The Research Of BVT.2733 And Pioglitazone In The Mechanism Of Insulin Resistance

The research of BVT.2733 and Pioglitazone in the mechanism of insulin resistanceObjective:Metabolic disorders,such as obesity and type 2 diabetes,have assumed epidemic proportions and present major challenges for healthcare systems. Excessive glucocorticoid exposure causes central obesity,hypertension, dyslipidaemia and insulin resistance,as seen with elevated plasma cortisol in Cushing's syndrome.11β-hydroxysteroid dehydrogenase type 1(11β-HSD1)is now recognised as an abundant and physiologically important enzyme. 11β-HSD1 activates functionally inert glucocorticoid precursors(cortisone)to active glucocorticoids(cortisol)within insulin target tissues,such as adipose tissue,thereby regulating local glucocorticoid action.BVT.2733 is a selective inhibitor of murine 11β-HSD1 which decreases the active of 11β-HSD1 shown to decrease blood glucose levels and gluconeogenic.Peroxisome proliferatoractivated receptor-γ(PPARγ)is a member of the hormone receptor superfamily of nuclear transcription factors.It plays a critical role in adipocyte differentiation and the development of type 2 diabetes mellitus.The most extensively employed insulin-sensitizing drugs,thiazolidinedione derivatives (such as Pioglitazone),have been found to possess a high affinity for PPARγ. In addition,the binding affinity of the TZDs to PPARγseems to closely correlate with the potency of their insulin-sensitizing actions.We compared the different effect and pathway of BVT.2733 and Pioglitazone on insulin resistance,and then investigated the mechanisms of BVT.2733 on insulin resistance and type 2 diabetes mellitus,by using the DIO(diet-induced obese) mice model.Methods:1.After having balanced for 3d,the C57BL/6J mice were randomly divided into the normal diet group and high-fat diet(HFD)group.After 20 weeks, the obese mice were randomly divided into obese control group,BVT.2733 group,PGZ group,and BVT.2733+PGZ group.And they were orally administered placebo,BVT.2733,PGZ,BVT.2733+PGZ separately for two weeks.The levels of plasma glucose and serum insulin were measured by Biochemistry technology and Radioimmunity.The adipocyte sizes also were observed by Immunohistochemistry.2.The adiponectin mRNA expression levels from adipose tissue were analyzed by real-time quantitative PCR.The levels of plasma adiponectin was measured by ELISAResults:1.The weight raised(P＜0.05)and plasma glucose and serum insulin levels raised(P＜0.01)in HFD group,and the adipocyte sizes were bigger. Comparing to obese controls,in BVT.273 and PGZ group,serum insulin levels,HOMA-IR significantly reduced(P＜0.01)and the adipocyte sizes reduced.Markedly,the weight lost significantly in BVT.2733 group but the combination of BVT.2733 and PGZ group,serum insulin levels, HOMA-IR didn't reduce.2.At a molecular level,while plasma adiponectin level raised(P＜0.01),both the mRNA expressions of adiponectin upregulated(p＜0.05)in PGZ group, but their expressions in BVT.2733 group didn't alter significantly.Conclusion:1.Pioglitazone could improve insulin resistance by influencing the expression of adipocytokines.2.BVT.2733 could lose weight significantly and improve insulin resistance, but couldn't influence the expression of adipocytokines.3.The combination of BVT.2733 and Pioglitazone didn't have synergistic action.