Single-Dose Metformin Enhances Bile Acid–Induced Glucagon-Like Peptide-1 Secretion in Patients With Type 2 Diabetes

Context: Despite a position as the first‐line pharmacotherapy in type 2 diabetes, the glucose‐lowering mechanisms of metformin remain to be fully clarified. Gut‐derived modes of action, including suppression of bile acid reabsorption and a resulting increase in glucagon‐like peptide‐1 (GLP‐1) secretion, have been proposed. Objective: The aim of this study was to assess the GLP‐1 secretory and glucometabolic effects of endogenously released bile, with and without concomitant single‐dose administration of metformin in patients with type 2 diabetes. Design: Randomized, placebo‐controlled, and double‐blinded crossover study. Setting: This study was conducted at Center for Diabetes Research, Gentofte Hospital, Denmark. Patients: Fifteen metformin‐treated patients with type 2 diabetes; all participants completed the study. Interventions: Four experimental study days in randomized order with administration of either 1500 mg metformin or placebo in combination with intravenous infusion of cholecystokinin (0.4 pmol × kg−1 × min−1) or saline. Main Outcome Measure: Plasma GLP‐1 excursions as measured by baseline‐subtracted area under the curve. Results: Single‐dose metformin further enhanced bile acid‐mediated induction of GLP‐1 secretion (P = 0.02), whereas metformin alone did not increase plasma GLP‐1 concentrations compared with placebo (P = 0.17). Metformin, both with (P = 0.02) and without (P = 0.02) concomitant cholecystokinin‐induced gallbladder emptying, elicited reduced plasma glucose excursions compared with placebo. No GLP‐1‐mediated induction of insulin secretion or suppression of glucagon was observed. Conclusions: Metformin elicited an enhancement of the GLP‐1 response to cholecystokinin‐induced gallbladder emptying in patients with type 2 diabetes, whereas no derived effects on insulin or glucagon secretion were evident in this acute setting.