Effects of endogenous GLP-1 and GIP on glucose tolerance after Roux-en-Y gastric bypass surgery

Abstract

-Exaggerated secretion of glucagon-like peptide 1 (GLP-1) is important for postprandial glucose tolerance after Roux-en-Y gastric bypass (RYGB), whereas the role of glucose-dependent insulinotropic polypeptide (GIP) remains to be resolved. We aimed to explore the relative importance of endogenously secreted GLP-1 and GIP on glucose tolerance and ␤-cell function after RYGB. We used DPP-4 inhibition to enhance concentrations of intact GIP and GLP-1 and the GLP-1 receptor antagonist exendin-(9 -39) (Ex-9) for specific blockage of GLP-1 actions. Twelve glucose-tolerant patients were studied after RYGB in a randomized, placebo-controlled, 4-day crossover study with standard mixed-meal tests and concurrent administration of placebo, oral sitagliptin, Ex-9 infusion, or combined Ex-9-sitagliptin. GLP-1 receptor antagonism increased glucose excursions, clearly attenuated ␤-cell function, and aggravated postprandial hyperglucagonemia compared with placebo, whereas sitagliptin had no effect despite two-to threefold increased concentrations of intact GLP-1 and GIP. Similarly, sitagliptin did not affect glucose tolerance or ␤-cell function during GLP-1R blockage. This study confirms the importance of GLP-1 for glucose tolerance after RYGB via increased insulin and attenuated glucagon secretion in the postprandial state, whereas amplification of the GIP signal (or other DPP-4-sensitive glucose-lowering mechanisms) did not appear to contribute to the improved glucose tolerance seen after RYGB.Roux-en-Y gastric bypass; glucagon-like peptide-1; glucose-dependent insulinotropic polypeptide; exendin-(9 -39); dipeptidyl peptidase-4 inhibition ROUX-EN-Y GASTRIC BYPASS (RYGB) is an effective treatment of severe obesity and induces large and sustainable weight loss, which is superior to diet, intensive lifestyle, or pharmaceutical interventions (47, 51). Moreover, RYGB improves glycemic control within days after surgery, before major weight loss (24), and induces remission of type 2 diabetes in the majority of patients (5, 47). Patients with preoperative normal glucose tolerance (NGT) also display changed postprandial glycemic profile after RYGB with increased peak plasma glucose, followed by a lower nadir (24,45). A combination of improved hepatic insulin sensitivity induced by hypocaloric postoperative diet (18), rapid glucose absorption (19), and exaggerated postprandial insulin secretion seems to be responsible for the early changes in glucose metabolism after RYGB in patients with NGT and type 2 diabetes (3).The postprandial gastrointestinally induced stimulation of insulin secretion, the incretin effect, is due to the insulinotropic effects of the two hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (38,56). In glucose-tolerant subjects, GLP-1 and GIP contribute nearly equally to the incretin effect, which explains up to 70% of the postprandial insulin secretion (36,38,56). The incretin effect is severely impaired in type 2 diabetes (35) but is also reduced in obese people with NGT ...

The impact of EndoBarrier gastrointestinal liner in obese patients with normal glucose tolerance and in patients with type 2 diabetes

“…Expediting undigested nutrients to the distal small intestines ought to increase the secretion of the glucose‐lowering and satiety‐promoting hormone GLP‐1. Consistent with the hindgut hypothesis and a previous DJBS study, DJBS implantation increased GLP‐1 responses in T2D subjects, but less so than RYGB . Similar to the aforementioned Dutch DJBS study, the augmented GLP‐1 secretion did not seem to affect insulin or glucagon, perhaps explaining the inconspicuous changes in glucose excursions.…”

Glucose Metabolism After Gastric Banding and Gastric Bypass in Individuals With Type 2 Diabetes: Weight Loss Effect

“…However, the role of GIP as a mediator of the enhanced incretin effect and improved β-cell function after RYGB or LAGB is less well defined, mainly because of the lack of a specific inhibitor available for human testing. A nonspecific amplification of GIP signaling with DPP-4 inhibition did not modify glucose tolerance after RYGB (37). The postprandial change in GIP levels is less consistent after RYGB (6,38) and is of a lesser magnitude than the change in GLP-1 levels.…”

Incretin hormones: Their role in health and disease

“…In fact, the typically increased concentrations of both GLP‐1 and PYY seem to reduce appetite and food intake synergistically . GLP‐1 and GIP appear to be the factors that best explain the improvement in glycaemic control following gastric bypass . However, weight loss after gastric bypass also occurs in GLP‐1 receptor knock‐out animals .…”