Elimination of the action of glucagon-like peptide 1 causes an impairment of glucose tolerance after nutrient ingestion by healthy baboons.

Abstract

Glucagon-like peptide 1 (GLP-1) is an insulinotropic hormone released after nutrient ingestion which is known to augment insulin secretion, inhibit glucagon release, and promote insulin-independent glucose disposition. To determine the overall effect of GLP-1 on glucose disposition after a meal we studied a group of healthy, conscious baboons before and after intragastric glucose administration during infusions of saline, and two treatments to eliminate the action of GLP-1: (a) exendin-[9-39] (Ex-9), a peptide receptor antagonist of GLP-1; or (b) an anti-GLP-1 mAb. Fasting concentrations of glucose were higher during infusion of Ex-9 than during saline (4.44 +/- 0.05 vs. 4.16 +/- 0.05 mM, P < 0.01), coincident with an elevation in the levels of circulating glucagon (96 +/- 10 vs. 59 +/- 3 ng/liter, P < 0.02). The postprandial glycemic excursions during administration of Ex-9 and mAb were greater than during the control studies (Ex-9 13.7 +/- 2.0 vs. saline 10.0 +/- 0.8 mM, P = 0.07; and mAb 13.6 +/- 1.2 vs. saline 10.6 +/- 0.9 mM, P = 0.044). The increments in insulin levels throughout the absorption of the glucose meal were not different for the experimental and control conditions, but the insulin response in the first 30 min after the glucose meal was diminished significantly during treatment with Ex-9 (Ex-9 761 +/- 139 vs. saline 1,089 +/- 166 pM, P = 0.044) and was delayed in three of the four animals given the neutralizing antibody (mAb 946 +/- 262 vs. saline 1,146 +/- 340 pM). Thus, elimination of the action of GLP-1 impaired the disposition of an intragastric glucose meal and this was at least partly attributable to diminished early insulin release. In addition to these postprandial effects, the concurrent elevation in fasting glucose and glucagon during GLP-1 antagonism suggests that GLP-1 may have a tonic inhibitory effect on glucagon output. These findings demonstrate the important role of GLP-1 in the assimilation of glucose absorbed from the gut.