The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain
Open accessAbstract
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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In the citing paper
“Metformin may cause lactic acidosis through impairment of oxidative phosphorylation.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [464]
In the citing paper
“it has been shown to accumulate in mitochondria due to the membrane potential across the mitochondrial inner membrane”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Owen et al. 2000
In the citing paper
“However, metformin, one of the commonly prescribed drugs for treating type II diabetes, is safe despite acting as a mitochondrial complex I inhibitor that impairs respiration (Bridges et al., 2014; El-Mir et al., 2000; Owen et al., 2000; Wheaton et al., 2014).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Owen et al., 2000
In the citing paper
“This inhibition would in turn decrease the ATP/AMP ratio activating AMPK (127–129).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [128]
In the citing paper
“As pointed out by Fontaine, a problem associated with accepting the argument that the therapeutic effects of metformin result from inhibition of complex 1, as depicted in Figure 1, are the high concentrations used in the cell culture studies described by El Mir et al. and Owen et al. (127, 128, 133).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [128]
In the citing paper
“Given the evidence that metformin acts through the mitochondrial electron transport chain (ETC) by inhibiting complex I(46, 210–212) (Figure 8)”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [210]
Citations
Cites
Kinaan, M., Ding, H., & Triggle, C. R. (2015) · Medical Principles and Practice · doi:10.1159/000381643 · Cited by 1,515
El-Mir, M.-Y., Nogueira, V., Fontaine, E., Avéret, N., Rigoulet, M., & Leverve, X. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.1.223 · Cited by 1,399
Ebert, B. L., Firth, J. D., & Ratcliffe, P. J. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.49.29083 · Cited by 569
Accumulation of Metformin by Tissues of the Normal and Diabetic Mouse
Wilcock, C., & Bailey, C. J. (1994) · Xenobiotica · doi:10.3109/00498259409043220 · Cited by 418
Hundal, H. S., Ramlal, T., Reyes, R., Leiter, L. A., & Klip, A. (1992) · Endocrinology · doi:10.1210/endo.131.3.1505458 · Cited by 243
Perriello, G., Misericordia, P., Volpi, E., Santucci, A., Santucci, C., Ferrannini, E., Ventura, M. M., Santeusanio, F., Brunetti, P., & Bolli, G. B. (1994) · Diabetes · doi:10.2337/diab.43.7.920 · Cited by 227
Argaud, D., Roth, H., Wiernsperger, N. F., & Leverve, X. M. (1993) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1993.tb17886.x · Cited by 151
Biguanide-associated lactic acidosis. Case report and review of the literature
Gan, S. C. (1992) · Archives of Internal Medicine · doi:10.1001/archinte.152.11.2333 · Cited by 129
Halestrap, A. P. (1987) · Biochemical Journal · doi:10.1042/bj2440159 · Cited by 120
Self-citationFischer, Y., Thomas, J., Rosen, P., & Kammermeier, H. (1995) · Endocrinology · doi:10.1210/endo.136.2.7835271 · Cited by 114
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Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13505 · Cited by 5,652
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
Ward, P. S., & Thompson, C. B. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.014 · Cited by 3,233
Fundamentals of Cancer Metabolism
DeBerardinis, R. J., & Chandel, N. S. (2016) · Science Advances · doi:10.1126/sciadv.1600200 · Cited by 3,013
The mechanisms of action of metformin
Rena, G., Hardie, D. G., & Pearson, E. R. (2017) · Diabetologia · doi:10.1007/s00125-017-4342-z · Cited by 2,287
Tacke, F., Horn, P., Wai-Sun Wong, V., Ratziu, V., Bugianesi, E., Francque, S., Zelber-Sagi, S., Valenti, L., Roden, M., Schick, F., et al. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.04.031 · Cited by 2,210
Metadata
- 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
- 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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