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  • Desfaits Diabetes Care 1998 PDF

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    Sastra Wijaya
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    Desfaits Diabetes Care 1998 PDF

    Загружено:

    Sastra Wijaya

    Авторское право:

    © All Rights Reserved
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    из 7
    e/Education/Nutrit romsaie ost 2 PU24276ENGO suictazise Ma om BE 2 Normalization of Plasma Lipid Peroxides, Monocyte Adhesion, and Tumor Necrosis Factor-c Production in NIDDM Patients After Gliclazide Treatment ANNE-Cecite Desens, PHO. (wan Sees, MD, PHD Genevieve REMIER, uo, PHD OBJECTIVE — To evaluate the effect of lictaide administration 1o NIDDM patients on 1) monocyte alles ws vulased endothelial els, 2) plasma evokineand lipid perowide loves and 3) monocyte cytokine production RESEARCH DESIGN AND METHODS — Poorly controled lyburde-reated diabenc patients (n= 8) and healthy control subjects (n= 8) were reerited. At the Beginning ofthe Flug alpbonde was replaced by an equivalent hypoglycemic dose of glilaside Serum and ‘ronocytes were solated from blood obtained from contol and diabeue subjects before and ter 3 months of treatment wich glaze. RESULTS — Plasma lipid perowide levels and monocyte adhesion to endotheliat cells are enhanced im NIDDM patients snd gliclazide adminusration totally reverses these sbnormal (ie: Beloeglclsidetesiment serum levels of evtokines did not differ in the contro andthe tiabeve groups. with he exception of an enancement of tumor necrosis factor-a (TNFa) and ‘nterieukin-@ (iL) m NIDDM subjects. Basal and lipopolysaccharide (LPS)-sumulsted mono- {te production of nterleukin-18,1L-6, and IL-8 did aot dlr erween the two groups. Fur ‘Rermore, basal monocyte production of TNF was sila in the conttol and the diabetic [roups whereas a marked increase inthe LPS-stimulated monocyte production of TNF-a was Sbserred inthe NIDDM group. Cliclasde teatment lowered LPS-stimulated TNF-a produc: tion by dabece monocytes 0 levee stilt to those observed in contro subjects. CONCLUSIONS — Giiciside administration to NIDDM patients inhibits the increased Sdhesiveness of diabenic monocytes to endothelial cell and reduces the production of TNF-a by these eels These results suggest that reatment of NIDDM subjects with ghlazide may be beneficial inthe prevention of atherosclerosis associated with NIDUM. ‘oxidatively modified LDLs in athero- algo increase the expression of celladhesion genesis (1.2) alteration of LDLs by molecules thereby enhancing endothelial jonidative process results in their unregu- cll adherence of mononucear cells (6,7) lated uptake by macrophages leading to Finally, modified LDLs enhance the pro: S= lines of evidence implicate foam cell formation (3-5). Oxidized LDLs From he Metabolic Unt. CHEM Reset Cente, ot. Dame Pasion and Deparmen of Nero ‘rmly of Morea. Mone Quebec. Canada. "Adireas comespondence and rept rere o Dr. Geneve Rarer, CHUM Researc Cente, Note- pate Parloe Sef four] de sve, Y822 1560 Sherbrooke Se Eas, Mons! Quebe, MRL 40 nada Ema remergSere umoteaca ected for pcan Luly 997 ad aceped reve form 28 Nove [997 [Sbecsnose: SAE bovine a endthel ONIEAL Dube muna ssh medium’ ELAM. scien ELISA cay inbedrmunosvben asi, #CS lal tum. FCP hb gow [os ARB hexades) crime hyamine smn bromide. IEAM tenella sll adheswh mules. 1CE ulncte growth actor IL teak LPS ppolacthande MDA. maiondalgchy de, MPO. mona peepee 28S phvephte hula sana. TB4,thosbarbsune acid. TBARS. hsbarune sees W slonances TEP wnsaoyptepore. TGF uatslorminggranth Cor TSF Homoe aeeross itor CERO RRUE, Gi senon mekee VeGr vnelr ences gro ee dlucuon of several proatherogene factors including growth factors (8) and cytokines (6). NIDDM is closely associated with the development ofaceleratedatheroscleross (10), Diabet patients Show increased ev eis ofcrealating died ipoproweins (1) and enbanced oxdation of thetr plasma UDL (11.12). Increased lipeprocein oxidae tion im diabetws (or in sates of vhvonic Iypergyezma) may be responsible fr ihe previously documented increase in the Expresion of exelating adhesion mole cules (13) and tn te produexion of camer reerosis ctor (TNF-a) (13.15). 2 bev mediator of insulin resistance (16). 19 NIDDM subjects Gliclarde, 4 second-generaton sul fonlurea, ts widely used nthe eaten of NIDDM patients, Beside is metaboin etlects (17), ghelande possesses some To metabolic eecs specially elated 0 3s Colar disease im chabetes Reverthy a fteetadical scavenging actity ofthis 54 has been repored (18) We have previous shown that glclasde reduced in vio. vs ula celmediated LDL oxadaion and ox zed LDL-induced monacye adhesion 19 tured endothelal ells (19) Based these Findings, we exaust in che presect study the elect of giclazide administration to NIDDM subjecs on serum pid peroude levels, monocyte adhesion, and monocyte mediated LDL oxidation. We also meas: uted serum and wonoeyte denved eyiokine levels in NIDDM paras before ard at slclazide eaten RESEARCH DESIGN AND METHODS Subjects ‘The study group compnsed eight NIDOM patients and eight healthy conto! subjects ‘The NIDDM patents, four women and four sme, gave witen consent ro panicipate in is study, which was approved by che Noite-Damne Hospral Research and Ethics commitees. All patients were selected from fur diabetic auxpatent clinic for peor dia betes conitol caused by lack of adherence co SSE CaP ET Ne AT Antioxidant effect of gliclazide in NIDDM patients Gietary regimes (HbA, 29%), glyburide treatment, no decompensated cardiac renal conditions, and nonsmoking, Their sean = SD (range) age was 61 2 5 years (55-70), BM 29 + 3 kg/m? (26-34), dure tion of NIDDM 10 2 9 years G-30), HbA 12 196 (8.215), and dally gyounde dose 16.5 258mg (5-20) ll pats were also treated wh maori: Nowe ofthe paseres \were primarily insulin dependent. One of, them twas a candidave for insulin substtu- sion and was swtiched at the end of this study from ghclazide to insulin. Four patients were hypertensive and treated with ACE inhibiors, four were hypennglycen demic, two had macroanghopathy, and five had microangiopathy (retinopathy or micro- albuminuria), Control subjects, matched Sach patien's for sex and BM were recruited from the hospital ai and relatives. Since age does not infiuence the vanables under study (20,21), control subjects and patients were not matched forage. Subjects ‘with infectious or inflammatory conditions or treated by antinflsmmatory or andiox- dant drugs were excluded from the study In this pilot study, NIDDM patients were -sutiched for 3 months from giyburde to an equivalent hypoglycemic dose of gllazide (5 img of ghybunde equivalent 10 80 mg of sliclazide). Venous blood samples were Dbiained from control subjects and. from [NIDDM patients before and after 3 months of treatment with gliclazide. Reagents Dulbecco’ minimal essential medium (DMEM) and t-glutamine were obiained from ICN Biochemicals (Costa Mesa, CA) KeMI-J040 was purchased from Gibeo (Grand Island, NY) and peneilin-strepto mycin and fetal call serum (FCS) were sbained from Flow Laboratones (McLean, ‘Va and Hyelone Laboratories (Logan, UT), respectively Thiobarbiuric acid (TBA) and teiraethoxypropane (TEP) were purchased from ICN Biachemicals. Danisdine dihy pmelA CuSO, At che end of phate-buffered saline without caleum oF is ase we DiETES Cane, VOLUME FT, MALT, AP TOR 0 i : é g 3 3 5 3 z conmot. aaron arrexn chGaube — outiaaoe Figure magnesium (PBS-A). Adherent cells were lysed in 50 ul of HTAB (0.5%) in PBS¥A at pH 6.0 for 30 min. Quanuificauon of adher- fent monocytes was made by measuring. monocyte myeloperoxidase (MPO) activ (28), Brefly, MPO activity was devermined by the addon to each well of 250 ul of dlianisidine cihydrochiorde (0.2 mg/ml in PBS.A) warmed up at 37°C and mixed with hydrogen peroxide (0.4 rmolA final con= centration). fier 2-5 min of incubation, the optical densicy ofthe plate wells was read at 450 nm using a Terk multscan spec ‘wophotometer (Flow Laboratones). Measurements of serum adhesion molecule levels Serum adhesion molecule levels were ‘measured by enzyme-linked immunosor- bent assay (ELISA), using commercial kits purchased from RED Systems (Minneapo- lis, MN). Measurements of serum and ‘monocyte cytokine levels Serum eytoxine levels and monocyte cytokine production were measured by ELISA using commercial kits (RED Sys. fems), Serum growth factors were meas: tired by ELISA R&D Systems), and serum nsulinlike growth IGF leve were quantified using 2 highly sensitive and specific radioimmunoassay (Diagnost Systems Labs, Webster, TX. Statistical analysis Saristical analysis of the results was per- Manacyte adheson in NIDDM pacens before and ater glace treatment Res expresed as adhesion over contol vac, Daa vepresen the mean 2 SE." P0005 5 cones formed by one-way analysis of variance fal- lowed by the Tukeys test. The Spearman rank corelation test was used to evaluate correlation between lipid peroxides levels and monocyte adhesion 0 cultured endothelial cells. Results were expressed as mean # SE, RESULTS Serum lipid peroxide levels in control subjects and diabetic patients Serum lipid peroxide levels of NIDDM patients before glclazide administration were 96 2 LL nmolml as compared wih, 58 20.6 nmol! in control subjects (P< i gle (0003) (Table 1). Afier 3 raonuls 350 reg 20 200 150 100 SERUM CAMs (1% over control) * | ELAM Figure 2—Serum evel of cll ahesion molec and ft 35E "P< 005 vs. conta abject, Desfats, Serv, anu Renter clazide weatment, lipid peroxide levels ‘were reduced in che NIDDM group t ev els similar to those observed in the control ‘group (Table 1) Monocyte-mediated LDL oxidation in control subjects and diabetic patients, “To evaluate the role of monocytes in the ‘enhanced lipoprotein oxidation assoeated swith NIDDM, we measured the in vt ability of conirol and diabeu moneys oxidize LDL. Our results showed thor monoeyte-mediateé LDL oxdarion assessed oy the TBARS assty did erween the control and the groups neath! adminsication, Control and diahetie monocyte adhesion to cultured endothelial cells To assess the adhesiveness of diabetic monocytes to the endothelium, we meas tured the adhesion of control and diabettc monocytes to BAE cells, A marked increase tn the adhesion of diabetic monocyte endothelial cells vas observed before gl clande treatment (163 24% over conirl values, P <0.005) (Fig. 1) This crease was positively corelated (7 = 074. P< (0,01) with enhanced lipid peroxide levels observed in diabetic patients. Glicazide administration totaly reversed this anor aly, lowering monocyte adhesion in NIBOM patients to levels ieentca to those observed in conteol subjects (Fig, Serum levels of soluble adhesion ‘molecules Serum levels of E-selectin (ELAM-1), inte Célula cel) alles molecule (ICAM*D. (Econteor «id JEaBEFORE GLICLAZIDE| [MAFTER GLICLAZIDE | TCAM-L es im control subjects and in NIDDM parents before CAMA Jilande treatment. Results were expressed as % over cotrlvlues. Dats werent the mean Bianeres CR, VOLUME BT, NOOR S, APR TSH oo) Antioxidant effect of gliclaside in NIDDM patients Table Serum levels of cytokines and {growth fctorsin NIDDM patens and control subjects NIDDM Control Cytokines __pauents__ subjects FOFbipym) 1992060 2692083 IGFAtnemi) 134532 “130526 Teipipgm 0225004 0.252008 Ls tggmd 3372068" 099016 TGE-B (ng/ml) 0.552005 0592004 TNF-a py) 1286008" 1082010 VEGE pgm 3342103 382249 Dao ne mes 25E POOL TF

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