Resveratrol Increases Glucose Induced GLP-1 Secretion in Mice A Mechanism which Contributes to the Glycemic Control 英文参考文献.docVIP

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Resveratrol Increases Glucose Induced GLP-1 Secretion in Mice A Mechanism which Contributes to the Glycemic Control 英文参考文献.doc

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Resveratrol Increases Glucose Induced GLP-1 Secretion in Mice A Mechanism which Contributes to the Glycemic Control 英文参考文献

ResveratrolIncreasesGlucoseInducedGLP-1Secretionin Mice:AMechanismwhichContributestotheGlycemic Control Thi-MaiAnhDao1,2,3,Aure′lieWaget1,2,PascaleKlopp1,2,MatteoSerino1,2,ChristelleVachoux1,2 ,Laurent Pechere4,DanielJ.Drucker5,SergeChampion3,SylvainBarthe′lemy6,YvesBarra3,Re′myBurcelin1,2* ,Eric Se′re′e3* 1Institut National de la Sante′ et de la Recherche Me′dicale U1048, Institut de recherche sur les Maladies Me′taboliques et Cardiovasculaire, I2MC, Toulouse, France, 2Universite′ deToulouse,UPS,InstitutdesMaladiesMe′taboliques etCardiovasculaires(I2MC),Hopital? deRangueil,Toulouse,France,3InstitutNationaldelaRecherche Agronomique 1260, Faculte′ de Pharmacie, Marseille, France, 4ENTERONOVA SAS, Incubateur Midi-Pyrenne′es, Toulouse, France, 5Department of Medicine, Samuel LunenfeldResearchInstitute,MountSinaiHospital,UniversityofToronto,Toronto,Ontario,Canada,6YVERYSARL,Marseille,France Abstract Resveratrol(RSV)isapotentanti-diabeticagentwhenusedathighdoses.However,thedirecttargetsprimarilyresponsible for the beneficial actions of RSV remain unclear. We used a formulation that increases oral bioavailability to assess the mechanismsinvolvedintheglucoregulatoryactionofRSVinhigh-fatdiet(HFD)-feddiabeticwildtypemice.Administration of RSV for 5 weeks reduced the development of glucose intolerance, and increased portal vein concentrations of both Glucagon-likepeptid-1(GLP-1)andinsulin,andintestinalcontentofactiveGLP-1.Thiswasassociatedwithincreasedlevels of colonic proglucagon mRNA transcripts. RSV-mediated glucoregulation required a functional GLP-1 receptor (Glp1r) as neither glucose nor insulin levels were modulated in Glp1r-/- mice. Conversely, levels of active GLP-1 and control of glycemia were further improved when the Dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin was co-administered with RSV.Inaddition,RSVtreatmentmodifiedgutmicrobiotaanddecreasedtheinflammatorystatusofmice.Ourdatasuggest thatRSVexertsitsactionsinpartthroughmodulationoftheenteroendo