Exenatide 对高脂诱导胰岛素抵抗大鼠胰岛素敏感性及糖脂代谢的影响

目的 探讨Exenatide对高脂诱导胰岛素抵抗大鼠胰岛β细胞功能、胰岛素敏感性及糖脂代谢的影响. 方法 高脂诱导胰岛素抵抗大鼠给予Exenatide 6周后,采用静脉葡萄糖耐量(IVGTT)和胰岛素耐量(ITT)试验以及扩展胰岛素钳夹技术测定胰岛素敏感性和糖脂代谢,并观察血浆脂联素水平的变化.结果 高脂大鼠(HF)经Exenatide处理后,Lee′s指数、空腹血浆游离脂肪酸(FFA)、甘油三酯、胆固醇明显降低(均P＜0.01);IVGTT和ITT明显改善,胰岛素分泌水平增高,高剂量组(HFH)较低剂量组(HFL)上述指标改善更为明显.同时,HFH组血浆脂联素水平也明显升高(P＜0.01).在钳夹稳态时,HF组与对照组(NC)相比,血浆FFA、胰岛素水平均明显升高(均P＜0.01),葡萄糖输注率(GIR)、葡萄糖清除率(GRd)明显降低(均P＜0.01),且胰岛素对肝糖输出(HGP)的抑制作用明显障碍(仅抑制26%).经Exenatide(2 μg/kg)处理以后,血浆FFA、胰岛素水平则明显降低(均P＜0.01),GRd、GIR明显升高(均P＜0.01),胰岛素对HGP的抑制作用明显增强(抑制72%).结论 对高脂喂养大鼠用Exenatide预处理可能通过促进β细胞胰岛素分泌和上调血浆脂联素水平,改善糖脂代谢而使机体胰岛素敏感性增加.

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.