The Importance of Endogenously Secreted GLP-1 and GIP for Postprandial Glucose Tolerance and β-Cell Function After Roux-en-Y Gastric Bypass and Sleeve Gastrectomy Surgery

Abstract

Enhanced secretion of glucagon-like peptide-1 (GLP-1) seems to be essential for improved postprandial β-cell function after Roux-en-Y gastric bypass (RYGB) but is less studied after sleeve gastrectomy (SG). Moreover, the role of the other major incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is relatively unexplored after bariatric surgery. We studied the effects of separate and combined GLP-1 receptor (GLP-1R) and GIP receptor (GIPR) blockade during mixed meal tests in unoperated (CON), SG-operated, and RYGB-operated people with no history of diabetes. Postprandial GLP-1 concentrations were highest after RYGB but also higher after SG compared with CON. In contrast, postprandial GIP concentrations were lowest after RYGB. The effect of GLP-1R versus GIPR blockade differed between groups. GLP-1R blockade reduced β-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the surgical groups but had no effect in CON. GIPR blockade reduced β-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the CON and SG groups but had no effect in the RYGB group. Our results support that GIP is the most important incretin hormone in unoperated people, whereas GLP-1 and GIP are equally important after SG, and GLP-1 is the most important incretin hormone after RYGB.

Insulinotropic effect of endogenous incretins is greater after gastric bypass than sleeve gastrectomy despite diminished beta-cell sensitivity to plasma incretins

“…The most robust glycemic and β-cell effects of endogenous GLP-1 in our experiment, particularly in GB subjects, were observed during post-OGTT nadir glycemic levels where the plasma concentrations of GLP-1 return to baseline. This is consistent with a recent study which reported a significant increase in nadir glucose concentrations, as well as AUC glucose after the first hour of meal study, after GLP-1R blockade in GB and SG(19).…”

“…Moreover, we did not measure active GIP, however, it can be assumed that a GIP is also increased in parallel to a GLP-1. However, it is unlikely that increased disposition index as observed in in GB subjects in the present study is mediated by enhanced a GIP since blocking GIPR in patients with GB has no effect on post-meal ISR or glucose concentrations(19). Furthermore, our findings can’t give insights into glycemic effects of DPP4i in bariatric subjects with diabetes since our subjects had no known history of diabetes.…”

“…Previously, using a GLP-1 receptor (GLP-1R) antagonist, we demonstrated that the contribution of endogenous GLP-1 to postprandial β-cell secretion during a hyperglycemic clamp is 2- to 3-fold larger in GB than matched non-operated controls(18). However, blocking GLP-1R during meal ingestion in GB patients had only a modest effect on prandial insulin secretion rate (ISR) compared to non-operated controls despite a 10-fold increase in GLP-1 secretion (10, 19, 20). Because of this discrepancy, we examined the effect of infusion of increasing doses of GLP-1 or GIP on glucose-stimulated ISR and found that in non-diabetic GB subjects the beta-cell sensitivity to exogenous incretins is markedly reduced(21).…”

GLP-1 enhances beta-cell response to protein ingestion independent of glycemia and bariatric surgery amplifies it

“…The weight-loss independent glycemic effect of gastric bypass surgery (GB) and sleeve gastrectomy (SG) has been partly attributed to altered prandial nutrient flux and metabolism mediated by enhanced secretion of insulinotropic gut factors, mainly glucagon-like peptide 1 (GLP-1) [1][2][3][4]. GLP-1 is a product of the preproglucagon gene, mainly secreted by intestinal Lcells in proportion to amount of ingested nutrient and acts through GLP-1 receptor (GLP-1R) expressed in various tissues including islet cells and specific brain regions [5].…”

“…We and others have shown that GLP-1R blockade has a greater effect to reduce the prandial insulin secretory response after gastric bypass (GB)[2, 4, 9–11] or sleeve gastrectomy (SG)[1], where both prandial GLP-1 secretion and glycemic excursion are augmented. Further, the increased insulinotropic effect of GLP-1 after GB is exaggerated in a discrete population suffering from the syndrome of hyperinsulinemic hypoglycemia and blocking GLP-1 action can correct hypoglycemia in affected patients, indicating that enhanced GLP-1-stimualted insulin secretion is a pathogenic factor in post-GB hypoglycemia.…”