Cited by 721Metabolism, Diabetes, and CancerDiabetes Treatment and ManagementNatural Antidiabetic Agents Studies

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Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus

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Foretz, Marc, Guigas, Bruno, Viollet, Benoit·2019·Nature Reviews Endocrinology

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Abstract

Despite its position as the first-line drug for treatment of type 2 diabetes mellitus, the mechanisms underlying the plasma glucose level-lowering effects of metformin (1,1-dimethylbiguanide) still remain incompletely understood. Metformin is thought to exert its primary antidiabetic action through the suppression of hepatic glucose production. In addition, the discovery that metformin inhibits the mitochondrial respiratory chain complex 1 has placed energy metabolism and activation of AMP-activated protein kinase (AMPK) at the centre of its proposed mechanism of action. However, the role of AMPK has been challenged and might only account for indirect changes in hepatic insulin sensitivity. Various mechanisms involving alterations in cellular energy charge, AMP-mediated inhibition of adenylate cyclase or fructose-1,6-bisphosphatase 1 and modulation of the cellular redox state through direct inhibition of mitochondrial glycerol-3-phosphate dehydrogenase have been proposed for the acute inhibition of gluconeogenesis by metformin. Emerging evidence suggests that metformin could improve obesity-induced meta-inflammation via direct and indirect effects on tissue-resident immune cells in metabolic organs (that is, adipose tissue, the gastrointestinal tract and the liver). Furthermore, the gastrointestinal tract also has a major role in metformin action through modulation of glucose-lowering hormone glucagon-like peptide 1 and the intestinal bile acid pool and alterations in gut microbiota composition.

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Authors: Foretz, M., Guigas, B., & Viollet, B.
Affiliations: Centre National de la Recherche Scientifique (FR)
Leiden University Medical Center (NL)
ORCID: Foretz, Marc
Guigas, Bruno
Viollet, Benoit
Venue: Nature Reviews Endocrinology
Publisher: Springer Science and Business Media LLC
Published: 2019-08-22
Volume: 15
Issue: 10
Pages: 569-589
ISSN: 1759-5029 (ISSN-L)
1759-5037
DOI: 10.1038/s41574-019-0242-2
OpenAlex: W2969928163
Cited by: 686
References: 261
Citations by year: 2026: 80 · 2025: 104 · 2024: 92 · 2023: 122 · 2022: 113 · 2021: 102 · 2020: 68 · 2019: 5
FWCI: 6.34
Type: journal article
Language: en
Open access: green
inserm.hal.science
Licence: other-oa
www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Reviews Endocrinology (publishedVersion)
PubMed (publishedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
HAL (submittedVersion, other-oa)
Leiden Repository (Leiden University) (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
Keywords: metformin, type 2 diabetes, glucoregulation, hepatic glucose production, gluconeogenesis, AMPK, mitochondrial complex I inhibition, hepatic insulin sensitivity, adenylate cyclase inhibition, FBP1, glycerol-3-phosphate dehydrogenase, redox state, meta-inflammation, obesity, gut microbiota, glucagon-like peptide-1, bile acids
MeSH terms: Gastrointestinal Microbiome, Animals, Diabetes Mellitus, Type 2, Electron Transport, Glucose, Humans, Hypoglycemic Agents, Metformin, AMP-Activated Protein Kinases

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Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus

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