GIP and GLP-1 Receptor Antagonism During a Meal in Healthy Individuals

Abstract

Abstract Context The actions of both endogenous incretin hormones during a meal have not previously been characterized. Objective Using specific receptor antagonists, we investigated the individual and combined contributions of endogenous glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) to postprandial glucose metabolism, energy expenditure, and gallbladder motility. Design Randomized, double-blinded, placebo-controlled, crossover design. Setting On four separate days, four liquid mixed meal tests (1894 kJ) over 270 minutes (min). Patients or Other Participants Twelve healthy male volunteers. Interventions Infusions of the GIP receptor antagonist GIP(3–30)NH2 (800 pmol/kg/min), the GLP-1 receptor antagonist exendin(9–39)NH2 (0–20 min: 1000 pmol/kg/min; 20–270 min: 450 pmol/kg/min), GIP(3–30)NH2+exendin(9–39)NH2, or placebo/saline. Main Outcome Measure Baseline-subtracted area under the curve (bsAUC) of C-peptide. Results Infusion of GIP(3–30)NH2+exendin(9–39)NH2 significantly increased plasma glucose excursions (bsAUC: 261 ± 142 mmol/L × min) during the liquid mixed meals compared with GIP(3–30)NH2 (180 ± 141 mmol/L × min; P = 0.048), exendin(9–39)NH2 (171 ± 114 mmol/L × min; P = 0.046), and placebo (116 ± 154 mmol/L × min; P = 0.015). Correspondingly, C-peptide:glucose ratios during GIP(3–30)NH2+exendin(9–39)NH2 infusion were significantly lower than during GIP(3–30)NH2 (P = 0.0057), exendin(9–39)NH2 (P = 0.0038), and placebo infusion (P = 0.014). GIP(3–30)NH2 resulted in significantly lower AUCs for glucagon than exendin(9–39)NH2 (P = 0.0417). Gallbladder ejection fraction was higher during GIP(3–30)NH2 compared with placebo (P = 0.004). For all interventions, energy expenditure and respiratory quotient were similar. Conclusions Endogenous GIP and GLP-1 lower postprandial plasma glucose excursions and stimulate insulin secretion but only endogenous GIP affects gallbladder motility. The two incretin hormones potentiate each other’s effects in the control of postprandial glycemia in healthy men.