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本文研究血管紧张素Ⅱ受体拮抗剂诺沙坦对非胰岛素依赖型糖尿病(non-insulin-dependent diabetes mellitus,NIDDM)大鼠胰岛素敏感性的改善作用,并探讨其作用机制。从饮水中给予正常或高脂喂养加小剂量链脲佐菌素(STZ)诱发的NIDDM大鼠诺沙坦(4 mg/kg),连续6周。分离骨骼肌,用免疫印迹法检测诺沙坦对胰岛素受体底物1(insulin receptor substrate 1,IRS-1)、蛋白激酶B(protein kinase B,PKB)和葡萄糖转运因子4(glucose transporter 4,GLUT4)的表达,以及IRS-1的磷酸化、IRS-1与磷脂酰肌醇3激酶(phosphatidylinositol(PI)3-kinase)的结合。口服葡萄糖耐量试验表明,口服诺沙坦可改善糖尿病大鼠胰岛素敏感性。在骨骼肌组织,NIDDM和正常大鼠的IRS-1、PKB和GLUT4蛋白表达无差异,且不受诺沙坦处理的影响。NIDDM大鼠胰岛素刺激后的骨骼肌IRS-1酪氨酸磷酸化水平、PI 3-kinase结合IRS-1的活性和PKB活性较对照组显著降低(P<0.01),且不能被诺沙坦改善。诺沙坦显著增加NIDDM大鼠肌细胞质膜(plasma membrane,PM)和T管(T-tubules,TT)胰岛素诱导的GLUT4的 含量(P<0.05)。与该结果一致的是,诺沙坦处理的NIDDM大鼠血糖水平较未处理NIDDM大鼠下降(P<0.05)。结果表明,诺沙坦可改善胰岛素抵抗状态,主要是通过非PI 3-kinase依赖的
This study was designed to investigate the effect of losartan, an angiotensin Ⅱ receptor antagonist, on insulin sensitivity in non-insulin-dependent diabetes mellitus (NIDDM) rats and its possible mechanism. NOSDM rats were given losartan (4 mg / kg) given normal or high-fat diet plus low-dose streptozotocin (STZ) for 6 weeks in drinking water. The skeletal muscle was isolated and the expression of insulin receptor substrate 1 (IRS-1), protein kinase B (PKB) and glucose transporter 4 GLUT4), as well as IRS-1 phosphorylation, IRS-1 binding to phosphatidylinositol (PI) 3-kinase. Oral glucose tolerance test showed that oral losartan can improve insulin sensitivity in diabetic rats. In skeletal muscle tissue, there was no difference in IRS-1, PKB and GLUT4 protein expression in NIDDM and normal rats, and was not affected by norosphatase treatment. IRS-1 tyrosine phosphorylation, PI3-kinase binding activity of IRS-1 and PKB activity of skeletal muscle of insulin-stimulated NIDDM rats were significantly lower than those of control group (P <0.01), and could not be improved by nozosta . Neosartan significantly increased insulin-induced GLUT4 content in plasma membrane (PM) and T-tubules (TT) of NIDDM rats (P <0.05). Consistent with this result, the blood glucose levels of nosartan-treated NIDDM rats were lower than those of untreated NIDDM rats (P <0.05). The results show that, Rosin can improve insulin resistance status, mainly through the non-PI 3-kinase-dependent