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.

Figure 1

Glucose, GLP-1, insulin, and C-peptide responses to meal ingestion. ILM (panels A–D) and RYGB responses (panels D–G) are shown at baseline (black circles), after equivalent reduction of 10% of initial body weight with saline (white circles), and after equivalent weight reduction with GLP-1R blockade (white squares). Data are presented as means (SEMs).

Figure 2

GLP-2, GIP, and glucagon responses to meal ingestion. ILM (panels A–C) and RYGB responses (panels D–F) are shown at baseline (black circles), after equivalent reduction of 10% of initial body weight with saline (white circles), and after equivalent weight reduction with GLP-1R blockade (white squares). Data are presented as means ± SEMs.

Figure 3

Calculated responses of insulin secretion and sensitivity in ILM and RYGB. Black bars indicate values at baseline (before weight loss); white bars indicate values after weight loss (−10% of initial body weight) with saline; gray hatched bars indicate values after weight loss (−10% of initial body weight) with Ex-9. Bar graphs of the area under the curve (AUC) for the ISI are shown in panel A, the MISI in panel B, and the DI in panel C. The data for the two intervention groups are model-based estimates for the ITT population. Data are presented as means ± SEMs. *P < 0.05; +P < 0.01; ++P < 0.001.

Figure 4

Calculated responses of hepatic glucose metabolism in ILM and RYGB. Black bars indicate values at baseline (before weight loss); white bars indicate values after weight loss (−10% of initial body weight) with saline; gray hatched bars indicate values after weight loss (−10% of initial body weight) with Ex-9. Bar graphs of the area under the curve (AUC) for basal EGP are shown in panel A, HIS in panel B, and hepatic insulin clearance (CI ratio) in panel C. The data for the two intervention groups are model-based estimates for the ITT population. Data are presented as means ± SEMs. *P < 0.05; +P < 0.01; ++P < 0.001.