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

• Published in: American journal of physiology: endocrinology and metabolism Vol. 310; no. 7; pp. E505 - E514
• Main Authors: Svane, Maria S., Bojsen-Møller, Kirstine N., Nielsen, Signe, Jørgensen, Nils B., Dirksen, Carsten, Bendtsen, Flemming, Kristiansen, Viggo B., Hartmann, Bolette, Holst, Jens J., Madsbad, Sten
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.04.2016
• Subjects: Adult; Blood Glucose - drug effects; Blood Glucose - metabolism; C-Peptide - metabolism; Cells; Cross-Over Studies; Enzyme-Linked Immunosorbent Assay; Female; Gastric Bypass; Gastric Inhibitory Polypeptide - metabolism; Gastrointestinal surgery; Glucagon - drug effects; Glucagon - metabolism; Glucagon-Like Peptide 1 - metabolism; Glucagon-Like Peptide-1 Receptor - antagonists & inhibitors; Glucose; Glucose Tolerance Test - methods; Humans; Hypoglycemic Agents - pharmacology; Linear Models; Male; Obesity - metabolism; Obesity - surgery; Peptide Fragments - pharmacology; Polypeptides; Postprandial Period; Single-Blind Method; Sitagliptin Phosphate - pharmacology; dipeptidyl peptidase-4 inhibition; Roux-en-Y gastric bypass; exendin-(9–39); glucose-dependent insulinotropic polypeptide; glucagon-like peptide-1
• ISSN: 0193-1849; 1522-1555; 1522-1555
• DOI: 10.1152/ajpendo.00471.2015

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 β-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 β-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 β-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.