Dose-related effects of GLP-1 on insulin secretion, insulin sensitivity, and glucose effectiveness in mice

We examined the dose-related net effects of glucagon-like peptide 1 (GLP-1) on insulin secretion, insulin sensitivity, and glucose disposal as derived from the minimal model of glucose disappearance in anesthetized mice. GLP- 1 dose dependently potentiated insulin secretion after glucose administrati on, with the half-maximal effect at 1 nmol/kg. GLP-1 also dose dependently reduced the area under the glucose curve (AUC(glucose)) and increased the g lucose elimination rate (KG) but did not affect the glucose effectiveness ( SG) Furthermore, the insulin sensitivity index (Sr) was reduced after admin istration of GLP-1. Because insulin secretion was stimulated to a larger de gree than SI was reduced, the peptide increased the global disposition inde x (GDI = AUC(insulin) x S-I). Matching plasma insulin levels after GLP-1 by exogenous insulin reproduced the influences of GLP-1 on AUC(glucose), K-G, S-I, and GDI. Finally, the GLP-1 receptor antagonist exendin-3-(9-39) inhi bited the actions of GLP-1. We conclude that GLP-1 increases glucose tolera nce in the mouse mainly by potently stimulating insulin secretion.