雷帕霉素对小鼠葡萄糖代谢水平的影响

Effects of rapamycin on glucose metabolism and insulin resistance in obese mice

目的探讨雷帕霉素对葡萄糖代谢水平影响的特点、机制。方法选择4周龄、雄性C57BL/6小鼠,高热量、高脂饮食喂养8周后为肥胖组(HF,n=18),普通饲料喂养为正常组(NC,n=18)。两组小鼠分别给予安慰剂(n=6)、腹腔注射雷帕霉素(2 mg/kg,隔日1次,n=6)、喂饮2.37%亮氨酸水(n=6),2周后分别行灌胃葡萄糖耐量试验(glucose tolerance test,GTT)、胰岛素耐受性试验(insulin tolerance test,ITT)以及胰岛组织病理学检查。结果正常组小鼠腹腔注射雷帕霉素后葡萄糖负荷30min血糖水平显著升高(与安慰剂组比P=0.038,与亮氨酸组比P=0.035)。肥胖组小鼠腹腔注射雷帕霉素后空腹血糖水平显著高于安慰剂组(P=0.031),葡萄糖负荷30 min血糖显著高于安慰剂组(P=0.013)、亮氨酸组(P=0.041)。仅正常组小鼠胰岛素敏感性与安慰剂组相比显著降低(P=0.039)。雷帕霉素干预后腹腔脂肪量显著减少(正常组与安慰剂组比P<0.001,肥胖组与安慰剂组比P=0.013)。结论雷帕霉素对哺乳动物糖代谢水平有显著影响,正常小鼠与机体胰岛素敏感性下降有关;肥胖小鼠与胰岛素分泌功能受损、胰岛素抵抗相关。

Objective To explore the effects of rapamycin on blood glucose level and insulin resistance in diet-in- duced obese mice. Methods Healthy 4 week-old male C57BL/6 mice were fed with high fat diet （ HF, n = 18 ） or nor- mal chow （normal control, NC, n = 18） for 8 weeks. Both control and obese mice were treated with placebo, rapamycin [ 2 mg/kg,intraperitonealy （ip） , Qod, n = 6 ] and 2.37% leucine-containing drinking water （ n = 6） for 2 weeks, respec- tively. Oral glucose tolerance test （OGTT） , insulin tolerance test （ITT） and morphological studies for pancreatic islets were performed. Results The normal mice treated with rapamycin showed a significant increase of glucose level at 30 mi- nutes after glucose challenge in comparison with the placebo- （P = 0. 038） and leucine-treated （P = 0. 035） groups. The rapamycin-treated obese mice showed a significantly elevated fasting glucose level compared with the placebo-treated obese mice （P = 0. 031 ）, and a higher glucose level at 30 minutes after glucose challenge than that in the placebo-treated mice （P =0. 013） and leucine-treated mice （P =0. 041 ）. The normal mice after rapamycin treatment had a decreased insulin sensitivity than those with placebo treatment （P = 0. 039）. Rapamycin treatment significantly reduced the peritoneal whiteadipose mass in both normal （P 〈 O. 001 ） and obese mice （P = 0. 013） than in the placebo controls. Conclusions Rapa- mycin had significant effect on glucose metabolism in mice. The impairment of glucose metabolism in normal mice after ra- pamyein treatment is correlated with decreased glucose tolerance, while the impairment of glucose metabolism in obese mice is resulted from reduced insulin secretion and increased insulin resistance.