胰岛素抵抗在非酒精性脂肪性肝病发生中的作用途径及中药干预研究

项目名称： 胰岛素抵抗在非酒精性脂肪性肝病发生中的作用途径及中药干预研究

项目编号： No.30873260

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 季光

作者单位： 上海市中医药研究院

项目金额： 31万元

中文摘要： 目的：观察胰岛素抵抗在 NAFLD形成中的动态规律；评价降脂颗粒对NAFLD的治疗作用及对胰岛素抵抗的调节机理。方法：大鼠按照体重随机分为0、2、4、6、8周（n=6）5个时点组，除0周组外，其他各组均给予高脂高糖饲料。分别对大鼠进行OGTT和ITT试验；观察大鼠血清和肝脏病理生化改变，评价胰岛素抵抗指数；检测肝组织胰岛素信号分子的mRNA和蛋白表达。大鼠造模8周后，按体重随机分为模型组、降脂颗粒组、吡咯列酮组，并设正常组（n=8）。治疗4周后对血清和肝脏组织学和生化学进行分析，检测相关指标。结果：高脂高糖饮食大鼠肝脏脂肪变逐渐加重；肝脏内TG含量明显增多；血脂代谢紊乱；胰岛素抵抗指数增加；肝脏胰岛素信号分子表达在2周组即出现异常改变。降脂颗粒可显著改善肝脏脂肪变和减少肝脏TG含量；升高肝糖原含量，改善糖耐量受损，改善肝组织胰岛素抵抗。结论：肝脏胰岛素抵抗先于全身胰岛素抵抗及肝脏脂肪变出现，表明肝脏胰岛素抵抗是NAFLD形成的起始因素；降脂颗粒可改善NAFLD大鼠肝脏脂肪变和降低肝脂肪含量，其效应可能通过改善胰岛素抵抗实现。

中文关键词： 非酒精性脂肪性肝病；胰岛素抵抗；信号转导；降脂颗粒

英文摘要： Aim : To observe the dynamic development of insulin resistance in nonalcoholic fatty liver disease（NAFLD）; To evaluate the effect of Jiangzhi granula (JZKL) on rats with NAFLD and the mechanism involved in insulin resistance.Methods: Male Wistar rats were randomly divided into 5 groups（n=6/group）, except the rats in 0 week group, rats were all given high fat high sucrose diet for 2, 4, 6 , 8weeks respectively. In every time point, 6 rats were given OGTT and ITT, serum and hepatic pathology and biochemical items were observed; insulin resistance index was calculated; molecules in hepatic insulin signaling were analyzed by RT-PCR and Western blotting. The NAFLD rats were then randomly divided into model group, pioglitazone group and JZKL group（n=8/group）, and the rats were given normal chow as control group (n=8). After 4 weeks treatment, the exactly above tests were detected. Results: Compared with 0 week group, other groups demostrated aggravated liver steatosis, incresed body weight, liver weight, liver index and liver triglyceride; serum TC, TG, LDL, FFA higher and HDL lower; both serum insulin and glucose raised; OGTT curve and area under curve were increased while ITT decreased, liver InsR and P-IRS1 protein were downregulated from 2week group, the IRS1 mRNA was reduced from 4 week group, and the InsR protein was decreased from the 6week group. Compared with the model group, JZKL can significantly improve liver steatosis, reduce liver TG; decrease hepatic glycogen and improve OGTT; upregulate liver IRS-1 expression and activation.Conclusion: Hepatic insulin resistance are the initiation of NAFLD, and JZKL can effectively improve liver steatosis and reduce liver TG. It possibly through regulating hepatic inulin resistance.

英文关键词： non-alcoholic fatty liver disease; insulin resistance; signal transduction; Jiangzhi Granula