Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Shitsukawa, Tohon, Ehime, Japan.
J Hypertens. 2010 Jul;28(7):1471-81. doi: 10.1097/HJH.0b013e32833bc420.
The renin-angiotensin system affects insulin sensitivity mainly through the angiotensin II type 1 receptor. In this study, the effects of renin inhibition on insulin resistance and adipose tissue dysfunction were explored in type 2 diabetic KK-A(y) mice.
Male KK-A mice were treated with a direct renin inhibitor, aliskiren, administered subcutaneously at a dose of 50 mg/kg per day for 14 days using an osmotic minipump. This dose of aliskiren strongly inhibited plasma renin activity and lowered blood pressure about 17% in KK-A(y) mice. Aliskiren decreased body weight and plasma glucose level, and increased plasma insulin level in a fed condition. Aliskiren also lowered the plasma levels of cholesterol, fatty acids and triglycerides. In the oral glucose tolerant test, the plasma glucose elevation after glucose load was reduced by aliskiren, without a significant change in insulin level. Insulin tolerance test showed that aliskiren enhanced insulin's effect on plasma glucose. Aliskiren also reduced the epididymal adipose tissue mass by 25% and retroperitoneal adipose tissue mass by 35%. In adipose tissue, expression of the insulin receptor was not changed by aliskiren; however, expression of insulin receptor substrate-1, glucose transporter type 4, adiponectin, peroxisome proliferator-activated receptor-gamma and CCAAT/enhancer-binding proteindelta was increased by aliskiren. Moreover, NADPH oxidase activity and expression of inflammatory factors were reduced in adipose tissue. Aliskiren increased the pancreatic beta-cell area in KK-A(y) mice.
These results suggest that renin inhibition by aliskiren improved insulin resistance and adipose tissue dysfunction in type 2 diabetic mice through an increase in insulin sensitivity, insulin secretion and adipocyte differentiation, and a reduction of oxidative stress.
肾素-血管紧张素系统主要通过血管紧张素 II 型 1 型受体影响胰岛素敏感性。在本研究中，探讨了肾素抑制剂对 2 型糖尿病 KK-A(y) 小鼠胰岛素抵抗和脂肪组织功能障碍的影响。
雄性 KK-A 小鼠每天通过皮下渗透泵给予 50mg/kg 的直接肾素抑制剂阿利克仑，连续治疗 14 天。该剂量的阿利克仑能强烈抑制血浆肾素活性，并使 KK-A(y) 小鼠的血压降低约 17%。阿利克仑降低了体重和空腹血糖水平，并增加了血浆胰岛素水平。阿利克仑还降低了胆固醇、脂肪酸和甘油三酯的血浆水平。在口服葡萄糖耐量试验中，葡萄糖负荷后血糖升高被阿利克仑降低，而胰岛素水平没有明显变化。胰岛素耐量试验表明，阿利克仑增强了胰岛素对血糖的作用。阿利克仑还使附睾脂肪组织减少 25%，腹膜后脂肪组织减少 35%。在脂肪组织中，阿利克仑并未改变胰岛素受体的表达；然而，胰岛素受体底物-1、葡萄糖转运蛋白 4、脂联素、过氧化物酶体增殖物激活受体-γ 和 CCAAT/增强子结合蛋白 δ 的表达增加。此外，脂肪组织中的 NADPH 氧化酶活性和炎症因子的表达减少。阿利克仑增加了 KK-A(y) 小鼠的胰岛 β 细胞面积。
这些结果表明，阿利克仑通过增加胰岛素敏感性、胰岛素分泌和脂肪细胞分化，以及减少氧化应激，改善了 2 型糖尿病小鼠的胰岛素抵抗和脂肪组织功能障碍。
