肝糖异方通过上调肝脏IRS2/PI3K信号通路改善肝硬化大鼠的胰岛素抵抗  

Gantangyi Decoction Up-Regulates Hepatic IRS2/PI3K Signaling Pathway to Improve Insulin Resistantce in Cirrhotic Rats

作　　者：陈冻伢 熊静芳[2] 徐燕芳 冯慧[1] 徐建军[1] 徐虹[1] CHEN Dongya;XIONG Jingfang;XU Yanfang;FENG Hui;XU Jianjun;XU Hong(Department of Gastroenterology and Hepatology, Hangzhou Red Cross Hospital, Hangzhou 310003, Zhejiang, China;Department of Geriatrics, Hangzhou Red Cross Hospital, Hangzhou 310003, Zhejiang, China;Department of Internal Medicine, Linan Hospital of Traditinal Chinese Medicine, Linan 311300, Zhejiang, China)

机构地区：[1]杭州市红十字会医院消化科,浙江杭州310003 [2]杭州市红十字会医院老年病科,浙江杭州310003 [3]临安市中医院内科,浙江临安311300

出　　处：《中华中医药学刊》2018年第4期883-886,I0010,共5页Chinese Archives of Traditional Chinese Medicine

基　　金：国家自然科学基金青年科学基金项目(81102707);浙江省医药卫生科技计划项目(2013KYA165,2015KYB314,2015KYB316,2016KYB247);杭州市科技发展计划重点专病专科项目(20150733Q39)

摘　　要：目的：探讨肝糖异方对肝硬化大鼠胰岛素抵抗的影响以及对肝脏中胰岛素受体底物2/磷脂酰肌醇-3-激酶（IRS2/PI3K）信号通路的影响。方法：40只SD大鼠随机分为正常组、模型组、肝糖异方组和二甲双胍组,每组各10只。制备四氯化碳和高脂高糖饮食复合肝硬化大鼠模型,肝糖异方组大鼠予肝糖异方灌胃（1 m L/100 g）,二甲双胍组大鼠予二甲双胍（200 mg·kg（-1）·d（-1））灌胃。对肝组织进行苏木素-伊红染色,口服葡萄糖耐量试验,检测空腹血清胰岛素,计算胰岛素抵抗指数HOMA-IR,免疫印迹法检测肝组织中IRβ和IRS2的表达,比色法检测PI3K活性。结果：四氯化碳和高脂高糖饮食复合肝硬化模型大鼠中检测到显著的葡萄糖不耐受和胰岛素抵抗。肝糖异方和二甲双胍显著减轻模型大鼠的肝纤维化程度和脂肪样变,改善葡萄糖不耐受和胰岛素抵抗。正常组大鼠肝组织中IRβ的蛋白表达量是模型组的3.13倍（P〈0.001）,肝糖异方组和二甲双胍组的肝脏中IRβ的表达量分别是模型组1.71倍和1.92倍（均P〈0.001）,有统计学差异。各组大鼠肝脏中的IRS2含量无显著差异,但正常组的IRS2磷酸化水平显著高于模型组,是模型组的2.02倍（P〈0.001）。肝糖异方组和二甲双胍组的IRS2磷酸化水平与模型组相比显著增高,分别是模型组的2.30倍和2.25倍（均P〈0.001）。与正常组相比较,模型组大鼠肝组织的PI3K活性显著下降（P〈0.01）,而肝糖异方组和二甲双胍组的PI3K活性比模型组显著增加（P〈0.01）。结论：肝糖异方汤能显著减轻肝硬化大鼠的肝脏损害,减轻葡萄糖不耐受和胰岛素抵抗,上调肝脏中IRβ的表达及其下游的IRS2/PI3K信号通路。Objective： To investigate the influence of Gantangyi Decoction on insulin resistance and hepatic IRS2/PI3 K signaling pathway in cirrhotic rats. Methods： Forty Sprague-Dawley rats were randomly divided into 4 groups： control group（ n = 10）,model group（ n = 10）,Gantangyi Decoction group（ n = 10） and Metformin group（ n = 10）. Cirrhosis was induced by subcutaneous injection of CCl_4 in combination with high-fat and high-sucrose diet feeding. The rats in Gantangyi Decoction group and metformin group were administrated intragastrically with Gantangyi Decoction at a dose of 1. 5 g/100（ g·day） and metformin at a dose of 200 mg/（ kg·day）,respectively. The morphologic change of liver was evaluated by Hematoxylin-eosin staining and the oral glucose tolerance test was performed. Fasting serum insulin level was determined to calculate HOMA-IR. The expressions of insulin receptor（ IR） and insulin receptor substrate2（ IRS2） in the liver were detected by Western blotting. PI3 K activity was determined by colorimetric method. Results：Significantly impaired glucose tolerance and increased HOMA-IR were detected in the model group. The treatment ofGantangyi Decoction or metformin effectively alleviated liver damages,improved the impaired glucose tolerance and reduced HOMA-IR. Compared to the model group,the expression of IRβ in the liver of control rats was remarkably increased and was 3. 13-fold over the model group（ P 〈0. 001）. IRβ expressions in the liver of the Gantangyi Decoction group and metformin group were 1. 71-fold and 1. 92-fold over the the model group,respectively（ both P 〈0. 001）.No significant differences were detected in the expression of IRS2 among the four groups. However,the phosphorylation of IRS2 was significantly higher compared to the model group and 2. 02-fold over the model group（ P 〈0. 01）. IRS2 phosphorylations were increased significantly to 2. 30-fold and 2. 25-fold over the model group by Gantangyi Decoction and metformin,respectively（ bo

关 键 词：肝糖异方 二甲双胍 肝硬化 胰岛素抵抗 胰岛素受体 胰岛素受体底物2/磷脂酰肌醇-3-激酶信号通路 

分 类 号：R285.5[医药卫生—中药学]