Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide,regulates fasting glycemia and nonenteral glucose clearance in mice

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptid e (GIP) potentiate glucose-stimulated insulin secretion after enteral nutri ent ingestion. We compared the relative incretin and nonincretin actions of GLP-1 and GIP in +/+ and GLP-1R-/- mice using exendin(9 -39) and immunopur ified anti-GIP receptor antisera (GIPR Ab) to antagonize GLP-1 and GIP acti on, respectively. Both antagonists produced a significant increase in glyce mic excursion after oral glucose loading of +/+ mice (P < 0.05 for antagoni sts vs, controls). Exendin(9-89) also increased blood glucose and decreased glucose-stimulated insulin in +/+ mice after ip glucose loading [0.58 +/- 0.02 vs. 0.47 +/- 0.02 ng/ml in saline- vs. exendin(9-39)-treated mice, res pectively, P < 0.05]. In contrast, GIPR Ab had no effect on glucose excursi on or insulin secretion, after ip glucose challenge, in +/+ or GLP-1R-/- mi ce. Repeated administration of exendin(9-39) significantly increased blood glucose and reduced circulating insulin levels but had no effect on levels of pancreatic insulin or insulin messenger RNA transcripts. In contrast, no changes in plasma glucose, circulating insulin, pancreatic insulin content , or insulin messenger RNA were observed in mice, 18 h after administration of GIPR Ab. These findings demonstrate that GLP-1, but not GIP, plays an e ssential role in regulating glycemia, independent of enteral nutrient inges tion in mice in vivo.