Metformin enhances bile acid-induced GLP-1 secretion in type 2 diabetes

Metformin enhanced bile acid-induced GLP-1 secretion among patients with type 2 diabetes, researchers in Denmark reported.

“Metformin is the recommended first-line pharmacotherapy of type 2 diabetes and continues to be the most widely used glucose-lowering drug in these patients,” Andreas Brønden, MD, PhD, of the center for diabetes research at Gentofte Hospital, University of Copenhagen, and colleagues wrote. “The glucose-lowering mechanisms of metformin have not been fully clarified despite the fact that the drug class of biguanides was introduced more than 50 years ago.”

The researchers performed a randomized, placebo-controlled, double blind crossover study to evaluate the effects of endogenously released bile on GLP-1 secretion and glucose metabolism both with and without metformin. All participants had metformin-treated type 2 diabetes (n = 15).

For 4 days, participants were randomly assigned 1,500 mg of metformin or placebo combined with IV cholecystokinin (0.4 pmol/kg/min) or saline solution after an overnight fasting period. Patients remained at the testing facility for 4 hours, and the researchers drew blood samples at 30, 15 and 0 minutes before infusion, followed by 10, 20, 30, 45, 60, 75, 90, 120, 150, 180, 210 and 240 minutes after infusion.

Metformin enhanced bile acid-mediated induction of GLP-1 secretion, the researchers reported (P = .02), although compared with placebo, metformin alone did not raise plasma concentrations of GLP-1 (P = .17). Metformin reduced excursions of plasma glucose both with and without concomitant cholecystokinin-induced gallbladder emptying (P = .02), Brønden and colleagues wrote. The researchers observed no GLP-1-mediated induction of insulin secretion or glucagon suppression.

“In conclusion, we found single-dose administration of metformin to enhance bile acid-induced GLP-1 secretion in patients with type 2 diabetes, whereas no significant isolated effect of metformin on GLP-1 secretion was observed,” Brønden and colleagues wrote.

“The underlying mechanisms of metformin-induced GLP-1 secretion remain speculative, but might involve metformin-mediated modulation of bile acid circulation with potential subsequent implications for bile acid receptor activation in the GLP-1-secreting L cells, as well as sensitization of these enteroendocrine cells by metformin,” they wrote. – by Andy Polhamus

Disclosures: Brønden reports no relevant financial disclosures. Please see the full study for all other authors’ relevant financial disclosures.