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

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Abstract

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.

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