Liraglutide enhances insulin sensitivity by activating AMP-activated protein kinase in male Wistar rats.

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.