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

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

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B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。

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-[ 3^H ] 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.