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Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus
Open accessAbstract
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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“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).”
From Diabetes and Sarcopenic Obesity: Pathogenesis, Diagnosis, and Treatments (2020) · cites this paper as [183]
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Metadata
- 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
- 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
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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