Ras Inhibition Induces Insulin Sensitivity and Glucose Uptake 英文参考文献.docVIP

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Ras Inhibition Induces Insulin Sensitivity and Glucose Uptake 英文参考文献.doc

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Ras Inhibition Induces Insulin Sensitivity and Glucose Uptake 英文参考文献

RasInhibitionInducesInsulinSensitivityandGlucose Uptake AdiMor1,ElizabetaAizman1,JacobGeorge2,YoelKloog1* 1DepartmentofNeurobiology,GeorgeS.WiseFacultyofLifeSciences,TelAvivUniversity,Tel-Aviv,Israel,2DepartmentofCardiology,KaplanMedicalCenter,Rehovot, affiliatedtotheHebrewUniversity—HadassahMedicalSchool,Jerusalem,Israel Abstract Background: Reduced glucose uptake due to insulin resistance is a pivotal mechanism in the pathogenesis of type 2 diabetes. It is also associated with increased inflammation. Ras inhibition downregulates inflammation in various experimentalmodels.TheaimofthisstudywastoexaminetheeffectofRasinhibitiononinsulinsensitivityandglucose uptake,aswellasitsinfluenceontype2diabetesdevelopment. Methods and Findings: The effect of Rasinhibition on glucose uptake was examined both in vitro andin vivo.Ras was inhibitedincellstransfectedwithadominant-negativeformofRasorby5-fluoro-farnesylthiosalicylicacid(F-FTS),asmall- molecule Ras inhibitor. The involvement of IkB and NF-kB in Ras-inhibited glucose uptake was investigated by immunoblotting. High fat (HF)-induced diabetic mice were treated with F-FTS to test the effect of Ras inhibition on induction of hyperglycemia. Each of the Ras-inhibitory modes resulted in increased glucose uptake, whether in insulin- resistantC2C12myotubesinvitroorinHF-induceddiabeticmiceinvivo.RasinhibitionalsocausedincreasedIk Bexpression accompaniedbydecreasedexpressionofNF-kB.Infat-induceddiabeticmicetreateddailywithF-FTS,boththeincidenceof hyperglycemiaandthelevelsofseruminsulinweresignificantlydecreased. Conclusions:InhibitionofRasapparentlyinducesastateofheightenedinsulinsensitizationbothinvitroandinvivo .Ras inhibitionshouldthereforebeconsideredasanapproachworthtestingforthetreatmentoftype2diabetes. Citation: Mor A, Aizman E, George J, Kloog Y (2011) Ras Inhibition Induces Insulin Sensitivity and Glucose Uptake. PLoS ONE 6(6): e21712. doi:10.1371/ journal.pone.0021712 Editor:JosephNajbauer,CityofHopeNationalMedicalCenter