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Type: Journal article
Title: Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes
Author: Bahne, E.
Sun, E.W.
Young, R.L.
Hansen, M.
Sonne, D.P.
Hansen, J.S.
Rohde, U.
Liou, A.P.
Jackson, M.L.
de Fontgalland, D.
Rabbitt, P.
Hollington, P.
Sposato, L.
Due, S.
Wattchow, D.A.
Rehfeld, J.F.
Holst, J.J.
Keating, D.J.
Vilsboll, T.
Knop, F.K.
Citation: JCI Insight, 2018; 3(23):e93936-1-e93936-15
Publisher: American Society for Clinical Investigation
Issue Date: 2018
ISSN: 2379-3708
Statement of
Emilie Bahne, Emily W.L. Sun, Richard L. Young, Morten Hansen, David P. Sonne, Jakob S. Hansen, Ulrich Rohde, Alice P. Liou, Margaret L. Jackson, Dayan de Fontgalland, Philippa Rabbitt, Paul Hollington, Luigi Sposato, Steven Due, David A. Wattchow, Jens F. Rehfeld, Jens J. Holst, Damien J. Keating, Tina Vilsbøll, and Filip K. Knop
Abstract: Background: Metformin reduces plasma glucose and has been shown to increase glucagon-like peptide 1 (GLP-1) secretion. Whether this is a direct action of metformin on GLP-1 release, and whether some of the glucose-lowering effect of metformin occurs due to GLP-1 release, is unknown. The current study investigated metformin-induced GLP-1 secretion and its contribution to the overall glucose-lowering effect of metformin and underlying mechanisms in patients with type 2 diabetes. Methods: Twelve patients with type 2 diabetes were included in this placebo-controlled, double-blinded study. On 4 separate days, the patients received metformin (1,500 mg) or placebo suspended in a liquid meal, with subsequent i.v. infusion of the GLP-1 receptor antagonist exendin9-39 (Ex9-39) or saline. During 240 minutes, blood was sampled. The direct effect of metformin on GLP-1 secretion was tested ex vivo in human ileal and colonic tissue with and without dorsomorphin-induced inhibiting of the AMPK activity. Results: Metformin increased postprandial GLP-1 secretion compared with placebo (P = 0.014), and the postprandial glucose excursions were significantly smaller after metformin + saline compared with metformin + Ex9-39 (P = 0.004). Ex vivo metformin acutely increased GLP-1 secretion (colonic tissue, P < 0.01; ileal tissue, P < 0.05), but the effect was abolished by inhibition of AMPK activity. Conclusions: Metformin has a direct and AMPK-dependent effect on GLP-1-secreting L cells and increases postprandial GLP-1 secretion, which seems to contribute to metformin's glucose-lowering effect and mode of action.
Keywords: Diabetes; metabolism
Rights: Copyright 2018, American Society for Clinical Investigation.
DOI: 10.1172/jci.insight.93936
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