Endogenous GLP-1 Regulates Postprandial Glycemia in Humans: Relative Contributions of Insulin, Glucagon, and Gastric Emptying

Objective: Synthetic glucagon-like peptide-1 (7-36)amide (GLP-1) lowers postprandial (pp) glycemia by stimulating insulin and inhibiting glucagon release and delaying gastric emptying (GE). However, the biological effects of the endogenous peptide and their relative contributions to pp glycemia remain to be defined in detail. Using the specific GLP-1 receptor antagonist exendin(939)amide [Ex(9-39)], we studied the exact impact of GLP-1 after an oral meal in humans. Research Design and Methods: After a 50-min basal period, 12 healthy subjects ingested a 412-kcal mixed semisolid meal containing 30 g oatmeal, labeled with 99mTc-Sn-colloid. GE was measured by high-resolution scintigraphy until 210 min after meal ingestion. In random order, saline or Ex(9-39) at 900 pmol/kg.min was infused iv. Additionally, in six subjects gastric motility was measured by antroduodenal manometry and a gastric barostat in parallel. Results: Ex(9-39) increased pp blood glucose excursions during the first 60 min after the meal (43.9 +/- 5.4 vs. 35.9 +/- 3.6 mg/dl, P = 0.008; pp peak glucose 154.0 +/- 5.5 vs. 141.0 +/- 4.7 mg/dl, P = 0.009). Insulin increased slightly with Ex(9-39), whereas the insulin to glucose ratio was unchanged. pp glucagon was significantly increased with Ex(9-39) (7.5 +/- 2.4 vs. 3.2 +/- 2.1 pg/ml, P = 0.024). GE and accordingly gastric motility did not change with Ex(9-39). Multiple linear regression analysis revealed only changes of pp glucagon to be significantly associated with increased pp glycemia under Ex(9-39) (R = 0.678, P = 0.015). Conclusions: Released after an oral meal, GLP-1 lowers pp glycemia. In this study, the inhibition of glucagon release was a major determinant of the acute GLP-1 action in healthy subjects. In contrast, gastric emptying was not changed by GLP-1 receptor antagonism. (J Clin Endocrinol Metab 96: 229-236, 2011)