Cited by 686Metabolism, Diabetes, and CancerDiabetes Treatment and ManagementNatural Antidiabetic Agents Studies

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

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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Crossref · 10.1038/s41574-019-0242-2

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  • Metformin decreases fasting plasma glucose concentration and hemoglobin A1c by conserving β-cell function or by decreasing liver glucose production (hepatic gluconeogenesis).

    “A considerable number of studies have also found that metformin decreases fasting plasma glucose (PG) concentration and hemoglobin A1c by conserving the β-cell function or by decreasing liver glucose production (hepatic gluconeogenesis) (181–184).”

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Authors
Foretz, M., Guigas, B., & Viollet, B.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Leiden University Medical Center (NL)
Venue
Nature Reviews Endocrinology
Published
2019-08-22
Volume
15
Issue
10
Pages
569-589
ISSN
  • 1759-5029 (ISSN-L)
  • 1759-5037
OpenAlex
W2969928163
Cited by
686
References
258
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
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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