Effects of exenatide on insulin sensitivity and glucose-lipid metabolism in insulin resistant rats induced with high fat chow

Objective To investgate the effects of exenatide on islet β-cell function, insulin sensitivity and glucose-lipid metabolism in insulin resistant rats induced by high-fat-chow. Methods High fat-fed rats were treated with exenatide for 6 weeks. The insulin sensitivity, islet β-cell function and glucose lipid metabolism in awake rats were evaluated by intravenous glucose tolerance test (IVGTT), insulin tolerance test (ITT) and hyperinsulinemic-euglycemic clamp technique combined with 3-[3H] glucose as a tracer. In addition, plasma adiponectin level was measured by ELISA. Results Lee′s index and levels of plasma free fatty acids (FFA), triglyceride and total cholesterol were significantly reduced in high fat-fed rats after exenatide treatment for 6 weeks (all P＜0.01). In these rats exenatide also improved IVGTT and ITT, and increased the level of insulin secretion, especially when a high dose was given. In addition, plasma adiponectin level was also significantly increased in the group with high dose exenatide (HFH, P＜0.01). During the clamp steady-state, there were significant increases in plasma FFA and insulin and significant decreases in glucose infusion rate (GIR), glucose disposal rate (GRd) in high-fat group (HF) compared to control group (NC, all P＜0.01). The suppressive effect of insulin on hepatic glucose production (HGP) was significantly blunted (only 26%) in HF group. In HFH group, plasma insulin and FFA levels were significantly decreased (both P＜0.01), GIR and GRd were significantly increased (both all P＜0.01), and HGP was suppressed by 72%. Conclusion It is possible that exenatide pretreatment ameliorates high-fat induced insulin resistance by promoting β-cell insulin secretion, elevating adiponectin level, and improving glucose-lipid metabolism. Key words: Exenatide; Insulin resistance; Glucose-lipid metabolism; Adiponectin