坎地沙坦增强肥胖大鼠胰岛素敏感性

Effects of Candesartan on Insulin Sensitivity in Fatty Rats

目的坎地沙坦对高脂饮食所致肥胖大鼠胰岛素敏感性的影响及其可能机制。方法4～6周龄雄性Wistar大鼠随机分为普通饲料组（NC，n=15），高脂饲料组（HF，n=15）和高脂饲料坎地沙坦药物组（HF＋C，n=15）。药物组每天灌胃坎地沙坦西酯8mg／kg，其他两组分别给予等量生理盐水。喂养16周后用光学显微镜观察附睾脂肪细胞大小，用正常血糖高胰岛素钳夹技术的葡萄糖输注率评价胰岛素抵抗，用酶联免疫吸附试验检测血清血管紧张素Ⅱ（AngⅡ），用免疫组化法检测大鼠骨骼肌葡萄糖转运蛋白4（GLUT4）表达，免疫印迹检测骨骼肌GLUT蛋白的表达，检测空腹血糖、空腹胰岛素、三酰甘油（TG）和总胆固醇（TC）等生化指标，计算胰岛素敏感指数（ISI）。结果1）HF＋C组的脂肪细胞体积较HF组明显减小，血清血管紧张索Ⅱ明显增加，骨骼肌GLUT4表达明显下降。2）坎地沙坦明显降低总胆固醇、空腹胰岛素水平[总胆固醇，HF＋C组：（1．37±0．39）比HF组：（2．01±0．26）mmol／L，P〈0．01；空腹胰岛素，HF＋C组：（3．03±1．37）比HF组：（4．8±2．8）mU／L，P〈0．01]，提高胰岛素敏感指数水平[胰岛素敏感指数，HF＋C组：（57．9±11．8）×10^-3比HF组：（29．4±9．0）×10^-3，P〈0．01]。3）坎地沙坦还提高稳态葡萄糖输注率[稳态葡萄糖输注率，HF＋C组，（22．4±5．1）比HF组：（13．5±3．9）mmol／L，P〈0．01]，加强骨骼肌组织GLUT4表达[积分光密度，HF＋C组：（64．8±6．8）比HF组：（32．5±9．6），P％0．01]。结论坎地沙坦可以增强高脂喂养大鼠的胰岛素敏感性，高血AngⅡ致脂肪细胞体积增大及骨骼肌GLUT4的低表达是胰岛素抵抗的可能原因。

Objective To investigate the effects of candesartan on insulin sensitivity in high-fat diet induced obesity in rats and its possible mechanisms. Methods IR rat model was established by feeding 4--6 week-old male Wistar rats with high fat diet and were randomly divided into normal chow group （NC, n= 15）, high fat diet group （HF, n= 15） and high-fat diet with daily candesartan treatment group （HF＋C, n= 15）. Candesartan was administered by gavage at doses of 8 mg/kg body weight per day. Sixteen weeks later, adipocyte size was examined by light microscopy, glucose infusion. Euglycemic hyperinsulinemic clamp technique was used to determine the insulin sensitivity. Serum angiotensin Ⅱ （Ang Ⅱ ） was determined by enzyme linked immunosorbent assay （ELISA）. Activation of glucose trarsporter 4（GLUT4） in skeletal muscles were detected by immunohistochemical SP method, GLUT4 expressions were assayed by Western blotting. Body weights, fast plasma glucose （FPG）, insulin （FINS）, triglyceride （TG）, cholesterol （TC） were determined and the insulin sensitivity index （ISI） was calculated. Results 1）Candesartan markedly decreased adipocyte size without changing the number of adipocytes. 2 ）TC and FINS group were lower than those of HF group （TC, HF＋C group： 1.4±0.4 vs HF group： 2.0±0. 3 mmol/L, P 〈0.01 ; FINS, HF＋C group： 3.0± 1.4 vs HF group： 4.8±2.8 mU/L, P〈0. 01）, while candesartan significantly increased ISI（ISI, HF＋C group： 57.9±11.8× 10^-3 vs HF group： 29.4±9.0× 10^-3 , P〈0. 01 and the SSGIR （SSGIR, HF＋C group： 22.4±5.1 vs HF group： 13.5±3.9 mmol/L, P〈0.01）, while was associated with enhanced GLUT4 expression in skeletal muscles （ IOD, HF＋ C group： 64.8 ± 6.8 vs HF group： 32. 5 ± 9.6, P 〈0.01）. Conclusion Our results suggest that candesartan might act as insulin sensitizer, demonstrated by lowering fast plasma insulin, increases in insulin sensitivity index associated with accentuations of GLUT4 protein expression in skeletal muscles in fatty rats.