft hegu ide lines .Clin icalgu id eline sthatare evidence based, with formal eviden cerev iewsincorporat edintothe irde velopmen tprocess,andth ath avebe enstr in gent lyand au thoritat ive lyt estedr eceivemuchst ron gerpositiv eresponse sfr omphysiciansandinte grat ioninto practice(88,94). Easyacce ssibility andu ser-frien dlyformatsforusingt hegu ide linesr easonably in abusypr acticeare oftenpr erequ isite st osu ccessfulimplementation (95).Toolst hat supportth eguidelines, in clu din g documentation forms,ph ysicianor dersh eets, patient surve ys,an ddat acollectionfor ms,fr eque ntlyare deve lopedforuse in con ju nction wit hth eguidelin es.In creasedeffortsar ebeingmadet oprovideonlin e an dWeb-basedap plications.Gaining accesstothe guidelin escan alsobe combin edwithth edata collectionan dvariance-tr ackingmechanisms. Theobjectivesoft heclinicalguidelin esare (a)tosupport optimal clin icalpr actice,(b)t oinfluen ceclin icalbe haviortoprod uceimpr ove dpatien tou tcomes, and (c)to en suret hat patien ts'ex pectationsareinforme dan dreasonable(3). Ifguidelinesaredeve lopedandimplement edbylocalorganizationsorcare grou ps,th eysh ouldbeb ased onth ecollaborationofaninte rdisciplinar yclinicalteamt hat haspe rfor medacare fulreviewofcu rren t eviden ce,literature ,an dreliableclinicalpractice. P. 788
CARE COORDINATION, UTILIZATION MANAGEMENT, AND CASE MANAGEMENT

Carecoor din ation ,ut ilizationmanagement, and c asemanagement arecr iticaltothe impleme ntationofa succe ssfuldiabete sdisease-man agemen tprogram.The p opu lationwith patien tswith diabete s en compasse sasignificantn umb erwhoare activelyexp eriencingse riousorlife -thre aten in g complication s,havebee nident ifiedasb ein gin ah igh -risk categ oryfordev elopment ofcomplication s,or demon strateth epotent ialforprogressiontoahigh -risk lev el. Inadd ition,be cause ofth ecomplexityof managin gthisdifficu lt ch ronicdise aseonad ailybasis, patien tsrequ ir ethe in tensive su pportan d coordination offer edbydisease -manageme ntprogramsviacareandcasemanag eme nt. Pat ien tswith diabet esne edtohav easup port ive serviceav ailable thatisge are dtoassist themtowardbe tter self-
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management andsu bseque ntlytoan improvedqu ality oflife. The p roce ssesofcarecoor din ation,u tilizationmanagement, and caseman agement arecloselyrelate din th emanageme ntofthe fu nctionsreq uiredforensu ringth atth epat ie ntre ceiv esopt imalle velsofcare an dservicesatthe rig httime and in t hemost appropriate settings .These p roce ssesare nece ssary th rou ghoutt hecontinu umofcarean dhaveproven tobe highlyeffectiveinincre asingqu alit yand costeffect ive nessofcare . The r oleofthecasemanagerh asexpande dbeyondth eoriginalcont extofacut e,inpatientcareand ext endsint ocontinu edmanagementofthe patien t'scareth rou ghout t heoutp atient andcommu nity expe rienceandth ecoord in ation with primarycar e.The caseman agersu pportsth edise ase-man age men t processfromt hepe rspectiveofbot hth ein div idu alpatien tan dthep opu lationasawhole.The case manager'sresponsibilitiesincludeth efollowing: Coordin ating t hepatient'scare throug houtth econ tinuu m, ther ebyfacilit atingth each ie vement of optimalqu ality out comesinclin icalcare,cost-e ffe ctivene ss,an dpatien tsatisfact ion Assessingpatientst oident ifyspe cificcase -manage me nt/care-coord in ation nee ds Assessingandrisk-stratifyin gpat ien tstoide ntifypat ie ntsinth ehigh-r iskpopulat ion Collaboratingwithawidev arietyofme mbe rsofamu ltidisciplinar yhealt hcar eteaminmultiple sett in gstop lan,imp lemen t,an devalu ate patien tcare andt here latedcare-deliverysyst ems
Coordin ating multipleservicesandre sou rcesrequ ir edbyth epat ie ntan dfamily Mon itoringandtr ackingpatie ntre spon sean dou tcomest otr eatmen tan dchan gesinrisklevel Iden tifyin gvarian cesth ataffectth equalityandcostofcareandpar ticipatin gin the developmen t an dimplementation ofshort-andlon g-ter mpatie ntcarestrategies Pe rfor mingu tilizationrev ie wandman agemen ttoe nsur ethatap propr iateser vice sandr esourcesare providedinare asonable ,high-qu alit y,an dcost -effectiveman ner Assistin gan dguidin gpat ien tsan dfamiliesin commu nicat in gwith healt hcar eprovide rsan din mane uver in gthrough the health care systemwit houtdifficu lt y Assessingandinte grating t hepatient'sphysical,ps ychosocial,economic, andlifestylecircumstan ces intoan e ffectivecase-manageme ntplan Analyz in g,monitoring,ande valuat in gcomplexpat ie ntinformation ove rsign ifican tper iodsversu s concen trat in gon specificepisodes
Quality Improvement
Amajorpu rposeofdisease-management p rogr amsistosupportqu ality-improvemen tin it iativ esan dto provideasyst emforoutcome san alysis. With in the con textofadiabe tesdisease-manageme ntpr ogram, th eevalu ativeprocesst hat con tributest oeffe ctiv equalityimp rove me ntisreorgan iz edtoencompass en tir epopulation s.In t hispopu lation -based conce pt,th eab ilit ytostrat ifyforriskan dide ntifyhigh-r isk pat ie nts;todeve lopan dimpleme ntbe st-practiceprotocols,gu ide lines, in terv entions,andprocesse s; an dtomeasure patien tan dsystemresponse sandoutc omesisincr easinglyimportantt oth emany stakeholdersinhe althcarede livery . Int egrationofvaluable dataon patien tou tcomeint oth equality-improveme ntpr ograme nablescare providerstorespond t oth ephy sical, psychological,fun ction al,an denvironment alnee dsofpatie ntsin th epop ulation wit hdiabet es.Consisten tan dreliablereportingst ructu respr ovideamech an ismfor ut iliz in gthed atain meaningfulan dproductiveways.In clu din gthe p erspect ive softh epat ien tan dcare providerinth eevalu ationofqu alit ypromotesacompreh ensiveviewpoint.Prompt responsetoth edat a th rou ghth edeve lopmentandimplemen tationofp lansfor improvementorcorrect ive action stren gth ens th eprograman din creasesit scredibility. Someofthe in dicator smeasure dtoevaluatequ ality andincorporatedintothe quality-impr ove men t programar ele velofclin icalq uality;acce ssibility tocareandserv ices; t hepatient'squalityoflifeand fun ction alstatu s;le velsofsatisfaction ;andleve lsofutilization man age men t.
Level of Clinical Quality

The leve lofclinicalqu ality canbe evaluatedbyassessingpatientout comes,aswellaspr oce sses.For pat ie ntswithdiabe tes,t hepr imaryclinicalin dicatorthatprovideseviden ceofimprov eme ntisthe Hb A 1 c level.Oth eroutcomestomeasure in clu dephysiologicparamet ers,r ate sofacu teandchr on ic complication s,an dmortalityr ates. Processe stomeasureforcompliance with expect edstandar dsofcare includefoot examinat ions, compreh ensiveey eexaminations, bloodpressu remeasu rements, HbA 1 c mon itoring, lipid -profilemonitoring,andu rin aryp rot ein /microalbumin scree ning(96,97).
Accessibility to Care and Services
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Forboth patien tsan dcarepr ovider s,acce ssibility t oprompt,re liable, andcomprehe nsivecar ean d serv ice sisofparamoun tcon cern .Availabilityofclinicalcar ean deducation alandsu pportprogramsar e importanttopat ie ntswithdiabe tes.Prompt responsetimesan dexped itioussche dulin gpromoteth e sen seofse curityandfortifiest heper ception ofh igh -qualitycare.
Quality of Life and Functional Status

Evaluat ionofqualityoflifean dfunct ionalstatusinclud esmonitoringfor improvement sinse lf-care abilit y,ach ie vements in individ ual-an dpop ulation -base dgoalsforself-manageme ntandbeh aviorchange, t reatme ntandfollowupcomplian cerates,andpatie ntandfamilycomp rehe nsion ofself-management. P. 789
Satisfaction Levels
Toobtain acompre hen siv eviewofh owth equalityandeffect ive nessofthe diabete sd isease management isper ceiv ed,assessmentsn eedtoconsidersatisfaction lev elsfr omthe p erspect ive sof multiplest akeh olders int hecare-deliverypr oce ss:patien ts,families,careproviders, payer s,employer s, an dot hers. Theindicat orsforsuch assessmen tin clu delevelsofsatisfactionwit hth ecare prov ide d,th e acce ssibilit ytocareandserv ice s,an dther esultantoutcome softh ecar eprovide d.
Utilization Management
Ut iliz ation manageme ntandquality improvementareoftenv eryclose lylinked. Det ermin in gan d mon itoringth eapp ropr iaten essofcarean dserv icesandproact ive ly d ire ctin gcar etot hemost suitable an dpert in entse ttingsaffe ctthe qualityofcarefr omallpe rspectives. Redu ctionsinu nne cessar yor pre vent ablehospitaliz ation san deme rgen cydepartmentvisits,aswellaslostwork andsch ooldays, decr eases inacuitylevels,andn eedformu lt iple,h igh -cost servicescer tainly,contr ibu tetoah igh er levelofqu alit yofcarean dtoalower lev eloffin an cialriskforthe care p rov ider .
DATA MANAGEMENT AND TECHNOLOGY

Advancedte chnology isesse ntialin the curre ntcomplicate dhealth care in dustr y,withitsnee dfor managin gen ormou samou ntsofdetailedandcomplexpatient information.Th eestablishmen tofdisease management h aspromote dthe need forincre asinglypowe rfulan dsoph ist icatedte chnologyt hat can supp ort multipledeman ds.Techn ologyisanimportantt oolindiseasemanagementandh asact ually becomeacriticaleleme ntforach ie vin gthe following: Est ablish me ntofadat a-management systemwith dat acollection /down load c apacityanddatamin in g ofamu lt itu deofdive rseandcompre hen sive patien tdat abase sthatallowcar eprovid erstocollate an dan alyzemultiple t ypesofdata,includingclin ical, in suranceclaims,utilization ,pharmacy, pat ie ntsu rvey, referr al,an dmarketing information(88). Imple men tat ionofacommunicationn etworkth atprovidesth eme ans forcareprovidersandpat ie nts tomain tainst ron gin teractiverelationsh ips. Acommu nicationnet work mayin clu deinter activeemail, v oicemail, Web-base dapplication s,orInte rnet application s(98). Inst itu tion oftrackingandmonitoringsyst emst hat alertth ecar eprovide rwhen in div idu alpatien ts req uireat tent ionorinter vent ion.
Imple men tat ionofreliable reportingmechanismst ocareprovidersre gardingindividualand collectivepatient information.
Tech nologycan beuse dtoe nhanceman yelementsofadiabe tesdiseas e-manageme ntpr ogrambu t shouldnotbeconsider edthe ent ire prog ram.Techn ologycan accomplishmanyt hings: Cont ribu tepositiv ely t opr ovidingacomprehe nsivene twor kamon gcare prov ide rsan dpatien ts Pr ovideon-t imecapabilityforrece ivinginformation Pr ovideacent raldatabase forpatientdata Syste mat ize and aut omate thedatacollec tion, stor age, analy sis, andre por tin gfun ctions(98)
Tech nologyshouldnotbeu sedtosubstitu teforthe human in teraction andpe rson alrelat ionsh ipsth at existbe tween patien tsand carepr ovider sb utshouldbeint egratedintothe dise ase-man agemen t programtofacilitateandstre ngth enth ose componen ts(98).
PHYSICIAN SUPPORT FOR DISEASE MANAGEMENT

Disease-management prog ramshav easignificantpote ntialtoimproveoutcome sandr educe c osts. Howe ver, manyphy sician sremainwar yaboutparticip ating, andph ysicianresistanceison eofthet op th reere asonswhy d isease-man agement programsare notimpleme nted (94). Severalfactorsin flu ence
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th ephysician'spersp ective.Dise ase-man age men tprogramsar ebuilt on soph isticatedan dcomplex infrastruct urest hat supportfocusedandcompr ehen siv emanagementofach ron icdiseasean dyield posit ive out comes.Physicians r eportth atgiven thatsameinfrast ructu rewithout adisease -manage me nt ven dor they cou ldprodu ceeven moreimp ressiveimprovemen tsin ou tcome(94). Posit ive out comesare bas edon the physician'scommitment toandbeliefin the dise ase-man agemen tprogram.Ifphy sician s per ceiv ethatth edise ase-man age men tprogramred ucesth eircon trolover t heman agemen tofpatient car eor dilute sthe irr elation shipswith the irpatient s,the ywillnotaccept thep rogr am. Seve ralsuccessfactorsthatinflu enc ephysicianparticipation havebee nid entified.Fir st,str uctu rin gthe programoneviden ce-basedme dicine estab lishescr edibilityan damore positivere spon sebyphy sician s. Edu cating t heph ysicianabout thepr ogram, it svaluetoth epat ien t,itssup port ofth ephysician 'srole in th ecoordination ofcar e,an ditsvalue t oth ephy sician isanimportantelemen t(94).Maximizingth e oppor tun itiesforphys ician stoh aveinp utinth edeve lopme nt, imple men tat ion, ande valuationofthe programhe lpst hembecome morecomfortable with theconce ptofdiseasemanagement. Modifyin gthe programacc ordingt oph ysician in putorpracticesbuildssupport. Demon stratedsu ccessofpositiv e outcome sin previou sactivitiesen cou ragesp hysicianstopar ticipat e.Str uctu rin gthe progr amsoth att he phy sician trulyownsan dchampion sthe programisanelement forsu ccess(98).The impetu softh e programshouldbet osu pport and st ren gthen the physician-patientr elation ship.The foun dat ionofan effect ive dise ase-man agemen tprogramthatwillfin dgreatersu ppor tamon gphysiciansisbuilton a tru stingrelationsh ipt hat Advocate sforth ewelfare andcareofthe patien t Rec ogn ize sandv aluesth eimportanceandcommit men toft heph ysiciantothe su ccessofthe program
Uph oldsth eau ton omyoftheph ysicianan dthe physician'scon trolovert hecareofthepatient Value sandincorporat esthe physician'sperspe ctivein tothed evelopmen tan dimpleme ntationofthe program Pr ovidesout comesth atarevalue -adde dasident ifiedasimport ant byphysiciansandpatients.
LIFESTYLE MODIFICATIONS AND PSYCHOSOCIAL ISSUES

Diabetesisach ron icdiseaseth ataffe ctsth epatien tphysically,psych ologically,socially, spir itu ally, cognitively,an deconomically .Itre quiresacarefu lbalanceofactivities,24-hour -a-day P. 790 management ,an dsign ifican tlifest yle chan ges.Livingwellwith diabete smeanscombiningalifelon g commit men ttomain tainingalifesty let hat balance ssou ndnu trition al,act ivity, andover allh ealthh abits withadhere ncetoast rict med ical-man agemen tregime n.Patien tswit hdiabet eslivewith itallday ,ever y day .Thepe rson 'sse lf-est eem,sen seofinde pende nce, andse lf-imageallexpe rie nceen or mousstr ainas hisorher lifestyleun dergoessignificant modificat ionsandalte rations.Providingsy stems,processes, and supp ort sthatassistth epatien ttole arnse lf-man agemen tofdiabe tesisan impor tan tfactorinth e he althcareplan . Edu cationreg ardingse lf-management andlifestylemodific ation isacrit icalcomp on entinh elpin g pat ie ntstakecontr olofdiabe tesan ditsimpact on t heirlive s.Edu cationab out managing diabetesis about masteringawide ran geofn ewskillsan dactivitie s,aswe llasabou tadaptingtolifewithachronic disease (99).Patientsarefacedwit hlearn in gself-manag eme ntskills, includ in gmonitorin gbloodglu cose levels,plan ningmeals,sch edulingmealsan dmed ications, and maint ainingex erciseprograms.The yalso ar efaced with thech alle ngeofle arn in gtop rioritizecommit men ttoatre atmen tplanoverothe r act ivities,t oman ageu nexpe ctedev ents ,todevelop con tin gency plans,t okn owwhe ntocon tact supp ort ive resources, an dtomaintainete rnalvigilancetostaywell.E ffectiveedu cat ionindiabet esselfmanagement isassociate dwith manypositiv eou tcomes, in clu din gimprovement in patient s'ph ysicaland emot ionalh ealth, improvement in abilitytoach ie veglycemicandmetaboliccont rol,aredu ctionin hospitalizations,areduc tionindiabe tes-re latedh ealthcarecosts,andfewe racu tean dchronic complication s. Patient svie wd iabetesasan int egralpartinth etotalit yofth eirlive sandn otasasep arateen tit y(100). Whe ndeve lopingan edu cation alplan, itisimportanttocon siderseve raltype sofexpe rienceint he pat ie nts'lives:th eemot ionalex perience ,th ebehaviorale xperien ce,th eabilit ytomak ean dmain tain lifest yle chan ge,andth estageofd evelop men t. The e motion alexper ien ceofapat ie ntisastronginflue nceonth epat ie nt'sabilitytocopean dtolearn. Apat ien t'se motion alexper ien ceen compasse sthep atient 'semot ionsasrelate dtolifeeven tsan d relat ionsh ips, aswellasthe emotion alresponse toh avingdiabe tes, anditssu bseque nteffe cton lifean d th osee vent sand r elation ships(101). Th eemot ionalre spon setodiabete sencompassesmany comple x feelings:confusion,gr ief, ang er,de nial,ambivalence ,an dguilt .Patientsoften feelov erwhe lmedan dou t ofcont rol.Th ebeh avior ale xperien ceincludesallthe actionsthatth epat ien tne edstoemp loytodeal effect ive lywith d iabetesman agemen tan dallth eass ociate demotionsan datt itu des.C hronicdisease
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req uiresasignificant adap tationprocess,andstr on gcopingsk illsareimportantt oolsforth epat ien t (102). Unde rstandingth edeve lopme ntalst ageofthe patien tiscriticalindeve lopingaplan that add ressesth especificneed softh epat ien t.
THE PATIENT'S ROLE IN DIABETES MANAGEMENT

The p atient playsthe mostimportantrolein diabete smanage me nt.Pat ien tswithdiabe tesmustper ceiv e th emse lve sasact ive ,empowe redmembersoftheh ealth caret eaman dbeabletoacce ptresponsibility forself-manage men tan dfor adhe rin gtotreatme ntplan s(100).Th eremustb eacommit men tto un derst andingt hediseaseaswellaspossibleandawillingn esstocon tin ue t olearn.Th epatien t'sactive par ticipationinde cisionmakingan dplann in gtreatment asamemberoftheh ealth caret eamcon tribut es subst ant iallytosucce ssfulse lf-man agemen t.The patien tmu stbeab let och ange behaviorsandlear n ne wskillstobe abletofeelbette r,tobeh ealthier ,an d,insomecases,tosur vive .Workingwithth e teamt oset goalsfortre atment andbe haviorallowsth epat ie nttohavemore imme diatecontr olove r car ethatreflects h isorh erprefe renc esan dpriorities.The patien tnee dstomak eappr opriatedecision s, multiplet imes,onadailybasisaboutself-managementandtoact on t hosedecision saccordin gly (100). The p atient mu sthav estrongcommun ication skillsandasense ofassertiven esstobeabletoinformth e he althcarete amwh endifficultie sarise,wh encircu mstancesch an gethatimpactthe treatmentplan ,or whe nthe goalsforglycemiccont rolhavenotbe enmet.
ISSUES THAT AFFECT PROFICIENT SELF-MANAGEMENT

Ch ang esin behaviorandadju stmentsoflifelonghabit sand ch oicesaredifficu lt proce sses.The difficu ltiesofle arn in gnewskills, u nde rstan dinghowan dwhytocon trolachronicdisease ,an dmanaging alltheassociat edfeelingsoften leadtofr ustration and d iscouragement .Someissuest hat c ompou nd th esefee lingsarestre ss,bur nout, coexistingcommonpsych iatriccon dit ions[e. g.,de pression (103, 104,105)],ph ysicalilln ess,n egative fe edback,lackofempowermen t,andlackofself-e fficacy. Anyofthe sefact orscanexe rtaforcefu linfluen ceonsucce ssfulself-carebe hav ior.Th emoreconfiden ta per son fe elsaboutper formingself-care behaviors, the morelike lyh eorshewillper formthosebe hav iors (102). Consisten tabilityt ocopewithemotionalst ressesindailylifecanbe acritic alc ompon ent in a per son 'ssucce ssin achievingsign ifican tchan gesinlife style.The abilitytochangeandoverallbeh avior ar ereflectionsoft heper son 'slevelofmat urityandcognition. Aperson'sc apacityt omaintain a complicatedr egimen hasaneffe cton self-carebe havior.
ROLE OF THE CARE PROVIDER

The carepr ovider'srole istodete rmine howt osu ppor tthe patien t'sabilit ytobecomeacompete ntselfmanagerindiabe tescare.Sev eralimportantste psmaximizeth esupportapatien tnee dsforlearning self-management:(a)performin ganaccurateandcompre hen siv epatien tasse ssmen t,(b)de velopinga mutu allytr ustingr elation ship,(c)sett in greason ablean dach iev ablegoals,(d)facilitatingan opt imal learn in gexpe rie nce, and(e )basingth elearn ingexpe rie nceone mpowerment ofth epatien t. Un derstandingt heimpactoftheman ycomplexcompone ntsofaperson'slifeonth elearn in gprocessisa fun dament alele me ntindev elopingandimplement in geffectivete aching st rat egie sthatsupporte ach individ ual.Impor tan tin for mationabou tape rson 'sre adinessandabilitytole arn aboutself-management can beobtaine dbyath or ou ghasse ssmen tth atinclude s(a)evalu atingt hepatient'scurr enth ealth status;(b)e valuatin gthe patien t'spsych ologicalst atu s,ability t ocope, ande motion alwe ll-being;(c) asse ssin gthe patien t'scognitiveskillsan dlite racyleve l;(d)ex ploringth epat ie nt'slifeexpe riences, par ticularlyin managin gdiabete s;(e)dete rmining t heleve lofunde rstandingth epat ien thasabout diabet esan dself-care;(f)de terminingth epatien t'sr elation shipwith care prov ide rs;(g)asse ssin gthe pat ie nt'scultural, social,andeconomicbackgroundanden viron me ntalinfluen ces;an d(h)assessingth e pat ie nt'sprioritiesan din tere sts. Arelat ionsh ipbasedonrespe ct,tr ust, andu nder stan din gsupportsth elear ningprocess.It isth e resp on sibilityofth ecare prov ide rtoe stablishan on ju dgmental, supportiveen viron me nt th aten ablesth epat ie nttobeamotiv ated ,active p articipant in thelearninge xperienc e(103). Commun ication and acceptance ofth epatien t'sch oicesareesse ntialtoaproductivee xperien ce. Incorporat in gthe expect ation sand valuesofthe patien tin tot hete ach in gplanprovidesabasefrom whichth epatie ntcanbecome effectiveinse lf-management (106). Goalspr ovideafr amewor ktog uidethe patien tan dthecareprovideriniden tify in gthespe cifictasksand act ivitiesth atn eedtobeachieved. Goalsar ecriticalt oolsint helear ningprocessandshoulden compass th ecommitmen ttob ehaviorch ange nece ssaryforsucce ssfulself-man age men t.Patien tsnee dtofe el accoun tab leforach ie vement ofstatedgoals,an dthe yrespondt ogoalsthatar ein dividu aliz edan d incorpor ate theirpriorit ie s.Settingg oalsth ataremeasu rable, attain able,andactionorient edhe lpsth e pat ie nttohaveaclearun derstandingofwhat isex pected . Animportantr oleforthe carepr ovider istofacilitateanop timallearn in gexpe rie nceforth epatien t.A cur rent goalfordiabet esedu cation ist oprovideprogramsorteachingsessionsth atinte grat ethe P. 791
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clin ical, behavioral, andpsy chosocialelementsofdiabet escare andse lf-man agemen t(100).Th epur pose ofd iabetese ducationisnotsimplytodeliv erinfor mationabou tth eimportan ceofmanaging d iabetesbu t alsotopr ovideinformation thatsupports t hepatient'sability tomake in formedde cision s(99).The learn in gprocessisdesignedt oaddressandincorpor atet hepatient'slived experien cewit hdiabet es (100). Educ ation isacon tin uousandinter activepr ocesst hat assesse sande ncouragespat ien tsto expr essth eir con cernsandqu estion s,pre sentsinformation thatadd ressesth ose issu es,andre vie ws strategiestodealwitht hebe havioralaspe ctsofman agingth eseissue sandconce rns. Pat ien tsar emore like lyt obee ngagedpar ticipantsinap roce ssthatisbasedonth eir exper ien cesan dconcern sand is per son allyre le van t.Empowermentisan importan tconceptt hat requ ire sther edesignoftrad itional methodsforproviding p atient education .Thee mpowerment modelpost ulatest hat thepatient is resp on sibleforproviding andman agingth emajorityofdiabet escare and isth usnotap assive par ticipantbu tthe cente rofde cisionmakingan dcon trolindailyman agemen tand treatme nt(102).As mentionede arlie r,th ehe althcareteamisresp on sibleforproviding t hepatientwith in formationen ablin g th epat ien ttomakeinforme ddecisions. Th epat ie nthasbot hth erightandth eresponsibilityt oper form inth eroleofequ alpartn erinth etre atment prog ram(101).It isth eresponsibilityofthe healt hcar e teamt oprovidean dfost eran env ironmen tthatsupportst hepatient'sdeve lopme ntordiscove ryoft he cap acitytoactivelysolve prob lemsofd iabetescare, t husr ein for cin gthe se nseofself-efficacyan d accoun tab ilit y.
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Chapter34 General Approach to the Treatment of Diabetes Mellitus

DIABETES AS A WORLDWIDE HEALTHCARE PROBLEM

CHANGING DIAGNOSTIC CRITERIA FOR DIABETES

The Patient History

1. HBA 1 c ,6. 0%to7.0%;orHbA 1 ,7%t o9%

Self-Monitoring of Blood Glucose

Glycosylated Hemoglobin Assays

Copyright (c)2000-2006OvidTech nologies,Inc. Version:rel10.4.1, Sou rceID1.12596.1. 143

Chapter35 Education in the Treatment of Diabetes

WHY IS SELF-MANAGEMENT EDUCATION IMPORTANT IN THE TREATMENT OF DIABETES?

Education Improves Well-Being and Quality of Life

Education Improves Self-Care Management

Education Improves Metabolic Control

Education Enhances the Prevention and Early Detection of Complications

Education Decreases Costs of Care

THE DIABETES EDUCATION PROGRAM

The Setting for Education

Times 7:30 8:00a.m. 8:00 9:15a.m. X

Check-in Choosefrom breakfastbuffet Computertime DiabetesKnow-how

Check-in Choosefrom breakfastbuffet Computertime BloodGlucose Interpretation

p.m. Lab 12:00 12:15 p.m. 12:15 1:00p.m. 1:00 2:00p.m. X X

Choosefromlunch buffet Exerciseclass

Choosefromlunch buffet Exercise Class/familysupport group SkillsTraining(as needed) Check-outwithcase manager

Choosefromlunch buffet BringingItall Together

SkillsTraining(as needed) Check-outwithcase manager

Who Should Be Educated

When Education Should Take Place

ONSET OF COMPLICATIONS AND OTHER MAJOR POINTS OF CHANGE

MAXIMIZING THE EFFICACY OF EDUCATION

Copyright (c)2000-2006OvidTech nologies,Inc. Version:rel10.4.1, Sou rceID1.12596.1. 143

Chapter36 Medical Nutrition Therapy

A BRIEF HISTORY OF NUTRITION AND DIABETES

GOALS OF MEDICAL NUTRITION THERAPY

Distribution of calories (%)

Year Before 1921 1921 1950 1971 1986 1994

Protein Starvation diets 10 20 20 1220 1020

20 40 45 <60 Basedonnutritionalassessment andtreatmentgoals

70 70 35 <30 Basedonnutritionalassessmentand treatmentgoals;<10%ofcaloriesfrom

Bloodglucoselevelsasnearnormalaspossibletosafelypreventorreducetheriskforcomplicationsof diabetes Optimalserumlipidprofiletoreducetheriskformacrovasculardisease Bloodpressurelevelsthatdecreasetheriskformacrovasculardisease

Copyright2003AmericanDiabetesAssocation.FromAmericanDiabetesAssociation.Evidence-based nutritionalprinciplesandrecommendationsforthetreatmentandpreventionofdiabetesandrelated complications.Diabetes Care2003;26:S51.ReprintedwithpermissionfromtheAmericanDiabetesAssociation.

Goals in Type 1 Diabetes

Goals in Type 2 Diabetes

th rou ghph ysicalactivit yfort hosewhoare ove rweightandinsulinresistant

Estimating caloric intake Basalcalories:10kcal/lbdesirablebodyweight Addcaloriesforactivity Ifsedentary,add10%ofestimatedbasecalories Ifmoderatelyactive,add20%ofestimatedbasecalories

AdaptedfromVinikA,WingRR.Nutritionalmanagementofthepersonwithdiabetes.In:RifkinH,PorteDJr, eds.Diabetes mellitus,4thed.NewYork:Elsevier,1990.

TABLE 36.4. Body

128 132 136 140 144 148 152 156

135 139 143 147 151 155 160 164

142 146 150 154 159 163 168 172

149 153 157 162 166 171 176 180

155 160 165 169 174 179 184 189

162 167 172 177 182 186 192 197

169 174 179 184 189 194 200 205

176 181 186 191 197 202 208 213

182 188 193 199 204 210 216 221

189 195 200 206 212 218 224 230

196 202 208 213 219 225 232 238

203 209 215 221 227 233 240 246

209 216 222 228 235 241 248 254

216 222 229 235 242 249 256 263

223 229 236 242 250 256 264 271

230 236 243 250 257 264 272 279