GLP-1 Plays a Limited Role in Improved Glycemia Shortly After Roux-en-Y Gastric Bypass: A Comparison With Intensive Lifestyle Modification

Abstract

Rapid glycemic improvements following Roux-en-Y gastric bypass (RYGB) are frequently attributed to the enhanced GLP-1 response, but causality remains unclear. To determine the role of GLP-1 in improved glucose tolerance after surgery, we compared glucose and hormonal responses to a liquid meal test in 20 obese participants with type 2 diabetes mellitus who underwent RYGB or nonsurgical intensive lifestyle modification (ILM) (n = 10 per group) before and after equivalent short-term weight reduction. The GLP-1 receptor antagonist exendin(9–39)-amide (Ex-9) was administered, in random order and in double-blinded fashion, with saline during two separate visits after equivalent weight loss. Despite the markedly exaggerated GLP-1 response after RYGB, changes in postprandial glucose and insulin responses did not significantly differ between groups, and glucagon secretion was paradoxically augmented after RYGB. Hepatic insulin sensitivity also increased significantly after RYGB. With Ex-9, glucose tolerance deteriorated similarly from the saline condition in both groups, but postprandial insulin release was markedly attenuated after RYGB compared with ILM. GLP-1 exerts important insulinotropic effects after RYGB and ILM, but the enhanced incretin response plays a limited role in improved glycemia shortly after surgery. Instead, enhanced hepatic metabolism, independent of GLP-1 receptor activation, may be more important for early postsurgical glycemic improvements.

Peripheral, but not central, GLP-1 receptor signaling is required for improvement in glucose tolerance after Roux-en-Y gastric bypass in mice

“…Here, we demonstrate that blockade of peripheral GLP-1R signaling partially reverses the improvement in oral glucose tolerance induced by RYGB, a result supported by studies performed in rats and human patients (4,9,26,32). In contrast, however, we found that neither peripheral nor central GLP-1R signaling is required for the weight loss observed after RYGB.…”

Gastric Bypass-Related Effects on Glucose Control, β Cell Function and Morphology in the Obese Zucker Rat

“…It has further been shown that patients who achieve similar weight loss after gastric banding, a procedure which does not affect the incretin response, and RYGB exhibit similarly improved insulin sensitivity and β cell function [21]. GLP-1 receptor antagonism has also been reported to not fully reverse the favourable effects on glycaemic control after RYGB in T2DM patients [22]. In fact, in the long term, weight loss maintenance has been identified as a critical factor for T2DM control after RYGB [23,24].…”

Immediate enhancement of first-phase insulin secretion and unchanged glucose effectiveness in patients with type 2 diabetes after Roux-en-Y gastric bypass

“…in the IGT and NGT groups, and clearly demonstrated in studies using pharmacological blockade of the GLP-1 receptor (29,30,51,54). It could be argued that the increased postprandial GLP-1 levels during the days preceding the IVGTT could in part explain the enhanced first-phase ISR and AIRg after RYGB, since pharmacological administration of GLP-1 or GLP-1 agonists have been shown to restore both first-and second-phase insulin secretion to iv glucose in patients with type 2 diabetes (17).…”

“…Increased glucagon-like peptide-1 (GLP-1) contributes importantly to increased postprandial insulin secretion after RYGB, as demonstrated in studies using pharmacological blockade of the GLP-1 receptor (29,30,51,54).…”