Emilie Bahne1, Emily W L Sun2, Richard L Young3,4, Morten Hansen1,5, David P Sonne1,6, Jakob S Hansen1, Ulrich Rohde1,5, Alice P Liou7, Margaret L Jackson7, Dayan de Fontgalland8, Philippa Rabbitt8, Paul Hollington8, Luigi Sposato8, Steven Due8, David A Wattchow8, Jens F Rehfeld9, Jens J Holst5, Damien J Keating2,4, Tina Vilsbøll1,10, Filip K Knop1,5,10. 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.
RCT Entities:
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.
Authors: Jean Grisouard; Katharina Timper; Tanja M Radimerski; Daniel M Frey; Ralph Peterli; Blerina Kola; Márta Korbonits; Paul Herrmann; Stephan Krähenbühl; Henryk Zulewski; Ulrich Keller; Beat Müller; Mirjam Christ-Crain Journal: Biochem Pharmacol Date: 2010-09-08 Impact factor: 5.858
Authors: Andrew J Mulherin; Amy H Oh; Helena Kim; Anthony Grieco; Lina M Lauffer; Patricia L Brubaker Journal: Endocrinology Date: 2011-10-04 Impact factor: 4.736
Authors: Garry G Graham; Jeroen Punt; Manit Arora; Richard O Day; Matthew P Doogue; Janna K Duong; Timothy J Furlong; Jerry R Greenfield; Louise C Greenup; Carl M Kirkpatrick; John E Ray; Peter Timmins; Kenneth M Williams Journal: Clin Pharmacokinet Date: 2011-02 Impact factor: 6.447
Authors: Yan Shu; Steven A Sheardown; Chaline Brown; Ryan P Owen; Shuzhong Zhang; Richard A Castro; Alexandra G Ianculescu; Lin Yue; Joan C Lo; Esteban G Burchard; Claire M Brett; Kathleen M Giacomini Journal: J Clin Invest Date: 2007-05 Impact factor: 14.808
Authors: Robert E Steinert; Joerg Schirra; Anne C Meyer-Gerspach; Philipp Kienle; Heiko Fischer; Felix Schulte; Burkhard Goeke; Christoph Beglinger Journal: Am J Clin Nutr Date: 2014-06-25 Impact factor: 7.045
Authors: Antonella Napolitano; Sam Miller; Andrew W Nicholls; David Baker; Stephanie Van Horn; Elizabeth Thomas; Deepak Rajpal; Aaron Spivak; James R Brown; Derek J Nunez Journal: PLoS One Date: 2014-07-02 Impact factor: 3.240
Authors: Ralph A DeFronzo; John B Buse; Terri Kim; Colleen Burns; Sharon Skare; Alain Baron; Mark Fineman Journal: Diabetologia Date: 2016-05-23 Impact factor: 10.122
Authors: Edgar G Dorsey-Trevino; Varinderpal Kaur; Josep M Mercader; Jose C Florez; Aaron Leong Journal: J Clin Endocrinol Metab Date: 2022-08-18 Impact factor: 6.134