ArticleThe Journal of biological chemistry2019
Low metformin causes a more oxidized mitochondrial NADH/NAD redox state in hepatocytes and inhibits gluconeogenesis by a redox-independent mechanism.
Article in The Journal of biological chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.
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Who cites it
52 citing papers in PubMed, 1 synthesis or guideline pooled it, 82 citations in OpenAlex.
- Efficacy of metformin therapy in patients with cancer: a meta-analysis of 22 randomised controlled trials.BMC medicine · 2022Pooled it
- Optimizing the Interaction of Exercise Volume and Metformin to Induce a Clinically Significant Reduction in Metabolic Syndrome Severity: A Randomised Trial.International journal of environmental research and public health · 2020Trial
- Metformin's disruption of gluconeogenesis in type 2 diabetes impairments of the cori and alanine cycles as hidden drivers of metabolic waste accumulation, NF-κBHIF-1α-mediated low-grade inflammation, and multisystem dysfunction.Problemy endokrinologii · 2026Review
- Toxicological profile of anti-diabetic drugs and emerging measures to reduce the toxic burden.Toxicology reports · 2026Review
- Diagnosing Metformin Intoxication with High-Resolution Platelet Respirometry: A Case Report.International journal of molecular sciences · 2026Article
- Repurposed metformin-apigenin combination therapy for metabolic dysfunction-associated steatohepatitis: from integrative multi-omics discovery toFrontiers in pharmacology · 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
- Metformin and Adipose Tissue: A Multifaceted Regulator in Metabolism, Inflammation, and Regeneration.Endocrinology and metabolism (Seoul, Korea) · 2025Review
- Molecular mechanisms of UCP1-independent thermogenesis: the role of futile cycles in energy dissipation.Journal of physiology and biochemistry · 2025Review
- Functional and Biochemical Analyses of Glycerol Kinase and Glycerol 3-phosphate Dehydrogenase in HEK293 Cells.The protein journal · 2025Article
- Overview of Metformin and Neurodegeneration: A Comprehensive Review.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Systems metabolic insights into kaempferol-mediated alleviation of alcoholic fatty liver disease.Frontiers in endocrinology · 2025Article
- Autophagy-NADFrontiers in molecular biosciences · 2025Review
- Metformin Effects on SHIP2, AMPKs and Gut Microbiota: Recent Updates on Pharmacology.Current medicinal chemistry · 2025Review
- Precision-cut liver slices as an ex vivo model to assess impaired hepatic glucose production.Communications biology · 2024Article
- Metformin: From Diabetes to Cancer-Unveiling Molecular Mechanisms and Therapeutic Strategies.Biology · 2024Review
- Metformin and the Liver: Unlocking the Full Therapeutic Potential.Metabolites · 2024Review
- Identification of glucose-independent and reversible metabolic pathways associated with anti-proliferative effect of metformin in liver cancer cells.Metabolomics : Official journal of the Metabolomic Society · 2024Article
- Advancements in precision medicine: multi-omics approach for tailored metformin treatment in type 2 diabetes.Frontiers in pharmacology · 2024Review
- Metformin: The Winding Path from Understanding Its Molecular Mechanisms to Proving Therapeutic Benefits in Neurodegenerative Disorders.Pharmaceuticals (Basel, Switzerland) · 2023Review
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 2 countries.
Funding
Abstract
The mechanisms by which metformin (dimethylbiguanide) inhibits hepatic gluconeogenesis at concentrations relevant for type 2 diabetes therapy remain debated. Two proposed mechanisms are 1) inhibition of mitochondrial Complex 1 with consequent compromised ATP and AMP homeostasis or 2) inhibition of mitochondrial glycerophosphate dehydrogenase (mGPDH) and thereby attenuated transfer of reducing equivalents from the cytoplasm to mitochondria, resulting in a raised lactate/pyruvate ratio and redox-dependent inhibition of gluconeogenesis from reduced but not oxidized substrates. Here, we show that metformin has a biphasic effect on the mitochondrial NADH/NAD redox state in mouse hepatocytes. A low cell dose of metformin (therapeutic equivalent: <2 nmol/mg) caused a more oxidized mitochondrial NADH/NAD state and an increase in lactate/pyruvate ratio, whereas a higher metformin dose (≥5 nmol/mg) caused a more reduced mitochondrial NADH/NAD state similar to Complex 1 inhibition by rotenone. The low metformin dose inhibited gluconeogenesis from both oxidized (dihydroxyacetone) and reduced (xylitol) substrates by preferential partitioning of substrate toward glycolysis by a redox-independent mechanism that is best explained by allosteric regulation at phosphofructokinase-1 (PFK1) and/or fructose 1,6-bisphosphatase (FBP1) in association with a decrease in cell glycerol 3-phosphate, an inhibitor of PFK1, rather than by inhibition of transfer of reducing equivalents. We conclude that at a low pharmacological load, the metformin effects on the lactate/pyruvate ratio and glucose production are explained by attenuation of transmitochondrial electrogenic transport mechanisms with consequent compromised malate-aspartate shuttle and changes in allosteric effectors of PFK1 and FBP1.
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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.