The Effect Of N-(Z)-9-octadecenyl-2-Propanesulfonamide And Its Mechanism Of Action On Insulin Resistance In Type 2 Diabetes Mellitus

Type 2 diabetes mellitus?T2DM?is one of the most serious health crisis in the past several decades.Agonists of peroxisome proliferator-activated receptor alpha/gama?PPAR?/??have emerged as an important pharmacological agent for improving insulin sensibility.Propane-2-sulfonic acid octadec-9-enyl-amide?N15?is a novel PPAR?/?dual agonist synthesized in our laboratory.The present study investigates the efficacy and safety of N15 on insulin resistance regulation in streptozotocin?STZ?or high fat diet and streptozotocin?HFD+STZ?-induced diabetic mice and in palmitic acid?PA?-induced HepG2 cells.We also aimed to reveale the underlying mechanism involving in anti-insulin resistance actions of N15,in order to provide theoretical basis for T2DM clinical treatment.Our results showed that N15 significantly reduced the levels of blood glucose,serum insulin and the homeostatic model assessment of insulin resistance?HOMA-IR?were significantly reduced to levels equivalent in non-diabetic mice.N15 remarkably improved glucose and insulin tolerance at 6^th week post-treatment.Moreover,N15triggered favorable changes in plasma lipids,that were identified by a significant decrease in TC,TG,LDL-C levels.In vitro,N15 significantly up-regulated glucose consumption and down-regulated glucose production in PA-induced HepG2 cells.Furthermore,the expression of key gluconeogenic enzyme phosphoenolpyruvate carboxykinase?PEPCK?and glucose-6-phosphatase?G6Pase?were down-regulated significantly in PA-induced HepG2 cells and HFD+STZ induced liver tissue following N15 treatment.However,these beneficial changes in glucose consumption,gluconeogensis and the expression of PEPCK and G6Pase induced by N15 were almost completely reversed by the PPAR?inhibitor T0070907.Similarly,these changes in the levels of FBG,FIns and HOMA-IR following by N15 were all substantially reversed by GW9662 treatment.In present study,N15 treatment had no influence on the concentrations of glutamic-oxalacetic transaminase?AST?,glutamic-pyruvic transaminase?ALT?in serum and cell viability in vitro,as well as the expression in apoptosis related protein.These are the opposite of piglitazone.Our data demostrated that N15,a novel PPAR?/?agonist,exerted advantageous effects on glucose and lipid metabolism without causing serious side effects detected in existing PPAR?agonists.These roles may be due to its beneficial effects on PPAR?mediated inhibition of gluconeogensis.Therefore,our results suggested that N15 may be a potential and effective compound against type 2 diabetes.