A GIP Receptor Agonist Exhibits β-Cell Anti-Apoptotic Actions in Rat Models of Diabetes Resulting in Improved β-Cell Function and Glycemic Control 英文参考文献.docVIP

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A GIP Receptor Agonist Exhibits β-Cell Anti-Apoptotic Actions in Rat Models of Diabetes Resulting in Improved β-Cell Function and Glycemic Control 英文参考文献.doc

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A GIP Receptor Agonist Exhibits β-Cell Anti-Apoptotic Actions in Rat Models of Diabetes Resulting in Improved β-Cell Function and Glycemic Control 英文参考文献

AGIPReceptorAgonistExhibitsb-CellAnti-Apoptotic ActionsinRatModelsofDiabetesResultinginImproved b-CellFunctionandGlycemicControl ScottB.Widenmaier1,Su-JinKim1,GaryK.Yang1,ThomasDeLosReyes1,CuilanNian1,AliAsadi1, YutakaSeino2,TimothyJ.Kieffer1,YinNamKwok1,ChristopherH.S.McIntosh1* 1DepartmentofCellularandPhysiologicalSciencesandtheDiabetesResearchGroup,LifeSciencesInstitute,UniversityofBritishColumbia,Vancouver,BritishColumbia, Canada,2DepartmentofDiabetesandClinicalNutrition,KansaiElectricPowerHospital,Osaka,Japan Abstract Aims:ThegastrointestinalhormoneGIPpromotespancreaticisletfunctionandexertspro-survivalactionsonculturedb-cells. However, GIP also promotes lipogenesis, thus potentially restricting its therapeutic use. The current studies evaluated the effectsofatruncatedGIPanalog,D-Ala2-GIP1–30(D-GIP1–30),onglucosehomeostasisandb-cellmassinratmodelsofdiabetes. Materials and Methods: The insulinotropic and pro-survival potency of D-GIP1–30 was evaluated in perfused pancreas preparationsandculturedINS-1b-cells,respectively,andreceptorselectivityevaluatedusingwildtypeandGIPreceptor knockoutmice.EffectsofD-GIP1–30onb-cellfunctionandglucosehomeostasis,invivo,weredeterminedusingLeanZucker rats,obeseVancouverdiabeticfattyrats,streptozotocintreatedrats,andobeseZuckerdiabeticfattyrats,witheffectsonb- cellmassdeterminedinhistologicalstudiesofpancreatictissue.LipogeniceffectsofD-GIP1–30wereevaluatedoncultured 3T3-L1adipocytes. Results: Acutely, D-GIP1–30 improved glucose tolerance and insulin secretion. Chronic treatment with D-GIP1–30 reduced levelsofisletpro-apoptoticproteinsinVancouverdiabeticfattyratsandpreservedb-cellmassinstreptozotocintreatedrats andZuckerdiabeticfattyrats,resultinginimprovedinsulinresponsesandglycemiccontrolineachanimalmodel,withno changeinbodyweight.Ininvitrostudies,D-GIP1–30exhibitedequivalentpotencytoGIP1–42onb-cellfunctionandsurvival, butgreatlyreducedactiononlipoproteinlipaseactivityin3T3-L1adipocytes. Conclusions: These findings demonstrate