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

Am J Physiol Endocrinol Metab. 2016 Apr 1;310(7):E505-14. doi: 10.1152/ajpendo.00471.2015. Epub 2016 Jan 19.


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.

Keywords: Roux-en-Y gastric bypass; dipeptidyl peptidase-4 inhibition; exendin-(9–39); glucagon-like peptide-1; glucose-dependent insulinotropic polypeptide.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism*
  • C-Peptide / metabolism*
  • Cross-Over Studies
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Gastric Bypass*
  • Gastric Inhibitory Polypeptide / metabolism*
  • Glucagon / drug effects
  • Glucagon / metabolism*
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucagon-Like Peptide-1 Receptor / antagonists & inhibitors
  • Glucose Tolerance Test / methods
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Linear Models
  • Male
  • Obesity / metabolism
  • Obesity / surgery*
  • Peptide Fragments / pharmacology
  • Postprandial Period
  • Single-Blind Method
  • Sitagliptin Phosphate / pharmacology


  • Blood Glucose
  • C-Peptide
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Peptide Fragments
  • exendin (9-39)
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1
  • Glucagon
  • Sitagliptin Phosphate