Exendin-4改善胰岛素抵抗的作用机制研究

目的探讨exendin-4（exenatide）对高脂诱导胰岛素抵抗（IR）大鼠胰岛素敏感性（IS）改善的机制及对脂肪细胞因子的影响。方法健康雄性SD大鼠随机分为正常饮食组（NC）、高脂组（HF）和高脂＋Exenatide组（HE）。HE组给予exenatide（2μg／kg，Et二次）腹腔注射6周，用静脉胰岛素耐量试验评价各组IS变化，观察各组肌肉和脂肪组织胰岛素信号传导、脂肪细胞因子表达和血浆浓度变化。结果6周后，HE组Lee＇s指数、空腹血浆FFA、TG、TC均较NC组降低（P均〈0．01），IR明显改善；胰岛素刺激后HE组肌肉和脂肪组织IRS-1酪氨酸磷酸化升高（P〈0．05）；HF和HE组血浆内脏脂肪素（visfatin）水平明显降低（P〈0．05，P〈0．01），但HE组脂联素（APN）血浆水平和脂肪组织mRNA表达明显高于HF和NC组（P均〈0．01）。结论Exenatide明显改善了高脂大鼠IR，其胰岛素增敏机制可能与增强IRS-1酪氨酸磷酸化以及对APN、visfatin等脂肪细胞因子的影响有关。

The study of mechanism for exendin-4(exenatide)improving insulin resistance

Objective To investigate the effects of exendin-4 （exenatide） on insulin sensitivity and adipocytokine in high-fat-fed rats. Methods Rats were divided randomly into normal-chow group （NC）, high-fat group （HF） and high-fat＋exendin treated group （HE）. HE rats were given exenatide （2μg/kg） twice daily for 6 wk. The insulin sensitivity was evaluated by intravenous insulin tolerance test （IVITT）. Insulin-stimulated changes in insulin signal transduction, visfatin and adiponectin mRNA expressions as well as their plasma levels were also observed in these rats. Results Plasma free fatty acids （FFA）, triglyceride （TG）, total cholesterol （TC） levels were significantly reduced after exenatide treatment （in HE rats all P〈0.01）, And IVITT parameters were also improved in these rats. Insulin-stimulated IRS-1 tyrosine phosphorylation was slightly increased in exenatide-treated rats as compared with HF rats （P〈 0.05）. In addition,plasma visfatin level was significantly reduced in HF and HE groups as compared with controls （P〈0.05 and P〈0.01）. The adiponectin mRNA expression in adipose tissues and circulating adiponectin level were significantly elevated in exenatide-treated rats as compared with untreated rats and controls （P 〈 0.01 ）. Conclusions Chronic exenatide treatment improves insulin resistance in high-fat-fed rats , and the changes of IRS-1 tyrosine phosphorylation and adiponectin may be related to the role of exenatide in elevating insulin sensitivity.