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 administration, 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 glucose elimination rate (K(G)) but did not affect the glucose effectiveness (S(G)). Furthermore, the insulin sensitivity index (S(I)) was reduced after administration of GLP-1. Because insulin secretion was stimulated to a larger degree than S(I) was reduced, the peptide increased the global disposition index (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) inhibited the actions of GLP-1. We conclude that GLP-1 increases glucose tolerance in the mouse mainly by potently stimulating insulin secretion.