Single-dose Metformin Enhances Bile Acid-Induced GLP-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 GLP-1 secretion, has been proposed.

Objective: The aim of this study was to assess the GLP-1 secretory and gluco-metabolic effects of endogenously released bile, with and without concomitant single-dose administration of metformin in patients with type 2 diabetes.

Design: Randomised, placebo-controlled, and double-blinded cross-over study.

Setting: The study was conducted in a specialized research facility at Center for Diabetes Research, Gentofte Hospital, Denmark. ClinicalTrials.gov (NCT02497313).

Patients: The trial included 15 metformin-treated patients with type 2 diabetes; all participants completed the study.

Interventions: Four experimental study days in randomized order with administration of either metformin 1,500 mg or placebo in combination with intravenous infusion of cholecystokinin (0.4 pmol/kg/min) 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 to 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 to placebo. No GLP-1-mediated induction of insulin secretion or suppression of glucagon were 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 the acute setting.