Yamazaki Satoru, Satoh Hiroaki, Watanabe Tsuyoshi
Department of Nephrology, Hypertension, Diabetology, Endocrinology, and Metabolism, Fukushima Medical University, Fukushima 960-1295, Japan.
Endocrinology. 2014 Sep;155(9):3288-301. doi: 10.1210/en.2013-2157. Epub 2014 Jun 20.
We investigated the effects of liraglutide on insulin sensitivity and glucose metabolism in male Wistar rats. The rats were fed a normal chow diet (NCD) or a 60% high-fat diet (HFD) for a total of 4 weeks. After 3 weeks of feeding, they were injected with liraglutide once a day for 7 days. Subsequently, euglycemic-hyperinsulinemic clamp studies were performed after fasting the animals for 8 hours. During the clamp studies on the NCD-fed rats, the glucose infusion rate required for euglycemia was significantly higher in the liraglutide group than in the control group. The clamp hepatic glucose output was significantly lower in the liraglutide group than in the control group, but the insulin-stimulated glucose disposal rate did not change significantly in the liraglutide groups. The clamp studies on the HFD-fed rats revealed that the glucose infusion rate required to achieve euglycemia was significantly higher in the liraglutide group than in the control HFD group, and the insulin-stimulated glucose disposal rate increased significantly in the liraglutide groups. The clamp hepatic glucose output decreased significantly in the liraglutide groups. Consistent with the clamp data, the insulin-stimulated phosphorylation of Akt and AMP-activated protein kinase was enhanced in the livers of the NCD- and HFD-fed rats and in the skeletal muscles of the HFD-fed rats. Oil red O staining indicated that liraglutide also improved hepatic steatosis. In summary, our studies suggest that in normal glucose tolerance states, liraglutide enhances insulin sensitivity in the liver but not in skeletal muscles. However, in insulin-resistant states, liraglutide improves insulin resistance in the liver and muscles and improves fatty liver.
我们研究了利拉鲁肽对雄性Wistar大鼠胰岛素敏感性和葡萄糖代谢的影响。将大鼠分为两组，分别喂食普通饲料（NCD）或60%高脂饲料（HFD），持续4周。喂食3周后，每天给它们注射一次利拉鲁肽，共注射7天。随后，在动物禁食8小时后进行正常血糖-高胰岛素钳夹试验。在对喂食NCD的大鼠进行钳夹试验期间，利拉鲁肽组维持正常血糖所需的葡萄糖输注速率显著高于对照组。利拉鲁肽组钳夹试验中的肝脏葡萄糖输出显著低于对照组，但利拉鲁肽组胰岛素刺激的葡萄糖处置率无显著变化。对喂食HFD的大鼠进行的钳夹试验显示，利拉鲁肽组实现正常血糖所需的葡萄糖输注速率显著高于HFD对照组，且利拉鲁肽组胰岛素刺激的葡萄糖处置率显著增加。利拉鲁肽组的钳夹肝脏葡萄糖输出显著降低。与钳夹数据一致，在喂食NCD和HFD的大鼠肝脏以及喂食HFD的大鼠骨骼肌中，胰岛素刺激的Akt和AMP激活的蛋白激酶磷酸化增强。油红O染色表明利拉鲁肽还改善了肝脏脂肪变性。总之，我们的研究表明，在正常糖耐量状态下，利拉鲁肽可增强肝脏而非骨骼肌的胰岛素敏感性。然而，在胰岛素抵抗状态下，利拉鲁肽可改善肝脏和肌肉的胰岛素抵抗，并改善脂肪肝。
