目的 研究尿石素A（UA）对2型糖尿病模型小鼠肝脏胰岛素信号通路的影响及与自噬的关系。方法 将C57BL/6小鼠按体质量随机分成4组，即对照组、模型组、尿石素A（50 mg/kg）组、尿石素A（50 mg/kg）联合氯喹（50 mg/kg）组，高脂饲料喂养6周后，ip链脲佐菌素（STZ）建立2型糖尿病模型。各组小鼠ig给药7周，检测小鼠体质量、饮水量、血脂、空腹血糖（FBG）、空腹胰岛素（FINS）水平；计算胰岛素抵抗指数（HOMA-IR）、胰岛素敏感指数（ISI）；HE染色观察小鼠肝组织病理变化；蛋白免疫印迹法检测小鼠肝组织磷酸化蛋白激酶B（p-Akt）、葡萄糖转运蛋白2（Glut2）、磷酸化糖原合酶激酶-3β（p-GSK3β）及自噬相关蛋白微管相关蛋白质1轻链3 II/I（LC3II/I）、选择性自噬接头蛋白（p62）表达水平。结果 与模型组比较，UA能够显著改善糖尿病模型小鼠肝组织脂肪变和水肿；显著降低血浆三酰甘油（TG）、游离脂肪酸（FFA）、低密度脂蛋白-胆固醇（LDL-C）、FBG、FINS水平，升高高密度脂蛋白-胆固醇（HDL-C）水平（P<0.01）；显著降低HOMA-IR，升高ISI（P<0.01）；上调肝组织p-Akt、Glut2、p-GSK3β、LC3II/I蛋白表达，抑制p62蛋白表达（P<0.01）。联合氯喹后，小鼠FBG、FINS、HOMA-IR增加，ISI降低（P<0.05）；肝组织水肿和脂肪病变明显加重；肝组织p-Akt、Glut2、LC3II/I蛋白表达水平降低，p62蛋白表达水平升高（P<0.05），显示自噬抑制剂氯喹明显削弱了UA的作用。结论 UA可能是通过激活肝脏自噬改善糖尿病小鼠肝脏胰岛素抵抗。

Objective To investigate the effect of urolithin A (UA) on liver insulin signaling pathway in type 2 diabetes model mice and its relationship with autophagy. Methods C57BL/6 mice were randomly divided into four groups according to body weight, namely control group, model group, UA (50 mg/kg) group, UA (50 mg/kg) combined with chloroquine (50 mg/kg) group. After 6 weeks of high-fat diet, a type 2 diabetes model was established by ip streptozotocin (STZ). The mice in each group were ig administrated for 7 weeks, and their body weight, water intake, blood lipids, fasting blood glucose (FBG), and fasting insulin (FINS) levels were measured; HE staining was used to observe pathological changes in mouse liver tissue; Western blotting was used to detect mouse phosphorylated protein kinase B (p-Akt), glucose transporter 2 (Glut2), phosphorylated glycogen synthase kinase-3β (p-GSK3β) and autophagy-related protein microtubule-related protein 1 light chain 3 II/I (LC3II/I) and selective autophagy linker protein (p62) expression levels. Results Compared with the model group, UA significantly improved liver tissue steatosis and edema in diabetic model mice, significantly reduced plasma triacylglycerol, free fatty acids, low-density lipoprotein-cholesterol, FBG, FINS levels, and increased high-density lipoprotein-cholesterol level (P<0.01); UA significantly reduced HOMA-IR and increased ISI (P<0.01), up-regulated the protein expression of p-Akt, Glut2, p-GSK3β, and LC3II/I in liver tissues, and inhibited the expression of p62 protein (P<0.01). Combined with chloroquine, FBG, FINS, and HOMA-IR in mice were increased, and ISI was decreased (P<0.05); Liver tissue edema and steatosis were significantly aggravated; The expression levels of p-Akt, Glut2, LC3II/I protein in liver tissue were decreased, and p62 protein expression levels were increased (P<0.05), indicating that the autophagy inhibitor chloroquine significantly weakened the effect of UA. Conclusion UA may improve liver insulin resistance in diabetic mice by activating liver autophagy.

R285.5

新疆维吾尔自治区自然科学基金资助项目（2017D01C204）；国家自然科学基金资助项目（81760767）；新疆医科大学博士启动基金（2019-017）；新疆医科大学研究生创新创业启动基金项目（CXCY2018006）；新疆自治区研究生科研创新项目（XJ2019G192）