目的 以高糖高脂饮食/STZ诱导的SD大鼠(Sprague-Dawley)为动物模型,研究在2型糖尿病大鼠中血管紧张素Ⅱ受体阻滞剂(ARB)改善胰岛素的代谢效应及对胰岛素引发的胰岛素受体底物1(IRS1)磷酸化、葡萄糖转运蛋白4(GLUT4)转位的影响,并研究其机制是否依赖于磷脂酰肌醇3激酶(PI3K)途径.方法 将42只SD大鼠随机抽取20只作为正常对照组,给予普通饮食,其余为糖尿病模型组22只,给予高脂高糖饮食及链脲佐菌素(STZ),空腹血糖(FBG)≥7.8 mmol/L且伴有胰岛素抵抗者为造模成功,成模大鼠共20只,将正常对照组分为对照组(A组,n=10)和对照处理组(B组,n=10);将糖尿病模型组分为糖尿病组(C组,n=10)和糖尿病处理组(D组,n=10),B组及D组给予ARB类药物氯沙坦(losartan)处理6周,A组及C组给予等量的0.9％氯化钠溶液.干预6周后称体重,断尾取血测空腹血糖及胰岛素水平,计算胰岛素敏感指数,麻醉动物在注射胰岛素15 min后取下老鼠后腿肌肉,储存备用.用逆转录-聚合酶链式反应(RT-PCR)测GLUT4、IRS1、PI3K、Akt mRNA的表达.结果 成功的制备了2型糖尿病大鼠模型,造模后,与A、B组比较,C、D组体重增加,空腹血糖、血浆胰岛素水平均升高(P<0.05),胰岛素敏感指数下降(P<0.05).氯沙坦干预后,与C组相比,D组体重增加,空腹血糖、血浆胰岛素水平降低,胰岛素敏感指数升高(P<0.05).RT-PCR结果显示:与A、B组比较,C、D组糖尿病大鼠GLUT4 mRNA表达降低(P<0.05),IRS1、PI3K、Akt mRNA表达差异无统计学意义(P>0.05).氯沙坦干预后,与C组比较,D组糖尿病大鼠GLUT4 mRNA表达差异无统计学意义(P>0.05),IRS1、PI3K、AktmRNA表达差异无统计学意义(P>0.05).A、B组比较,GLUT4、IRS1、PI3K、AktmRNA表达差异无统计学意义(P>0.05).结论 氯沙坦改善糖尿病大鼠IR,糖尿病处理组Ptyr-IRS1、GLUT4膜蛋白表达上升,Pser473-Akt的活性无差别,表明氯沙坦增加骨骼肌组织中GLUT4的转位有可能通过非PI3K途径.%Objective To investigate the effects of ARB in improving the metabolic effects of insulin and effects on phosphorylation of IRS1 induced by insulin and transposition of GLUT4 , and to explore whether its action mechanism depends on the pathway of PI3K. Methods Forty four SD rats were randomly divided into normal control group ( n =20) and model group ( n =22). The rats normal control group were fed with standard diet,however,the rats in model group were fed with high-fat and high-carbohydrate diet together with streptozotocin ( STZ ) . The rats with fasting plasma glucose ( FPG )≥7. 8mmol/L and insulin resistance were regarded as type 2 diabetic models. The rats in normal control group were randomly subdivided into control group A ( n =10) and treatment group B ( n =10),and 20 diabetic rats were randomly divided into NIDDM group C ( n =10) and NIDDM treatment group D ( n =10). The rats in group B and group D were treated with losartan for 6 weeks while the rats in group A and group C were treated with equivalent volume of 0. 9％ sodium chloride solution. Six weeks later, the rats were weighted, blood samples were collected to record glucose and insulin levers for calculation of ISI ( insulin sensitivity index) . Then the rats were fasted overnight and anesthetized for fifteen minutes before insulin injection. skeletal muscle was quickly removed from hind legs and stored at 80℃. RT PCR was used to detect the expression levels of GLUT4,IRS1,PI3K and AKT mRNA. Results As compared with those in group A and B, the body weight in group C and D was significantly increased, moreover, the levels of FPG, FINS were also significantly increased, however, ISI was decreased significantly( P <0. 05). After intervention with losartan, as compared with that in group C, the body weight in group D was increased, but the levels of FPG and FINS were decreased, moreover ISI was significantly increased ( P <0. 05). As compared with those in group A and B, the expression levels of GLUT4 mRNA in group C and D were significantly decreased ( P <0. 05),however, there were no differences in the expression levels of IRS1,PI3K and AKT ( P >0. 05). After intervention with losartan, there were no difference in the expression levels of GLUT4 mRNA between group C and group D ( P >0. 05),moreover there were nosignificant differences in the expression levels of IRS1,PI3K and AKT between the two groups ( P >0. 05). In addition there were no difference in the expression levels of GLUT4 mRNA, IRS1,PI-3K and AKT between group A and group B ( P >0. 05). Conclusion The losartan can improve IR of diabetic rats, increase the expression levels of Ptyr-IRS1 and GLUT4, and the action mechanism may be correlated with nonPI3 kinase pathway.
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