Cited by 2,157Metabolism, Diabetes, and CancerMitochondrial Function and PathologyDiabetes Treatment and Management

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Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain

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OWEN, Mark R., DORAN, Elena, HALESTRAP, Andrew P.·2000·Biochemical Journal

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Abstract

Although metformin is widely used for the treatment of non-insulin-dependent diabetes, its mode of action remains unclear. Here we provide evidence that its primary site of action is through a direct inhibition of complex 1 of the respiratory chain. Metformin (50 μM) inhibited mitochondrial oxidation of glutamate+malate in hepatoma cells by 13 and 30% after 24 and 60 h exposure respectively, but succinate oxidation was unaffected. Metformin also caused time-dependent inhibition of complex 1 in isolated mitochondria, whereas in sub-mitochondrial particles inhibition was immediate but required very high metformin concentrations (K0.5, 79 mM). These data are compatible with the slow membrane-potential-driven accumulation of the positively charged drug within the mitochondrial matrix leading to inhibition of complex 1. Metformin inhibition of gluconeogenesis from L-lactate in isolated rat hepatocytes was also time- and concentration-dependent, and accompanied by changes in metabolite levels similar to those induced by other inhibitors of gluconeogenesis acting on complex 1. Freeze-clamped livers from metformin-treated rats exhibited similar changes in metabolite concentrations. We conclude that the drug's pharmacological effects are mediated, at least in part, through a time-dependent, self-limiting inhibition of the respiratory chain that restrains hepatic gluconeogenesis while increasing glucose utilization in peripheral tissues. Lactic acidosis, an occasional side effect, can also be explained in this way.

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Authors: OWEN, M. R., DORAN, E., & HALESTRAP, A. P.
Affiliations: University of Bristol (GB)
ORCID: HALESTRAP, Andrew P.
Venue: Biochemical Journal
Publisher: Portland Press Ltd.
Published: 2000-06-07
Volume: 348
Issue: 3
Pages: 607-614
ISSN: 0264-6021 (ISSN-L)
1470-8728
DOI: 10.1042/bj3480607
PMC: PMC1221104
OpenAlex: W1995069275
Cited by: 2,157
References: 35
Citations by year: 2026: 64 · 2025: 78 · 2024: 92 · 2023: 125 · 2022: 127 · 2021: 157 · 2020: 163 · 2019: 144 · 2018: 142 · 2017: 144 · 2016: 139 · 2015: 126 · 2014: 135 · 2013: 112 · 2012: 75
FWCI: 4.10
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Biochemical Journal (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
UWE Research Repository (UWE Bristol) (submittedVersion, cc-by)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords: metformin, mitochondrial complex I inhibition, mitochondrial respiratory chain, type 2 diabetes, gluconeogenesis, hepatocytes, mitochondrial membrane potential, lactic acidosis, glucose utilization, mechanism of action
MeSH terms: Animals, Electron Transport, Gluconeogenesis, Hypoglycemic Agents, Liver, Male, Metformin, Mitochondria, NADH, NADPH Oxidoreductases, Submitochondrial Particles, Tumor Cells, Cultured, Signal Transduction, Rats, Wistar, Electron Transport Complex I, Rats

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Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain

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