目的探讨长期高脂饮食状态下不同剂量酒精摄入对大鼠胰岛素抵抗的影响及可能机制。方法清洁级Wistar大鼠,随机分为正常对照、高脂对照、高脂+5%、10%、20%、30%、40%酒精共7组。13w后,断头取血,测空腹血糖(FPG)及血胰岛素(FINS)浓度,计算胰岛素抵抗指数(homeostasis model assessment,HOMA-IR)及HOMA-β功能指数(HOMAβ-cellindex,HBCI)。RT-PCR法测定肝脏胰岛素受体底物-1(IRS-1),磷脂酰肌醇3激酶(PI-3K)、葡萄糖转运体-2(GLUT-2)的mRNA表达水平。Westernblotting测定肝脏PI-3K(p85α)、GLUT-2的蛋白表达水平。结果高脂对照组与正常对照组比,血胰岛素、HOMA-IR、HBCI明显升高(P<0.05),肝脏胰岛素信号传导关键分子没有显著差异。与高脂对照组比,高脂+酒精组空腹血糖、胰岛素抵抗指数明显升高(P<0.05),血胰岛素、胰岛β细胞功能指数明显下降(P<0.05);肝脏胰岛素信号传导关键分子mRNA、蛋白表达水平随酒精剂量的增加而逐渐下降。结论长期高脂饮食联合酒精摄入导致胰岛素抵抗;同时抑制肝脏胰岛素信号传导关键分子表达水平,在高剂量酒精组更明显,这可能是其导致胰岛素抵抗的分子机制。 Objective To investigate the effect of different doses of alcohol intake on insulin resistance and its possible mechanism in long-term high-fat diet. Methods Wistar rats were randomly divided into normal control, high fat control, high fat + 5%, 10%, 20%, 30% and 40% alcohol for 7 groups. After 13 weeks, the blood samples were decapitated, and the levels of fasting blood glucose (FPG) and insulin (FINS) were measured to calculate the homeostasis model assessment (HOMA-IR) and HOMA-β index (HBCA). The mRNA expression of hepatic insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI-3K) and glucose transporter-2 (GLUT-2) Western blotting was used to detect the protein expression of PI-3K (p85α) and GLUT-2 in liver. Results Compared with the normal control group, the levels of insulin, HOMA-IR and HBCI in the hyperlipidemic control group were significantly increased (P <0.05). There were no significant differences in the hepatic insulin signaling key molecules. Compared with the high-fat control group, the fasting blood glucose and insulin resistance index were significantly increased (P <0.05), and the function index of blood insulin and islet β-cell decreased significantly in high fat + alcohol group (P <0.05) , The level of protein expression decreased with the increase of the dosage of alcohol. Conclusion Long-term high-fat diet combined with alcohol intake leads to insulin resistance. At the same time, it inhibits the expression of hepatic insulin signaling key molecules in the high-dose alcohol group, which may be the molecular mechanism of insulin resistance.