Cited by 173Diabetes Treatment and ManagementMetabolism, Diabetes, and CancerPancreatic function and diabetes

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Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes

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Bahne, Emilie, Sun, Emily W. L., Young, Richard L., Hansen, Morten, Sonne, David P., Hansen, Jakob S., Rohde, Ulrich, Liou, Alice P., Jackson, Margaret L., de Fontgalland, Dayan, Rabbitt, Philippa, Hollington, Paul, Sposato, Luigi, Due, Steven, Wattchow, David A., Rehfeld, Jens F., Holst, Jens J., Keating, Damien J., Vilsbøll, Tina, Knop, Filip K.·2018·JCI Insight

DOI 10.1172/jci.insight.93936PMC PMC6328020

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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. TRIAL REGISTRATION: NCT02050074 (https://clinicaltrials.gov/ct2/show/NCT02050074). FUNDING: This study received grants from the A.P. Møller Foundation, the Novo Nordisk Foundation, the Danish Medical Association research grant, the Australian Research Council, the National Health and Medical Research Council, and Pfizer Inc.

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Authors: Bahne, E., Sun, E. W. L., 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., Vilsbøll, T., & Knop, F. K.
Affiliations: Gentofte Hospital (DK)
Flinders University (AU)
South Australian Health and Medical Research Institute (AU)
University of Copenhagen (DK)
Pfizer (United States) (US)
Discipline of Surgery, Flinders University, Adelaide, South Australia, Australia.
Corresponding author: Keating, Damien J.
Knop, Filip K.
ORCID: Sun, Emily W. L.
Young, Richard L.
Sonne, David P.
Hollington, Paul
Sposato, Luigi
Due, Steven
Wattchow, David A.
Rehfeld, Jens F.
Holst, Jens J.
Keating, Damien J.
Vilsbøll, Tina
Knop, Filip K.
Venue: JCI Insight
Publisher: American Society for Clinical Investigation
Published: 2018-12-06
Volume: 3
Issue: 23
ISSN: 2379-3708 (ISSN-L)
DOI: 10.1172/jci.insight.93936
PMC: PMC6328020
OpenAlex: W2903143648
Cited by: 173
References: 72
Citations by year: 2026: 15 · 2025: 22 · 2024: 28 · 2023: 23 · 2022: 18 · 2021: 30 · 2020: 22 · 2019: 15
FWCI: 13.32
Type: journal article
Language: en
Open access: gold
doi.org
Locations: JCI Insight (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders: AP Møller Fonden
the Novo Nordisk Foundation
Danish Medical Association
Australian Research Council (LP150100419)
National Health and Medical Research Council (APP1088737, APP1081182)
Pfizer (Emerging science grant)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
Keywords: metformin, glucagon-like peptide-1, GLP-1 secretion, type 2 diabetes, AMPK, exendin-9-39, GLP-1 receptor antagonists, postprandial blood glucose, L cells, glucose-lowering mechanism
MeSH terms: Adult, Aged, Aged, 80 and over, Australia, Blood Glucose, Diabetes Mellitus, Type 2, Double-Blind Method, Female, Humans, Male, Metformin, Middle Aged, Postprandial Period, Glucagon-Like Peptide 1

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Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes

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