ArticleProceedings of the National Academy of Sciences of the United States of America2022
Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 94 citations in OpenAlex.
- Maternal metformin treatment in obese pregnant dams normalizes neonatal sensory-motor reflexes.Molecular and cellular pediatrics · 2026Article
- Reductive death is averted by a conserved de novo lipogenic switch.Molecular cell · 2026Article
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- Sex-specific mitochondrial dysregulation and metformin response in Wilson disease.Scientific reports · 2026Article
- Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control.Nature metabolism · 2026Article
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- Metformin promotes mitochondrial integrity through AMPK-signaling in Leber's hereditary optic neuropathy.FEBS open bio · 2026Article
- Metabolic dysfunction-associated steatotic liver disease and steatohepatitis-associated hepatocarcinoma preclinical models.Nature reviews. Gastroenterology & hepatology · 2026Review
- Integrative Proteomic and Bioenergetic Profiling Reveals Diet- and Strain-Specific Mitochondrial Dysfunction in Cohen Diabetic Rat Hearts.Antioxidants (Basel, Switzerland) · 2026Article
- Tissue Iron Predicts Metformin Responsiveness in a Mouse Model and in Humans with Type 2 Diabetes.Diabetes, metabolic syndrome and obesity : targets and therapy · 2026Article
- Repurposed metformin-apigenin combination therapy for metabolic dysfunction-associated steatohepatitis: from integrative multi-omics discovery toFrontiers in pharmacology · 2026Article
- Hydrophilic metformin and hydrophobic biguanides inhibit mitochondrial complex I by distinct mechanisms.Nature structural & molecular biology · 2026Article
- Repurposing metformin for cardioprotection: mechanisms and therapeutic potential across cardiovascular pathologies.Frontiers in pharmacology · 2026Review
- Inhibition of hepatic gluconeogenesis in type 2 diabetes by metformin: complementary role of nitric oxide.Medical gas research · 2025Review
- Article
- From Diabetes to Degenerative Diseases: The Multifaceted Action of Metformin.International journal of molecular sciences · 2025Review
- Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycemic control.bioRxiv : the preprint server for biology · 2025Article
- Low-dose metformin requires brain Rap1 for its antidiabetic action.Science advances · 2025Article
- Variations in Human Milk Metabolites After Gestational Diabetes: Associations with Infant Growth.Nutrients · 2025Article
- The direct targets of metformin in diabetes and beyond.Trends in endocrinology and metabolism: TEM · 2025Review
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
Abstract
SignificanceMetformin is the most commonly prescribed drug for the treatment of type 2 diabetes mellitus, yet the mechanism by which it lowers plasma glucose concentrations has remained elusive. Most studies to date have attributed metformin's glucose-lowering effects to inhibition of complex I activity. Contrary to this hypothesis, we show that inhibition of complex I activity in vitro and in vivo does not reduce plasma glucose concentrations or inhibit hepatic gluconeogenesis. We go on to show that metformin, and the related guanides/biguanides, phenformin and galegine, inhibit complex IV activity at clinically relevant concentrations, which, in turn, results in inhibition of glycerol-3-phosphate dehydrogenase activity, increased cytosolic redox, and selective inhibition of glycerol-derived hepatic gluconeogenesis both in vitro and in vivo.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.