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JCI Insight. 2018 Dec 6;3(23). pii: 93936. doi: 10.1172/jci.insight.93936. [Epub ahead of print]

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

Author information

1
Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark.
2
Discipline of Human Physiology and Centre for Neuroscience, Flinders University of South Australia, Adelaide, Australia.
3
Adelaide Medical School, University of Adelaide, Adelaide, Australia.
4
Nutrition and Metabolism, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia.
5
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University Copenhagen, Copenhagen, Denmark.
6
Department of Clinical Pharmacology, Frederiksberg and Bispebjerg Hospital, University of Copenhagen, Denmark.
7
Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA.
8
Discipline of Surgery, Flinders University, Adelaide, South Australia, Australia.
9
Department of Clinical Biochemistry, Rigshospitalet, University Copenhagen, Copenhagen, Denmark.
10
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University Copenhagen, Copenhagen, Denmark.

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.

KEYWORDS:

Diabetes; Endocrinology; Metabolism

PMID:
30518693
DOI:
10.1172/jci.insight.93936
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