Wu Yong, Ouyang Jing-Ping, Zhou Yun-Feng, Wu Ke, Zhao De-Hai, Wen Chong-Yuan
Department of Pathophysiology, The College of Medicine, Wuhan University, Wuhan, Hubei 430071, China.
Sheng Li Xue Bao. 2004 Aug 25;56(4):539-49.
The specific inhibition of angiotensin II action at AT(1) receptors by losartan has been shown to decrease peripheral insulin resistance in type 2 diabetic patients and animal models. We examined the effect of losartan on the expression of insulin receptor substrate 1 (IRS-1), protein kinase B (PKB) and glucose transporter 4 (GLUT4), as well as the phosphorylation status of IRS-1 and the association between IRS-1 and phosphatidylinositol (PI) 3-kinase in skeletal muscle from fat-fed and-streptozotocin (STZ)-treated rats, an animal model of type 2 diabetes mellitus. In addition, the effects of losartan on GLUT4 translocation in muscle cells and on insulin sensitivity were also evaluated. Muscle tissues were isolated from male losartan-treated and untreated normal or non-insulin-dependent diabetes mellitus (NIDDM) rats with a dose of 4 mg/kg per day for 6 weeks. Oral administration of losartan improved insulin sensitivity, which was determined by an oral glucose tolerance test (OGTT). In skeletal muscles, the protein levels of IRS-1, PKB and GLUT4 in NIDDM rats were not significantly different from those of the control rats, and they were not affected by losartan. The levels of IRS-1 tyrosine phosphorylation, PI 3-kinase activity associated with IRS-1 and PKB activation after stimulation with insulin in muscle tissue of NIDDM rats were significantly decreased (P<0.01) compared with those in the control rats, while they were not increased by losartan. Losartan had a major effect on GLUT4 translocation in myocytes, as it significantly increased (P<0.05) the insulin-induced amounts of GLUT4 in plasma membrane (PM) and T-tubules (TT) in myocytes from NIDDM rats. Consistent with these results, the plasma glucose level in losartan-treated NIDDM rats was decreased (P<0.05) compared with that in untreated NIDDM rats. Our results suggest that losartan may exert beneficial effects on insulin resistance by increasing the translocation of GLUT4 in muscle tissue, which is probably associated with a non-PI 3-kinase-dependent mechanism.
氯沙坦对血管紧张素 II 在 AT(1) 受体处作用的特异性抑制已被证明可降低 2 型糖尿病患者和动物模型的外周胰岛素抵抗。我们研究了氯沙坦对胰岛素受体底物 1（IRS-1）、蛋白激酶 B（PKB）和葡萄糖转运蛋白 4（GLUT4）表达的影响，以及 IRS-1 的磷酸化状态和 IRS-1 与磷脂酰肌醇（PI）3-激酶在高脂喂养和链脲佐菌素（STZ）处理的大鼠骨骼肌中的关联，这是一种 2 型糖尿病动物模型。此外，还评估了氯沙坦对肌肉细胞中 GLUT4 转位和胰岛素敏感性的影响。从接受氯沙坦治疗和未治疗的雄性正常或非胰岛素依赖型糖尿病（NIDDM）大鼠中分离肌肉组织，剂量为每天 4 mg/kg，持续 6 周。口服氯沙坦改善了胰岛素敏感性，这通过口服葡萄糖耐量试验（OGTT）来确定。在骨骼肌中，NIDDM 大鼠中 IRS-1、PKB 和 GLUT4 的蛋白水平与对照大鼠相比无显著差异，且不受氯沙坦影响。与对照大鼠相比，NIDDM 大鼠肌肉组织经胰岛素刺激后 IRS-1 酪氨酸磷酸化水平、与 IRS-1 相关的 PI 3-激酶活性和 PKB 激活水平显著降低（P<0.01），而氯沙坦并未使其升高。氯沙坦对心肌细胞中 GLUT4 转位有主要影响，因为它显著增加（P<0.05）了 NIDDM 大鼠心肌细胞中胰岛素诱导的质膜（PM）和 T 管（TT）中 GLUT4 的量。与这些结果一致，氯沙坦治疗的 NIDDM 大鼠的血糖水平与未治疗的 NIDDM 大鼠相比有所降低（P<0.05）。我们的结果表明，氯沙坦可能通过增加肌肉组织中 GLUT4 的转位对胰岛素抵抗产生有益影响，这可能与一种非 PI 3-激酶依赖性机制有关。
