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Pathogenesisoftype1diabetesmellitus

Author: MassimoPietropaolo,MD
SectionEditor: IrlBHirsch,MD
DeputyEditor: JeanEMulder,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Feb2017.|Thistopiclastupdated:Oct11,2016.

INTRODUCTIONType1Adiabetesmellitusresultsfromautoimmunedestructionoftheinsulinproducing
betacellsintheisletsofLangerhans[1].Thisprocessoccursingeneticallysusceptiblesubjects,isprobably
triggeredbyoneormoreenvironmentalagents,andusuallyprogressesovermanymonthsoryearsduring
whichthesubjectisasymptomaticandeuglycemic.Thus,geneticmarkersfortype1Adiabetesarepresent
frombirth,immunemarkersaredetectableaftertheonsetoftheautoimmuneprocess,andmetabolicmarkers
canbedetectedwithsensitivetestsonceenoughbetacelldamagehasoccurred,butbeforetheonsetof
symptomatichyperglycemia[2].Thislonglatentperiodisareflectionofthelargenumberoffunctioningbeta
cellsthatmustbelostbeforehyperglycemiaoccurs(figure1).Type1Bdiabetesmellitusrefersto
nonautoimmuneisletdestruction(Type1Bdiabetes).(See"Classificationofdiabetesmellitusandgenetic
diabeticsyndromes".)

Thepathogenesisoftype1Adiabetesisquitedifferentfromthatoftype2diabetesmellitus,inwhichboth
decreasedinsulinrelease(notonanautoimmunebasis)andinsulinresistanceplayanimportantrole.
Genomewideassociationstudiesindicatethattype1andtype2diabetes'geneticlocidonotoverlap,
althoughinflammation(eg,interleukin1mediated)mayplayaroleinisletbetacelllossinbothtypes[3].(See
"Pathogenesisoftype2diabetesmellitus".)

Thepathogenesisoftype1diabetesmellituswillbereviewedhere.Thediagnosisandmanagementoftype1
diabetesarediscussedseparately.(See"Epidemiology,presentation,anddiagnosisoftype1diabetes
mellitusinchildrenandadolescents"and"Preventionoftype1diabetesmellitus"and"Managementoftype1
diabetesmellitusinchildrenandadolescents"and"Associatedautoimmunediseasesinchildrenand
adolescentswithtype1diabetesmellitus".)

GENETICSUSCEPTIBILITYPolymorphismsofmultiplegenesarereportedtoinfluencetheriskoftype
1Adiabetes(including,HLADQalpha,HLADQbeta,HLADR,preproinsulin,thePTPN22gene,CTLA4,
interferoninducedhelicase,IL2receptor(CD25),alectinlikegene(KIA0035),ERBB3e,andundefinedgene
at12q)[410].Ametaanalysisofdatafromgenomewideassociationstudiesconfirmedtheabove
associationsandidentifiedfouradditionalriskloci(BACH2,PRKCQ,CTSH,C1QTNF6)associatedwithan
increasedriskoftype1diabetes[11].

Inaddition,somelociconferringsharedriskforceliacdisease(RGS1,IL18RAP,CCR5,TAGAP,SH2B3,
PTPN2)havebeenidentified[12].Mostlocihavesmalleffects,andthevariantsstudiedarecommon.The
CCR5associationisofinterestinthata32basepairinsertiondeletioninachemokinereceptor,CCR5,
resultsinalossoffunctionand,whenhomozygous,atwofolddecreaseinriskoftype1diabetes.(See'MHC
genes'belowand'NonMHCgenes'belowand'Associationwithotherautoimmunediseases'below.)

Genesinboththemajorhistocompatibilitycomplex(MHC)andelsewhereinthegenomeinfluencerisk,but
onlyhumanleukocyteantigen(HLA)alleleshavealargeeffect,followedbyinsulingenepolymorphismsand
PTPNN22.AlthoughtheassociationofcertainHLAalleleswithtype1diabetesisstrong,thisgeneticlocusis
estimatedtoaccountforlessthan50percentofgeneticcontributionstodiseasesusceptibility.The

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associationsofotherlociareofamagnitudethatdonotcontributetopredictionofdiseasebutmayimplicate
importantpathways,suchasCCR5.

Inparticular,itisestimatedthat48percentofthefamilialaggregationcannowbeascribedtoknownloci,and
theMHCcontributes41percent[6].Asanexample,siblingswiththehighestriskHLADRandDQalleles(eg,
DR3/DR4heterozygotes),whoinheritbothHLAregionsidenticalbydescenttotheirdiabeticsibling,mayhave
ariskofdevelopingantiisletautoimmunityashighas80percentandasimilarlongtermriskofdiabetes[13].

Thelifelongriskoftype1diabetesismarkedlyincreasedincloserelativesofapatientwithtype1diabetes,
averagingapproximately6percentinoffspring,5percentinsiblings,and50percentinidenticaltwins(versus
0.4percentinsubjectswithnofamilyhistory)[1,14,15].Amonozygotictwinofapatientwithtype1diabetes
hasahigherriskofdiabetesthanadizygotictwin,andtheriskinadizygotictwinsiblingissimilartothatin
nontwinsiblings[14].

MHCgenesThemajorsusceptibilitygenesfortype1diabetes(calledIDDM1fortheMHClocus)areinthe
HLAregiononchromosome6p[16,17].ThisregioncontainsgenesthatcodeforMHCclassIImolecules
expressedonthecellsurfaceofantigenpresentingcellssuchasmacrophages.TheseMHCmolecules
consistofalphaandbetachainsthatformapeptidebindinggrooveinwhichantigensinvolvedinthe
pathogenesisoftype1diabetesarebound.MHCbindingofantigenallowsittobepresentedtoantigen
receptorsonTcells,whicharethemaineffectorcellsofthedestructiveautoimmuneprocess(figure2).(See
"Majorhistocompatibilitycomplex(MHC)structureandfunction".)

TheabilityoftheseclassIImoleculestopresentantigensisdependentinpartupontheaminoacid
compositionoftheiralphaandbetachains.Substitutionsatoneortwocriticalpositionscanmarkedlyincrease
ordecreasebindingofrelevantautoantigensandthereforethesusceptibilitytotype1diabetes[18,19].In
particular,morethan90percentofpatientswithtype1diabetescarryeitherHLADR3,DQB1*0201(also
referredtoasDR3DQ2)orDR4,DQB1*0302(alsoreferredtoasDR4DQ8),versus40percentofcontrols
witheitherhaplotypefurthermore,approximately30percentofpatientshavebothhaplotypes(DR3/4
heterozygotes),whichconfersthegreatestsusceptibility[17].

Theprevalenceofthishighriskgenotypeisremarkablyhighinsomepopulations.Asanexample,8.9percent
ofhealthywhiteteenagersinWashingtonstatehavetheDR4,DQB1*0302/DR3,DQB1*0201genotypeand2.4
percentofthegeneralpopulationofDenver,Colorado.Approximately5percentofchildrenwiththisgenotype
developtype1Adiabetesversusapproximately0.3percentofchildrenoverall[19,20].AsubsetofDR4
alleles,suchasDRB1*0403andDPB1*0402,decreasetheriskofdevelopmentofdiabetes,evenwiththe
highriskDQB1*0302allele[21,22].

Inaddition,theHLAalleleDQB1*0602confersprotectionagainstthedevelopmentoftype1diabetes.This
alleleispresentinapproximately20percentofthegeneralUSpopulation,butonly1percentofchildren
developingtype1Adiabetes.Oneprospectivestudyevaluated72relativeswithisletcellantibodies(ICA),75
percentofwhomcarriedthehighriskallelesDQB1*0302and/or*0201[23].Diabetesdevelopedin28ofthe
64subjectswhodidnothavetheDQB1*0602alleleversusnoneoftheeightwithit.NoothercommonDQ
alleleprovidessuchdramaticprotection.

Theprevalenceofthesegenesvarieswithethnicity,andexplainstoalargedegreewhytype1diabetesis
relativelycommoninScandinaviaandSardinia,butuncommoninChina(figure3).

NonMHCgenesAlthoughimportant,theMHCsusceptibilitygenesarenotsufficienttoinducetype1
diabetes,suggestingpolygenicinheritanceinmostcases[16].Animportantcomponentofthesusceptibilityto
type1diabetesresidesincertainnonMHCgenesthathaveaneffectonlyinthepresenceoftheappropriate
MHCalleles.

Inparticular,polymorphismsofapromoteroftheinsulingeneandanaminoacidchangeofalymphocyte
specifictyrosinephosphatase(termedlyp,PTPN22)areassociatedwiththeriskoftype1diabetesinmultiple
populations[2427].Arepeatsequenceinthe5'regionoftheinsulingeneisassociatedwithgreaterinsulin

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expressioninthethymusanditishypothesizedthatthiscontributestodecreasingthedevelopmentof
diabetes[28].Thepolymorphismoftheproteintyrosinephosphatase(PTP)geneinfluencesTcellreceptor
signaling,andthesamepolymorphismisamajorriskfactorformultipleautoimmunedisorders[29,30].

ApolymorphisminthecytotoxicTlymphocyteassociatedantigen4genewasshowntobeassociatedwith
theriskoftype1diabetesinametaanalysisof33studiesinvolvingover5000patients[31].

AdditionalevidencefortheroleofnonMHCgenescomesfromstudiesinNODmice(nonobesediabeticmice,
amajormodeloftype1Adiabetes).Thesemicedevelopspontaneousautoimmunediabeteswithstriking
similaritiestotype1diabetesinhumans[32].AutoimmuneinfiltrationoftheisletsofLangerhans(insulitis)
beginsatapproximately50daysofageandclinicaldiabetesappearsatapproximately120days.

InterferongammapositiveTcells(Th1cells)appeartobeanimportantmediatoroftheinsulitisinNODmice,
anddestructionoftheisletcellscanbeslowedbytheadministrationofantiinterferongammaantibodies.
Interferongammainducingfactor(IGIFalsocalledinterleukin18)andinterleukin12arepotentinducersof
interferongamma,andtheprogressionofinsulitisbeginsinparallelwithincreasedreleaseofthesetwo
cytokines[33].

Itwasinitiallythoughtthat,incontrasttoTh1cells,Th2cells(whichproduceinterleukin4,5,10,and13)
protectedagainsttheonsetandprogressionoftype1diabetes.However,Th2cellsalsoarecapableof
inducingisletcelldestructionand,therefore,theonsetandprogressionoftype1diabetesareprobablyunder
thecontrolofbothTh1andTh2cells[34].

Amoregeneralizableconceptisthattype1Adiabetesispreventedbyabalancebetweenpathogenicand
regulatoryTlymphocytes[35].AmajorsubsetofregulatoryTlymphocytestermedregulatoryTcells(Tregs)
expressthemarkersCD4andCD25ontheirsurfaceandlacktheIL7receptor.Tregsgenerallysuppressor
downregulateinductionandproliferationofeffectorTcellsandaredependentfordevelopmentupona
transcriptionfactortermedFOXP3.MutationsofFOXP3leadtolethalneonatalautoimmunity,includingtype1
diabetesinneonates.Thiscondition,thoughextremelyrare(see"IPEX:Immunedysregulation,
polyendocrinopathy,enteropathy,Xlinked"),isimportanttorecognizeasbonemarrowtransplantationcan
reverseit[36].(See"Overviewofautoimmunity",sectionon'Pathogeneticmechanisms'.)

STAT3mutationshavebeenidentifiedasamonogeniccauseofautoimmunity,includingtype1diabetes[37].
DenovogermlineactivatingSTAT3mutationsareassociatedwithaspectrumofearlyonsetautoimmune
disease,suchastype1diabetes,autoimmunethyroiddysfunction,andautoimmuneenteropathy.These
findingsemphasizethecriticalroleofSTAT3inautoimmunediseaseandcontrastwiththegermline
inactivatingSTAT3mutationsthatresultinhyperimmunoglobulinE(IgE)syndrome.(See"Autosomal
dominanthyperimmunoglobulinEsyndrome".)

AUTOIMMUNITYIsletcellautoantibodies(ICAs)werefirstdetectedinserumfrompatientswith
autoimmunepolyendocrinedeficiencytheyhavesubsequentlybeenidentifiedin85percentofpatientswith
newlydiagnosedtype1diabetesandinprediabeticsubjects[1].Radioassaysareavailabletodetect
autoantibodies,whichreactwithspecificisletautoantigens.(See"Predictionoftype1diabetesmellitus".)

Childrenwithtype1diabeteswhodonothaveisletcellorotherautoantibodiesatpresentationhaveasimilar
degreeofmetabolicdecompensationasdochildrenwhohavetheseantibodies,althoughthosewithmoreof
thedifferenttypesofantibodiesappeartohavethemostacceleratedisletdestructionandahigher
requirementforexogenousinsulinduringthesecondyearofclinicaldisease[38].AfewpatientsfromJapan
withoutobviousevidenceofisletautoimmunityhavebeendescribedinwhomtheonsetofhyperglycemiawas
abrupt,A1C(glycosylatedhemoglobinvalues)werenormal,andserumpancreaticenzymeconcentrations
werehigh[39].Itisnotclearwhetherthesepatientshadanunusuallyabruptonsetofautoimmunetype1A
diabetesornonautoimmuneisletdestruction(type1Bdiabetes),thoughwithstudiesindicatinghighrisk
humanleukocyteantigen(HLA)allelesintheseindividuals,rapidtype1Adiabetesintheabsenceofislet
autoantibodiesisapossibility.

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TargetautoantigensAnongoingsearchhasidentifiedseveralautoantigenswithinthepancreaticbeta
cellsthatmayplayimportantrolesintheinitiationorprogressionofautoimmuneisletinjury(table1)[1,40].
StudiesontheNOD(nonobesediabetic)mousemodelindicatethatproinsulin/insulinitselfisthelikelyprimary
targetfortheautoantibodies[41,42].Theautoimmuneresponsetoproinsulinsubsequentlyspreadstoother
autoantigens,suchasisletspecificglucose6phosphatasecatalyticsubunitrelatedprotein(IGRP),whichis
downstreamoftheimmuneresponsetoinsulin[42].DiabetesintheNODmousecanbeeliminatedby
changingaspecificaminoacidofinsulin[41].

Otherimportantautoantigensareglutamicaciddecarboxylase(GAD),insulinomaassociatedprotein2(IA2
andIA2beta),andtheautoantigenZnT8,azinctransporterofisletbetacells[4346].(See"Predictionof
type1diabetesmellitus",sectionon'Immunologicmarkers'.)

InsulinTheearlyappearanceofantiinsulinantibodiessuggeststhatinsulinisanimportantautoantigen
[47,48].DirectconfirmationofthishypothesishascomefromstudiesinNODmice.PathogenicCD8+Tcell
clonerecognizesanepitopeontheinsulinBchain[49]andamajortargetautoantigenforCD4TcellsofNOD
miceisinsulinpeptideBchainaminoacids9to23[41].SimilarTcellresponsesarefoundinperipheral
lymphocytesobtainedfrompatientswithrecentonsettype1diabetesandfromsubjectsathighriskforthe
diseasehavealsobeenreported[50].

Alsoconsistentwiththeimportanceofinsulinasanautoantigenisthedemonstrationthatknockoutsofthe
insulingenesinNODmicegreatlyinfluenceprogressiontodisease[51],andtheadministrationofinsulinorits
Bchainduringtheprediabeticphasecanpreventordelaydiabetesinsusceptiblemiceandperhapsin
humans.(See"Preventionoftype1diabetesmellitus",sectionon'Insulin'.)

Insulinautoantibodiesareoftenthefirsttoappearinchildrenfollowedfrombirthandprogressingtodiabetes,
andarethehighestinyoungchildrendevelopingdiabetes.Ofnote,onceinsulinisadministered
subcutaneously,essentiallyallindividualsdevelopinsulinantibodies,andthusinsulinautoantibody
measurementsafterapproximatelytwoweeksofinsulininjectionscannotbeusedasamarkerofimmune
mediateddiabetes(type1A)[48].

GlutamicaciddecarboxylaseAnotherimportantautoantigenagainstwhichantibodiesaredetectedis
theenzymeGAD,whichispresentintheisletsaswellasinthecentralnervoussystemandtestes[43].
AntibodiestoGAD(a65kDprotein)arefoundinapproximately70percentofpatientswithtype1diabetesat
thetimeofdiagnosis.

AutoantibodiesreactingwithGAD(antiGAD65antibodies)areprominentinhumanswithtype1diabetes.In
contrast,theNODmousedoesnotappeartoexpressGADautoantibodies[52]butdoesexpressinsulin
autoantibodies[53].NODmicerenderedtoleranttoGADdevelopdiabetes.ThiscoupledwithlackofGAD
expressionbymouseisletshascastdoubtonitsimportanceasapathogenicautoantigeninthismodel,
althoughinjectionsofGADpeptidesslowprogressiontodiabetes[54].

Insulinomaassociatedprotein2Anotherautoantigenisaneuroendocrineproteincalledinsulinoma
associatedprotein2(IA2),whichisaproteintyrosinephosphataserelatedprotein[44,45].IA2isgranule
membraneprotein,whosecytosolicdomainbindsbeta2syntrophin,anFactinassociatedprotein,andis
cleavedupongranuleexocytosis.Theresultingcleavedcytosolicfragment,ICA512CCF,reachesthenucleus
andupregulatesthetranscriptionofgranulegenes,includinginsulinandICA512[55].Inonestudy,antibodies
tothisantigenwerefoundintheserumof58percentofpatientswithtype1diabetesatthetimeofdiagnosis
[56].AutoantibodiestoIA2usuallyappearlaterthanautoantibodiestoinsulinandGAD,andarehighly
associatedwithexpressionofmultipleantiisletautoantibodiesandprogressiontodiabetes.Oneofthebest
predictorsofprogressiontotype1Adiabetesisexpressionoftwoorthreeautoantibodies:GAD,IA2or
insulinautoantibodies[57].

ZinctransporterZnT8Thecationeffluxzinctransporter(ZnT8)hasalsobeenidentifiedasa
candidatetype1diabetesautoantigen[46].Sixtyto80percentofpatientswithnewlydiagnosedtype1
diabeteshaveZnT8autoantibodies.Inaddition,26percentofsubjectswithantibodynegative(insulin,GAD,
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IA2andICA)type1diabeteshaveZnT8autoantibodies.Inchildrenfollowedfrombirthtothedevelopmentof
diabetesintheDiabetesAutoimmunityStudyintheYoung(DAISY)study,ZnT8autoantibodiesappearlater
thaninsulinautoantibodies[46],andtheantibodyistypicallylostveryearlyaftertheonsetofdiabetes[58].

Othertype1diabetesrelatedautoantigensAsautoimmunityintype1diabetesprogressesfrom
initialactivationtoachronicstate,thereisoftenanincreaseinthenumberofisletautoantigenstargetedbyT
cellsandautoantibodies.Thisconditionistermed"epitopespreading."Severalobservationsindicatethatislet
autoantibodyresponsesdirectedtomultipleisletautoantigensareassociatedwithprogressiontoovert
disease[57].Anumberofadditionaltype1diabetesrelatedautoantigenshavebeenidentified,whichinclude
isletcellautoantigen69kDa(ICA69),theisletspecificglucose6phosphatasecatalyticsubunitrelatedprotein
(IGRP),chromograninA(ChgA),theinsulinreceptor,heatshockproteins,theantigensjunB,16,CD38,
peripherinandglialfibrillaryacidicprotein(GFAP)[59].

Ithasbeenhypothesizedthatearlyautoimmunityinspontaneoustype1diabetescanalsotargetnervous
systemtissueelements,raisingtheconceptthatintype1diabetespathogeneticimmuneresponsesmayalso
benonbetacellexclusive[60].However,itremainstobeestablishedastowhetherornotthepresenceof
serologicresponsestoputativeneuronalantigensarepredictiveofthedevelopmentofsmallfiberneuropathy
(autonomicand/orsomatic)andfortheprogressiontoclinicaltype1diabetes.

RoleofcellularimmunityTheexistenceofIgGimmunoglobulinsdirectedtoepitopesofislet
autoantigensimpliestheinfluenceofTcellparticipationintheautoimmuneresponse.Whiletheroleof
autoimmunityinthepathogenesisoftype1diabetesandthefrequentdevelopmentofautoantibodiesarenot
inquestion,thereisincreasingevidenceforamajorroleofcellularimmunity.Theoccurrenceoftype1
diabetesina14yearoldboywithXlinkedagammaglobulinemiasuggeststhatBcellsarenotrequiredforthe
developmentofthedisorderandthatthedestructionofpancreaticbetacellsismediatedprincipallybyTcells
[61].

Theobservationthatthisboydidnotdevelopthedisorderuntilage14yearsmightimplythatnormalBcells
facilitatethedevelopmentofdiabetes,butarenotabsolutelynecessary.ThisissupportedbyastudyofNOD
mice,whichfoundthatwhenthemicewererenderedabsolutelydeficientinBcells,theincidenceofdiabetes
infemalemicedroppedfrom80percentto30percent,andthediseasedevelopedlaterinlife[62].Other
groupshavereportedalmostcompleteprotectionifautoantibodiesareabsent[63].

NaturallyprocessedepitopesofisletcellautoantigensrepresentthetargetsofeffectorandregulatoryTcells
incontrollingpancreaticbetacellspecificautoimmuneresponses[64].Inparticular,naturallyprocessedHLA
classIIallelespecificepitopesrecognizedbyCD4+Tcells,correspondingtotheintracellulardomainofIA2,
wereidentifiedafternativeIA2antigenwasdeliveredtoEBVtransformedBcellsandpeptideselutedand
analyzedbymassspectrometry[65].Furthermore,dendriticcellsubsetscanprocessandpresentsolubleIA
2toCD4+Tcellsaftershorttermculture,butonlyplasmacytoiddendriticcellsenhance(byasmuchas100
percent)autoantigenpresentationinthepresenceofIA2autoantibodypatientserum[66].Theplasmacytoid
subsetofdendriticcellsisoverrepresentedinthebloodclosetotype1diabetesonsetandshowsadistinctive
abilitytocaptureisletautoantigenicimmunecomplexesandenhanceautoantigendrivenCD4+Tcell
activation.ThissuggestsasynergisticproinflammatoryroleforplasmacytoiddendriticcellsandIA2
autoantibodiesintype1diabetes.Takentogether,theseobservationsmayleadtoidentificationofnovel
naturallyprocessedepitopesrecognizedbyCD4+Tcells,whichmayrepresentpotentialtherapeuticagents,
eitherinnativeformorasantagonisticalteredpeptideligands,forthetreatmentoftype1diabetes.

MolecularmimicryInitiatingfactorsoftheimmuneresponsearenotwellunderstood.Onepossibilityis
molecularmimicryduetohomologybetweenGADandaninfectiousagentsuchasCoxsackieBvirus(see
'Roleofviruses'below).Astudyoftheexpressionofabetacellspecific38kDaproteininratsprovidesan
alternativemodelforhowthismightoccur[67].Thisproteinisexpressedintheisletsatbirthandatalltimes
thereafterinstrainsthatareresistanttothedevelopmentofdiabetes,butisnotexpresseduntilday30in
diabetespronebiobreeding(BB)rats.Delayedexpressionofthisproteinmayleadtolossofselftolerance
andtheinitiationofanantibetacellautoimmuneresponse.
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TheroleofthethymusandlymphoidorgansThereisevidencetosuggestthatselfantigensare
naturallyexpressedinthethymusandperipherallymphoidorgans[6870].Tolerancetotissuerestrictedself
moleculesisbelievedtobeginatthelevelofthethymuswithnegativeselectionwherethedeletionof
thymocyteswithTcellreceptors(TCR)exhibitingstrongaffinitytowardsselfmoleculesareexpressedduring
maturationoftheimmunesystem[7173].Theinsulingeneisoneofthemostwidelystudiedgenesinboth
humansandmiceexhibitingthymicexpressionaswellasabetacellexpressiondependentassociationwith
type1diabetessusceptibility[41,69,7476].Forinstance,inhumanstheIDDM2susceptibilitylocusofthe
insulingene(INS)isaregionassociatedwithtype1diabetesandhasbeenfinelymappedtorevealVariable
NumberofTandemRepeat(VNTR)polymorphismsupstreamoftheINSpromoter.Thelengthofthese
repeatshasbeendirectlyimplicatedinthecontroloftheexpressionlevelsofinsulinmRNAinthethymus[76
79].Inadditiontoinsulin,isletcellautoantigen69kDa(ICA69),aneuroendocrineproteintargetedby
autoimmuneresponsesinhumanT1Dandinnonobesediabetic(NOD)mice[8082],isalsoexpressedinthe
thymus,andthelikelihoodthatthymiclevelsofICA69willaffectsusceptibilitytoT1Dthroughamechanism
similartothatshownfortheinsulinVNTRshasbeensuggested[69,83].Thishypothesisisprimarilybasedon
previousstudiesindicatingthatIA2,GAD,andICA69aretranscribedinthehumanthymusthroughoutfetal
lifeandchildhood[69,77,84,85],andthattheexistenceofDNAsequencevariationinNODmicewiththe
potentialforfunctionallyrelevanteffectsonIca1geneexpressioninthethymus.SuchvariationsintheIca1
promotermightleadtoanincreasedprobabilityoffailuretonegativelyselectICA69reactiveTcellclonesof
developingthymocytes[85].

ReversalofdiabetesinanimalmodelsReversaloftype1diabeteswithadministrationofcomplete
Freund'sadjuvant,animmunemodulator,hasbeenreportedinupto32percentoftreateddiabeticmice[86
88].Thisrecoveryisbelievedtobeduetoimmunomodulationofanunderlyingautoimmunecondition,
allowingproliferationofsmallnumbersofsurvivingisletcellsandrestorationofthebetacellmassinthe
mousepancreas.ArelatedadjuvantregimenusedinhumantrialsdidnotdelaylossofCpeptidesecretion
andotherimmunemodulators.Theimmunosuppressantmycophenolatemofetil,antiCD3antibody,andanti
CD20monoclonalantibodyareunderinvestigation[89,90].(See"Preventionoftype1diabetesmellitus",
sectionon'Preventionandreversalstrategies'.)

AssociationwithotherautoimmunediseasesPatientswithtype1diabetesareatincreasedriskfor
developingotherautoimmunediseases,mostcommonlyautoimmunethyroiditisandceliacdisease.This
associationisreviewedbrieflybelowandinmoredetailseparately.(See"Associatedautoimmunediseasesin
childrenandadolescentswithtype1diabetesmellitus".)

Thyroidautoimmunityisparticularlycommonamongpatientswithtype1Adiabetes,affectingmorethan
onefourthofindividuals,and2to5percentofpatientswithtype1diabetesdevelopautoimmune
hypothyroidism.(See"Associatedautoimmunediseasesinchildrenandadolescentswithtype1diabetes
mellitus",sectionon'Thyroidscreening'.)

Transglutaminaseautoantibodiesarepresentinapproximately10percentofpatients,andhalfofthese
patientshavehighlevelsoftheautoantibodyandceliacdiseaseonbiopsy[91,92].Inaddition,certain
alleles(eg,PTPN2,CTLA4,RGS1)conferageneticsusceptibilitytobothtype1diabetesandceliac
disease,suggestingacommonbiologicpathway[12].(See"Associatedautoimmunediseasesinchildren
andadolescentswithtype1diabetesmellitus",sectionon'Celiacscreening'and"Pathogenesis,
epidemiology,andclinicalmanifestationsofceliacdiseaseinadults",sectionon'Geneticfactors'and
"Diagnosisofceliacdiseaseinadults",sectionon'Antitissuetransglutaminaseantibodies'.)

Fewerthan1percentofchildrenwithtype1diabeteshaveautoimmuneadrenalitis.Inonereport,11of
629patients(1.7percent)withtype1diabetesbutnoneof239normalsubjectshadantibodiesdirected
against21hydroxylase,acommonautoantigeninprimaryadrenalinsufficiency[93].Threeofeight
patientswithanti21hydroxylaseantibodieshadadrenalinsufficiency.(See"Pathogenesisof
autoimmuneadrenalinsufficiency".)

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Type1diabetescanbeseenwithpolyglandularautoimmunedisease,especiallytypeII,inwhichadrenal
insufficiency,autoimmunethyroiddisease,andgonadalinsufficiencyaretheothermajorcomponents.
(See"Causesofprimaryadrenalinsufficiency(Addison'sdisease)".)

Raresyndromesassociatedwithtype1diabeteshaveshedimportantlightonpathogenesis.Theimmune
dysregulation,polyendocrinopathy,enteropathy,Xlinked(IPEX)syndromeisassociatedwithneonates
developingtype1diabetes.Theseinfantsusuallydieofoverwhelmingautoimmunity,inparticular,severe
enteritis.Theyhaveamutationofagenetermedfoxp3,a"masterswitch"forthedevelopmentofregulatoryT
cells.StudiesofthesyndromeandtherelatedanimalmodelprovidedramaticevidencethatregulatoryTcells
(formerlytermedsuppressorTcells)haveamajorphysiologicrole.TheAPSIsyndrome(Autoimmune
PolyendocrineSyndrometype1)iscausedbyamutationoftheAIREgene(autoimmuneregulator).This
genecontrolsexpressionofaseriesof"peripheral"antigensinthethymus,includinginsulin.Itisthoughtthat
thegeneprovidesprotectionfromautoimmunedisorders,includingtype1diabetes,viaitsinfluenceoncentral
Tcelltolerance[94].

ENVIRONMENTALFACTORSEnvironmentalinfluencesareanotherimportantfactorinthedevelopment
oftype1diabetes.Thebestevidenceforthisinfluenceisthedemonstrationinmultiplepopulationsofarapid
increaseintheincidenceoftype1Adiabetes[95,96].Theetiologyoftheincreaseisunknown.One
hypothesis,termedthehygienehypothesis,relatesimproved"sanitation"toincreasingimmunemediated
disorders[97].Twinstudiesindicatethatnotallmonozygotictwinsofprobandswithtype1diabetesdevelop
diabetes,althoughthecumulativeprevalenceincreaseswithlongtermfollowup[14,15,98].

PerinatalfactorsSeveralpregnancyrelatedandperinatalfactorswereassociatedwithasmallincrease
inriskoftype1diabetesinastudyof892childrenwithdiabetesand2291normalchildreninEurope[99].
Theywerematernalage>25years,preeclampsia,neonatalrespiratorydisease,andjaundice,especiallythat
duetoABObloodgroupincompatibilityprotectivefactorswerelowbirthweightandshortbirthlength.One
cohortstudyfoundarelativelyweakbutsignificantdirectassociationbetweenbirthweightandriskoftype1
diabetes[100]inasecondstudy,theassociationwaslimitedtocaseswithdiseaseonsetpriortoage10
[101].Postnataldietaryfactors,suchasvitaminDandomega3fattyacidingestionmayalsobeimportant
[102].(See'Roleofdiet'below.)

RoleofvirusesVirusescancausediabetesinanimalmodelseitherbydirectlyinfectinganddestroying
betacellsorbytriggeringanautoimmuneattackagainstthesecells[103].Althoughisolatedcasereports
havesuggesteddirectviraldestructionofbetacells[104],thisisprobablyextremelyrare.Acarefulautopsy
studyfoundnoevidenceforacuteorpersistinginfectionfromCoxsackie,EpsteinBarrvirus,mumps,or
cytomegalovirusinthepancreatictissueof75patientswhodiedwithinafewweeksofdevelopingtype1
diabetes[105].However,someunusualformsofdiabeteshavebeenassociatedwiththepresenceof
Coxsackievirusinalargenumberofbetacells[106].

Theimportanceofautoimmuneactivationisalsouncertain.CoxsackieBvirusspecificimmunoglobulinM
(IgM)responseshavebeenfoundin39percentofchildrenwithnewlydiagnosedtype1diabetes,compared
withonly6percentofnormalchildren[107].Twoadditionalfindingswerenotedinanotherreport[108]:

Coxsackievirusantibodytitersweresignificantlyhigherinpregnantwomenwhosechildrensubsequently
developedtype1diabetes,comparedwithpregnantwomenwhosechildrendidnotbecomediabetic.

Enteroviralinfectionswerealmosttwotimesmorecommoninsiblingswhodevelopedtype1diabetes
thaninsiblingswhoremainednondiabetic.

Theseobservationssuggestthatexposuretoenteroviruses,bothinuteroandinchildhood,caninducebeta
celldamageandleadtoclinicaldiabetes.Significanthomologyhasbeenfoundbetweenhumanglutamicacid
decarboxylase(GAD)andtheF2CproteinofCoxsackievirusB4,suggestingapossibleroleformolecular
mimicry[109,110].

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Thepossibilityofviralinducedautoimmunityormolecularmimicryissupportedbylongtermfollowupof
infantswiththecongenitalrubellasyndrome.Autoimmunediabetesandotherautoimmunediseasesmay
occur5to20yearsafterinfection,especiallyinthosesubjectswhohaveHLADR3[111,112].Unfortunately,
thelonglatentperiodbetweenpeakimmunologicactivityandclinicaldiseasemeansthatmeasuringviraltiters
attheonsetofhyperglycemiaisunlikelytobehelpful.

Theclearestassociationofviralinfectionwiththedevelopmentofspontaneousautoimmunediabetescomes
fromtheobservationthatbiobreedingdiabetesresistant(BBDR)rats,adiabetesresistantstrainofrats
relatedtoBBratsbutwithouttheseverelymphopeniaofBBrats,developdiabeteswheninfectedwiththe
Kilhamratvirus[113].Studiessuggestaroleforinnateimmunesystemactivationinthismodel.Inasimilar
manner,polyinosinic:polycytidylicacid(polyIC)injections(amimicofdoublestrandedRNAvirusesthat
inducesinterferonalphasecretion)caninducediabetesinthismodelandinamousemodel,whereinduction
ofinterferonalphaisessentialfordiabetesdevelopment[114].

Incontrasttotheabovereports,therearedatathatrefutetheroleofvirusesinthepathogenesisoftype1
diabetes[115,116].Inonereport,CoxsackieBvirusinfectionsinchildhoodwereassociatedwithtransient
productionofantibodiestoGAD,butnottype1diabetes[116].

Tofurtherconfusetheissue,thereisevidencethatvirusesmayprotectagainsttype1diabetes.InNODmice
andBBratsinoculationwithlymphocyticchoriomeningitisvirusatanearlyagereducedtheincidenceof
diabetes[117,118].Alsosupportingaprotectiveroleforvirusesistheobservationthatraisingnonobese
diabetic(NOD)miceandBBratsinpathogenfreeenvironmentsleadstoanincreasedincidenceoftype1
diabetes[119].

ChildhoodimmunizationTherehasbeenconcernthatchildhoodvaccinationmaybeassociatedwith
laterdevelopmentofchronicdiseases,includingtype1diabetes.However,immunizationofgenetically
predisposedinfants(siblingswithtype1diabetes)withviral(andbacterial)antigensdoesnotappeartobe
associatedwithanincreasedriskofdevelopingtype1diabetes[120].(See"Autismspectrumdisorderand
chronicdisease:Noevidenceforvaccinesorthimerosalascontributingfactor",sectionon'Type1diabetes
mellitus'.)

RoleofdietSeveraldietaryfactorsmayinfluencethedevelopmentoftype1diabetes,withmostattention
havingbeenpaidtocow'smilk[121].

Cow'smilkIthasbeenproposedthatsomecomponentofalbuminincow'smilk(bovineserum
albumin),thebasisformostinfantmilkformulas,maytriggeranautoimmuneresponse[122].Asanexample,
epidemiologicdatafromFinlandsuggestthatthereisanincreasedriskoftype1diabetesassociatedwith
introductiontodairyproductsatanearlyageandwithhighmilkconsumptionduringchildhood[122].
However,acrosssectionalstudyfoundnoevidenceofanassociationbetweenearlyexposuretocow'smilk
andthedevelopmentoftype1diabetes[123],andsomeprospectivestudieshavefoundnoassociation
betweenthedurationofbreastfeedingorintroductionofcow'smilkandthedevelopmentofisletautoimmunity
inchildrenathighriskoftype1diabetes[115,124].

Ithasalsobeensuggestedthatacellmediatedresponsetoaspecificcow'smilkprotein,betacasein,maybe
involvedinthepathogenesisoftype1diabetes.Inonereport,36patientswithrecentonsettype1diabetes
werecomparedwith36normalsubjects[125].Exposuretobovinebetacaseinledtoproliferationof
peripheralbloodTcellsin51percentofthepatientswithtype1diabetesversusonlyone(3percent)ofthe
normalsubjects.Inaddition,anepidemiologicalstudyofchildrenfrom10countriesrevealedastrong
correlationbetweentheincidenceoftype1diabetesandtheconsumptionofbetacasein[126].

Amoredetailedunderstandingofthecomplexproteincompositionofearlycow'smilkexposureisnecessary
tounderstanditsputativeeffectuponthedevelopmentoftype1diabetes.Randomizedtrialsofearly
nutritionalinterventionwithformulascontaininglesscomplexdietaryproteinsarereviewedseparately.(See
"Preventionoftype1diabetesmellitus",sectionon'Avoidanceofcow'smilk'.)

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VitaminDsupplementsAlthoughcow'smilkmaybeassociatedwithanincreaseofriskfortype1
diabetes,onecomponent,vitaminD,maybeprotective.(See"Preventionoftype1diabetesmellitus",section
on'VitaminDsupplements'.)

CerealsIninfantsathighriskfortype1diabetes,thetimingofinitialexposuretocerealsmayaffectthe
riskofdevelopingisletcellautoantibodies.Intwolargeprospectivecohortstudiesofnewbornsathighriskfor
type1diabetes(eitherafirstdegreerelative[127,128]orahighriskhumanleukocyteantigen(HLA)
genotype[127]),firstexposuretocerealbeforeagethreemonths[127,128]oraftersevenmonths[127]was
associatedwithanincreasedriskofdevelopingisletcellautoantibodies[127,128]andtype1diabetes
(adjustedhazardratio[HR]3.33,95%CI1.547.18forageatfirstexposuretoanycereal6months)
comparedwithinfantswhosefirstexposurewasbetweenagesfourtosixmonths[129].Theincreasedrisk
wasassociatedwithglutencontainingcerealsinonestudy[128],butwitheitherglutenorricecontaining
cerealsintheother[127].Earlyintroductionofgluten(<3monthsofage)increasestheriskofceliacdisease
[130].

Baseduponthesedata,wedonotrecommendchangingcurrentinfantfeedingguidelines,whichstatethat
cerealshouldbeintroducedbetweenagesfourandsixmonths.(See"Introducingsolidfoodsandvitaminand
mineralsupplementationduringinfancy",sectionon'Optimaltiming'.)

Omega3fattyacidsOmega3fattyacidsmaybeinvolvedinthedevelopmentofautoimmunityand
type1diabetes.Preliminarystudiesinanimalssupportaprotectiveroleofomega3fattyacidsinthe
inflammatoryresponseassociatedwithautoimmuneisletcelldestruction[131,132].Inacasecontrolstudy
fromNorway,childrenwithtype1diabeteswerelesslikelytobegivencodliveroil(containingomega3fatty
acidsandvitaminD)duringinfancythanchildrenwithoutdiabetes[102].Inaddition,alongitudinal
observationalstudyofchildrenatincreasedriskfortype1diabetesreportedaninverseassociationbetween
omega3fattyacidintakeanddevelopmentofisletautoimmunity(adjustedHR0.45,95%CI0.210.96)[133].
Aclinicaltrialofomega3fattyacidsupplementationininfantswithhighgeneticriskoftype1diabetesis
underway.(See"Preventionoftype1diabetesmellitus",sectionon'Omega3polyunsaturatedfattyacids'.)

Theroleofpolyunsaturatedfattyacidsinthepreventionofotherdiseasesisdiscussedseparately.(See
"Dietaryfat",sectionon'Polyunsaturatedfattyacids'.)

NitratesStudiesinColoradoandinYorkshire(UnitedKingdom)havefoundthattheincidenceoftype1
diabetescorrelateswiththeconcentrationofnitratesinthedrinkingwater[134].Theincidenceis
approximately30percenthigherinareaswithnitrateconcentrationsabove14.8mg/Lcomparedwithareas
withconcentrationsbelow3.2mg/L.

DETERMINANTSOFINSULINDEFICIENCYAlthoughglucosetolerancecanremainnormaluntilnearthe
onsetofclinicaltype1diabetes,measurementofpancreaticbetacellfunctionusuallyshowssubstantial
reductionininsulinsecretionduringthepreclinicalperiod[135,136].Impairedglucosetolerancefrequently
precedestheonsetofovertdiabetes[137].Themostwidelyusedtesttoestimatefunctioningbetacellmassis
measurementoftheacuteinsulinresponsetoanintravenousinjectionofglucose(AIRg).Thistest[138,139]
isused,alongwithimmunologicmeasurements,toidentifysubjectsathighriskfortype1diabetes.(See
"Predictionoftype1diabetesmellitus".)

Ithasbeenthoughtinthepastthatapproximately90percentofthebetacellmassneedstobedestroyed
beforehyperglycemiaoccurshowever,thisisprobablynottrue.Asanexample,theadministrationof
streptozotocininincreasingdosestoadolescentbaboonscaninducecompleteinsulindependency(withno
detectableAIRg)atatimewhen30to50percentofthebetacellmassisstillviable[140].Theprofound
insulindeficiencyinthissettingisoutofproportiontothelossoffunctioningcellsandmaybedueinpartto
theinhibitoryactionofcytokinesreleasedfrominflammatorycellsintheislets.Thefollowingobservationsare
consistentwiththeimportanceofsuchexternalfactors:

Whenseverelyinflamedisletsareremovedfrom12to13weekoldNODmiceandstudiedinculture,
insulinsecretiononday0isverylow,butthereisalmostcompleterecoveryoffunctionbydayseven
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(figure4)[141].

Histologicandinvitrophysiologicstudiesofthepancreasofapatientwhodiedsoonaftertheonsetof
type1diabetesrevealedthatasubstantialmassofbetacellswerestillviable[142].

Inamousemodelofdiphtheriatoxininducedbetacellapoptosis(characterizedbytheabsenceofan
inflammatoryreaction),cessationofdiphtheriatoxinexpressionwasassociatedwithbetacell
proliferation,recoveryofbetacellfunction,andsubsequentnormalizationofglucosehomeostasis,even
inahyperglycemicenvironment[143].Thesefindingsareincontrasttothoseobservedinautoimmune
andpharmacologic(streptozotocin)modelsofdiabetes,inwhichbetacellshavedemonstratedapoor
abilitytoregenerate.

Thesefindingsareofpotentialclinicalimportance,becausetheysuggestthatseverehyperglycemiadoesnot
necessarilyimplyirreversiblelossofalmostallfunctioningbetacells.Thus,stoppingtheautoimmuneprocess,
evenatthislatestage,mayallowsubstantialrecoveryofbetacellfunction.

Insulinlikegrowthfactor1(IGF1)isthoughttoplayaroleinisletdevelopmentandfunction.Intransgenic
mice,localexpressionofIGF1inbetacellsresultedinregenerationofpancreaticisletsandreversaloftype1
diabetes[144].However,inanotherstudy,betacellspecificdeletionoftheIGF1receptordidnotaffectbeta
cellmass,butresultedinhyperinsulinemiaandglucoseintolerance[145].ThissuggeststhattheIGF1
receptormaynotbecriticalforbetacelldevelopment,butisimportantforbetacellfunction.

CLINICALRESEARCHTheNationalInstitutesofHealthhasestablishedaprogramtermedTrialnetwhose
goalisthepreventionoftype1Adiabetesandpreventionoffurtherbetacelldestructioninpatientswith
recentonsetdiabetes.Relativesofpatientswithtype1Adiabetescanbescreenedforexpressionofislet
autoantibodiesandtrialsareavailabletostudyagentstohaltbetacelldestructioninmultiplecenters
throughouttheUnitedStatesandtheworld(www.diabetestrialnet.org).

INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"
and"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6th
gradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagiven
condition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easyto
readmaterials.BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,andmore
detailed.Thesearticlesarewrittenatthe10thto12thgradereadinglevelandarebestforpatientswhowant
indepthinformationandarecomfortablewithsomemedicaljargon.

Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremail
thesetopicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsby
searchingon"patientinfo"andthekeyword(s)ofinterest.)

Basicstopics(see"Patienteducation:Type1diabetes(TheBasics)")

BeyondtheBasicstopics(see"Patienteducation:Diabetesmellitustype1:Overview(Beyondthe
Basics)")

SUMMARY

Type1Adiabetesmellitusresultsfromautoimmunedestructionoftheinsulinproducingbetacellsinthe
isletsofLangerhans[1].Thisprocessoccursingeneticallysusceptiblesubjects,isprobablytriggeredby
oneormoreenvironmentalagents,andusuallyprogressesovermanymonthsoryearsduringwhichthe
subjectisasymptomaticandeuglycemic.Thislonglatentperiodisareflectionofthelargenumberof
functioningbetacellsthatmustbelostbeforehyperglycemiaoccurs(figure1).(See'Introduction'above.)

Polymorphismsofmultiplegenesareknowntoinfluencetheriskoftype1Adiabetes(HLADQalpha
HLADQbetaHLADR,preproinsulin,thePTPN22gene,andCTLA4),withwholegenomeanalysis
providingadditionalgenesandloci,suchasKIAA0035(alectin).Genesinboththemajor

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histocompatibilitycomplex(MHC)andelsewhereinthegenomeinfluencerisk,butonlyhumanleukocyte
antigen(HLA)alleleshavealargeeffect.(See'Geneticsusceptibility'above.)

Thereareanumberofautoantigenswithinthepancreaticbetacellsthatmayplayimportantrolesinthe
initiationorprogressionofautoimmuneisletinjuryincludingglutamicaciddecarboxylase(GAD),insulin,
insulinomaassociatedprotein2(IA2),andzinctransporterZnT8.Itisnotcertain,however,whichof
theseautoantigensisinvolvedintheinitiationoftheinjuryandwhicharesecondary,beingreleasedonly
aftertheinjury,thoughinthenonobesediabetic(NOD)mousemodelandmanincreasingevidencepoints
toinsulinastheprimaryimmunetarget.(See'Targetautoantigens'aboveand"Predictionoftype1
diabetesmellitus".)

Environmentalfactorsthatmayaffectriskincludepregnancyrelatedandperinatalinfluences,viruses,
andingestionofcow'smilkandcereals.(See'Environmentalfactors'above.)

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

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GRAPHICS

Timecourseoftype1diabetesmellitus

Timecourseofthedevelopmentoftype1diabetes.Geneticmarkersarepresentfrom
birth,immunemarkersfirstappearatthetimeoftheenvironmentaltriggeringevents,
andsensitivemetabolicmarkersofdeficientinsulinsecretionbegintoappearsoonafter
theonsetofbetacelldysfunction.However,clinicallyevidenttype1diabetesdoesnot
occuruntiltherehasbeenamuchgreaterlossoffunctioningbetacellmass.

Graphic66417Version2.0

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RepresentationofTcellactivation

Schematicrepresentationofinitiationoftheimmunologicresponsetoanantigen.The
antigenbindstoagrooveinMHCclassIImoleculesonantigenpresentingcells(such
asmacrophages).Thisbindingallowstheantigentobepresentedtoantigenreceptors
onautoreactiveCD4inducerorhelperTcellswhich,intype1diabetesmellitus,
initiateautoimmuneinjurytothepancreaticbetacells.Inaddition,therespective
bindingofB7proteinsandLFA3onantigenpresentingcellstoCD28andCD2onT
cellsareimportantcostimulatorypathwaysthatfurtherincreaseTcellactivation.
Othermoleculesalsocanparticipateintheimmuneresponse,suchasthebindingof
interleukin2toitsreceptor(IL2R).

MHC:majorhistocompatibilitycomplexLFA3:lymphocytefunctionalantigen3IL2R:
interleukin2receptor.

Graphic63541Version3.0

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Associationoftype1diabeteswithdiabetogenicgenes

Directcorrelationindifferentpopulationsbetweenthegenefrequencyof
"diabetogenic"HLADQgenotypes(whichlackaspartateatposition57onthe
betachain)andthepredictedandobservedincidenceoftype1diabetesmellitus
(per100,000population).

Datafrom:DormanJS,LaPorteRE,StoneRA,TruccoM,Worldwidedifferencesin
theincidenceoftypeIdiabetesareassociatedwithaminoacidvariationatposition
57oftheHLADQbetachain.ProcNatlAcadSciUSA199087:7370.

Graphic80483Version2.0

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Confirmedtargetsofautoantibodiesintype1diabetesofman

Insulin

Glutamicaciddecarboxylase

Insulinomaassociatedantigens2(alphaandbeta)

ZnT8(zinctransporter)

Graphic69086Version1.0

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RecoveryofinsulinsecretioninNODmice

Insulinreleasefromisolatedpancreaticisletsfromin12to13weekoldnonobese
diabetic(NOD)miceandnormalmiceonday0andday7inculture.Measurements
weremadeatbaselineduringincubationwithlowglucosemedium(B)andafter
incubationinhighglucosemedium(G).InsulinreleasefromtheisletsfromNODmicein
responsetoglucosewaslowonday0(secondpanel)butabovenormalbyday7
(fourthpanel),suggestingtheimportanceofinvivoinhibitoryfactorssuchaslocally
releasedcytokines.

Datafrom:StrandellE,EizirikDL,SandlerS.Reversalofbetacellsuppressioninvitroin
pancreaticisletsisolatedfromnonobesediabeticmiceduringthephaseprecedinginsulin
dependentdiabetesmellitus.JClinInvest199085:1944.

Graphic53657Version2.0

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ContributorDisclosures
MassimoPietropaolo,MD ClinicalTrialSupport:JanssenResearch&Development,LLC[ChairforType1
DiabetesDataMonitoringCommittee(golimumab)]. IrlBHirsch,MD Grant/Research/ClinicalTrialSupport:
NovoNordisk[Diabetes(Insulinaspart,insulindegludec,insulindetemir,liraglutide)].Consultant/Advisory
Boards:Abbott[Diabetes(Bloodglucosemeters)]IntarciaTherapeutics[Diabetes(Exenatide)]Roche
[Diabetes(Bloodglucosemeters)]. JeanEMulder,MD Nothingtodisclose

Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseare
addressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobe
providedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofallauthorsandmustconform
toUpToDatestandardsofevidence.

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