Exaggerated glucagon-like peptide 1 response is important for improved β-cell function and glucose tolerance after Roux-en-Y gastric bypass in patients with type 2 diabetes

Abstract

β-Cell function improves in patients with type 2 diabetes in response to an oral glucose stimulus after Roux-en-Y gastric bypass (RYGB) surgery. This has been linked to the exaggerated secretion of glucagon-like peptide 1 (GLP-1), but causality has not been established. The aim of this study was to investigate the role of GLP-1 in improving β-cell function and glucose tolerance and regulating glucagon release after RYGB using exendin(9-39) (Ex-9), a GLP-1 receptor (GLP-1R)-specific antagonist. Nine patients with type 2 diabetes were examined before and 1 week and 3 months after surgery. Each visit consisted of two experimental days, allowing a meal test with randomized infusion of saline or Ex-9. After RYGB, glucose tolerance improved, β-cell glucose sensitivity (β-GS) doubled, the GLP-1 response greatly increased, and glucagon secretion was augmented. GLP-1R blockade did not affect β-cell function or meal-induced glucagon release before the operation but did impair glucose tolerance. After RYGB, β-GS decreased to preoperative levels, glucagon secretion increased, and glucose tolerance was impaired by Ex-9 infusion. Thus, the exaggerated effect of GLP-1 after RYGB is of major importance for the improvement in β-cell function, control of glucagon release, and glucose tolerance in patients with type 2 diabetes.

FIG. 1.

Ex-9 (A) and paracetamol (B) concentrations throughout the experiment. Data are shown as means ± SE. Open symbols, dotted lines: saline infusion; solid symbols, solid line: Ex-9 infusion. Squares: before surgery, circles: 1 week after surgery, triangles: 3 months after surgery.

FIG. 2.

Glucose concentration (A) and ISR (B) profiles before (PRE) and 1 week (1WK) and 3 months (3MO) after RYGB with and without GLP-1R blockade. Data are shown as means ± SE. Open squares, dotted line: saline infusion; solid squares, solid line: Ex-9 infusion.

FIG. 3.

β-GS before (Pre) and 1 week (wk) and 3 months (mo) after RYGB with and without GLP-1R block. Data are shown as means ± SE. White bars, saline infusion; black bars, Ex-9 infusion. *P < 0.05 vs. Pre, **P < 0.01 vs. Pre. ††P < 0.01 vs. NaCl.

FIG. 4.

GLP-1 (A), GIP (B), and glucagon (C) concentration profiles before (PRE) and 1 week (1WK) and 3 months (3MO) after RYGB with and without GLP-1R blockade. Data are shown as means ± SE. Open squares, dotted line: saline infusion; solid squares, solid line: Ex-9 infusion.