二甲双胍对2型糖尿病模型大鼠胰岛素抵抗的影响

摘要

背景:目前已经发现的脂肪代谢相关基因有10余种,脂肪代谢相关基因介导的内分泌功能失常是导致胰岛素抵抗发生、发展的重要病理基础.目的:分析二甲双胍对2型糖尿病大鼠血脂水平、胰岛素抵抗相关基因及肝脏和胰腺组织病理学变化的影响.方法:通过4周高脂饮食结合腹腔注射链脲佐菌素(35 mg/kg)建立2型糖尿病大鼠模型.4周高脂饮食时,模型大鼠同时口服二甲双胍4周[400 mg/(kg?d)],对照组大鼠正常饮食,腹腔未注射链脲佐菌素.然后利用半定量RT-PCR、组织病理学及生化检测等方法进行相关分析.结果与结论:①二甲双胍通过恢复2型糖尿病大鼠正常血脂,改善胰岛素抵抗症状;②二甲双胍上调脂肪代谢相关胰岛素受体和基因乙酰辅酶A氧化酶,肉毒碱棕榈酰转移1和过氧化物酶体增殖物激活受体α;③二甲双胍治疗下调胎球蛋白A和视黄醇结合蛋白,2型糖尿病大鼠中降低的脂滴包被蛋白也恢复正常;④在胰腺内,二甲双胍处理诱导胰岛素分泌和胰腺β细胞再生;⑤结果说明,二甲双胍通过调节胎球蛋白A、视黄醇结合蛋白4、脂滴包被蛋白和脂肪代谢相关基因,改善2型糖尿病引起的胰岛素抵抗.%BACKGROUND:More than 10 kinds of lipid metabolism-related genes have been found, and endocrine dysfunction mediated by these genes is an important pathological basis for the occurrence and development of insulin resistance. OBJECTIVE:To investigate the effects of metformin on serum lipid profiles and the expression levels of various genes associated with insulin resistance, as well as the histopathological changes of the liver and pancreas in rats with type 2 diabetes melitus. METHODS:A type 2 diabetes mellitus rat model was established by feeding a high-fat diet to the rats for 4 weeks, combined with the intraperitoneal injection of streptozotocin (35 mg/kg). In the meanwhile, metformin was administered orally (400 mg/kg?d) (model group) or nothing (control group). Semi-quantitative RT-PCR, histopathological and biochemical examinations were then performed. RESULTS AND CONCLUSION:Metformin improved the symptoms of insulin resistance by normalizing the serum lipid profiles in the diabetic rats. Furthermore, metformin upregulated the expression levels of insulin receptors and genes associated with lipid metabolism, including acyl-CoA oxidase, carnitine palmitoyl transferase-1 and peroxisome proliferator activated receptor-α. In addition, metformin downregulated the expression levels of fetuin-A and retinol binding protein-4, and improved the expression of perilipin that had been reduced in the type 2 diabetes mellitus rats. Metformin was shown to induce positive signaling for insulin and the regeneration of pancreaticβcells in the pancreas. These results suggest that metformin ameliorates the insulin resistance induced by type 2 diabetes mellitus via regulating the expression levels of fetuin-A, retinol binding protein-4, perilipin and various genes associated with lipid metabolism.