Palmitate-Induced β-Cell Dysfunction Is Associated with Excessive NO Production and Is Reversed by Thiazolidinedione-Mediated Inhibition of GPR40 Transduction Mechanisms 英文参考文献.docVIP

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Palmitate-Induced β-Cell Dysfunction Is Associated with Excessive NO Production and Is Reversed by Thiazolidinedione-Mediated Inhibition of GPR40 Transduction Mechanisms 英文参考文献.doc

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Palmitate-Induced β-Cell Dysfunction Is Associated with Excessive NO Production and Is Reversed by Thiazolidinedione-Mediated Inhibition of GPR40 Transduction Mechanisms 英文参考文献

Palmitate-Inducedb-CellDysfunctionIsAssociatedwith ExcessiveNOProductionandIsReversedby Thiazolidinedione-MediatedInhibitionofGPR40 TransductionMechanisms SandraMeiduteAbaraviciene1,IngmarLundquist2,JurisGalvanovskis1,ErikFlodgren1,Bjo¨rnOlde2, AlbertSalehi1* 1DepartmentofClinicalScience,DivisionofEndocrinePharmacology,theMalmo¨ UniversityHospital(UMAS),Malmo¨,Sweden,2DepartmentofExperimentalMedical Science,UniversityofLund,Lund,Sweden Abstract Background:Type2diabetesoftendisplayshyperlipidemia.Weexaminedpalmitateeffectsonpancreaticisletfunctionin relationtoFFAreceptorGPR40,NOgeneration,insulinrelease,andthePPARcagonisticthiazolidinedione,rosiglitazone. Principal Findings: Rosiglitazone suppressed acute palmitate-stimulated GPR40-transduced PI hydrolysis in HEK293 cells andinsulinreleasefromMIN6ccellsandmouseislets.Culturingislets24hwithpalmitateat5mmol/lglucoseinducedb- celliNOSexpressionasrevealedbyconfocalmicroscopyandincreasedtheactivitiesofncNOSandiNOSassociatedwith suppressionofglucose-stimulatedinsulinresponse.Rosiglitazonereversedtheseeffects.TheexpressionofiNOSafterhigh- glucose culturing was unaffected by rosiglitazone. Downregulation of GPR40 by antisense treatment abrogated GPR40 expressionandsuppressedpalmitate-inducediNOSactivityandinsulinrelease. Conclusion: We conclude that, in addition to mediating acute FFA-stimulated insulin release, GPR40 is an important regulator ofiNOSexpression anddysfunctional insulinrelease during long-termexposure toFFA. The adverseeffects of palmitatewerecounteractedbyrosiglitazoneatGPR40,suggestingthatthiazolidinedionesarebeneficialforb-cellfunction inhyperlipidemictype2diabetes. Citation:MeiduteAbaravicieneS,LundquistI,GalvanovskisJ,FlodgrenE,OldeB,etal.(2008)Palmitate-Inducedb-CellDysfunctionIsAssociatedwithExcessive NO Production and Is Reversed by Thiazolidinedione-Mediated Inhibition of GPR40 Transduction Mechanisms. PLoS ONE 3(5): e2182. doi:10.1371/journal. pone.0002182 Editor:AdrianVella,MayoClinicCollege