ArticleThe Biochemical journal2000
Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain.
Article in The Biochemical journal, 2000. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02978547 (The Effects of Neoadjuvant Metformin on Tumour Cell Proliferation and Tumour Progression in Pancreatic Ductal Adenocarcinoma), which is not on this map. Cited by 1,047 papers, 6 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
The Effects of Neoadjuvant Metformin on Tumour Cell Proliferation and Tumour Progression in Pancreatic Ductal Adenocarcinoma
Who cites it
1,047 citing papers in PubMed, 6 syntheses or guidelines pooled it, 2,061 citations in OpenAlex.
- Targeting Ferroptosis as the Achilles' Heel of Breast Cancer: Mechanisms and Therapeutic Opportunities from a Comprehensive Systematic Review.International journal of molecular sciences · 2025Pooled it
- Impact of monotherapy and combination therapy with glucagon-like peptide-1 receptor agonists on exosomal and non-exosomal MicroRNA signatures in type 2 diabetes mellitus: a systematic review.Journal of translational medicine · 2025Pooled it
- EASL-EASD-EASO Clinical Practice Guidelines on the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).Obesity facts · 2024Guideline
- Knowledge mapping of metformin use on cancers: a bibliometric analysis (2013-2023).Frontiers in pharmacology · 2024Pooled it
- Short-term neonatal outcomes in women with gestational diabetes treated using metformin versus insulin: a systematic review and meta-analysis of randomized controlled trials.Acta diabetologica · 2023Pooled it
- After Dinner Rest a While, After Supper Walk a Mile? A Systematic Review with Meta-analysis on the Acute Postprandial Glycemic Response to Exercise Before and After Meal Ingestion in Healthy Subjects and Patients with Impaired Glucose Tolerance.Sports medicine (Auckland, N.Z.) · 2023Pooled it
- Trial
- Mechanism-Informed Pharmacotherapy Optimization and Deprescribing: A Redox-Mitochondrial Framework.Pharmacology research & perspectives · 2026Review
- AMPK-Directed Therapeutics for MASLD: Mechanistic Rationale, Activator Classes, and Clinical Translation.International journal of molecular sciences · 2026Review
- Divergent Retrograde Signaling Pathways Coordinate Longevity and Metformin Responses in Complex I and Complex IV DeficientbioRxiv : the preprint server for biology · 2026Article
- Metformin Attenuates the High-Glucose Effect on MORG1 Expression in HEK293 Cells.Current issues in molecular biology · 2026Article
- Ionomycin suppresses cancer cell growth by disrupting mitochondrial transcription.FEBS open bio · 2026Article
- Geroprotective Effects of Drugs Modulating Metabolic Pathways: Perspectives of Pharmacology in Anti-Aging Therapy.International journal of molecular sciences · 2026Review
- AMPK Therapy-A Little Goes A Long Way.Cells · 2026Review
- Metformin Enhances Antioxidant Defenses and Limits Lipid Peroxidation Through the Modulation of Nrf2/KEAP1 Pathway in Hippocampal Neurons Exposed to Amyloid-β Oligomers.Neurotoxicity research · 2026Article
- Dual Metabolic Targeting of Cancer: Lessons from Metformin and 2-Deoxy-D-Glucose Combinations.Cancers · 2026Article
- Mitochondrial metabolism and PD-1 blockade: mechanisms and therapeutic opportunities in cancer immunotherapy.Molecular biology reports · 2026Review
- The coordinated actions of metformin in the intestine and liver improves hyperglycemia.Cell reports · 2026Article
- Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer.Nature metabolism · 2026Article
- Mitochondrial Metabolic Reprogramming and Skin Immune Homeostasis: From Basic Mechanisms to Therapeutic Perspectives.Immune network · 2026Review
987 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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 microM) 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 (K(0.5),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, canal so be explained in this way.
Indexed as
Identifiers
10839993PMC1221104W1995069275What OpenQuestion holds
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.