ArticleThe Journal of biological chemistry2011
Metformin activates AMP kinase through inhibition of AMP deaminase.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 119 papers.
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Who cites it
119 citing papers in PubMed, 242 citations in OpenAlex.
- Extracellular Matrix-MYCAF Signatures Correlate with Resistance to Neoadjuvant aPD-L1 Immune Checkpoint Inhibition with Durvalumab + Metformin in HPV+ HNSCC.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Trial
- Trial
- Metformin in non-diabetic patients presenting with ST elevation myocardial infarction: rationale and design of the glycometabolic intervention as adjunct to primary percutaneous intervention in ST elevation myocardial infarction (GIPS)-III trial.Cardiovascular drugs and therapy · 2012Trial
- Research Progress on the Molecular Mechanism of Metformin Regulating AMPK Signaling Pathway in Inhibiting Liver Cancer.OncoTargets and therapy · 2026Review
- Controversial effects of metformin on human physiology and pathophysiology.Frontiers in pharmacology · 2026Review
- ToF-SIMS Reveals Metformin-Driven Restoration of Hepatic Lipid and Amino Acid Profiles in a Type 2 Diabetes Rat Model.International journal of molecular sciences · 2025Article
- Scrutiny of the Co-Cytotoxic Impact of Metformin-Omeprazole on the Cervical Cancer Cell Line and Their Aptitude to Target Heat Shock 60.Asian Pacific journal of cancer prevention : APJCP · 2025Article
- Metformin modulates the unfolded protein responses, altering lifespan and health-promoting effects in UPR-activated worms.PloS one · 2025Article
- Role of AMP deaminase in diabetic cardiomyopathy.Molecular and cellular biochemistry · 2024Review
- Effects of Biguanide-PROTACs in Pancreatic Cancer Cells.Molecules (Basel, Switzerland) · 2024Article
- Metformin inhibits high glucose-induced apoptosis of renal podocyte through regulating miR-34a/SIRT1 axis.Immunity, inflammation and disease · 2024Article
- Effects of long-term metformin administration associated with high-intensity interval training on physical performance, glycogen concentration, GLUT-4 content, and NMR-based metabolomics in healthy rats.Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologica · 2024Article
- Mito-metformin protects against mitochondrial dysfunction and dopaminergic neuronal degeneration by activating upstream PKD1 signaling in cell culture and MitoPark animal models of Parkinson's disease.Frontiers in neuroscience · 2024Article
- Combined Administration of Metformin and Vitamin D: A Futuristic Approach for Management of Hyperglycemia.Cardiovascular & hematological agents in medicinal chemistry · 2024Review
- Redox state and altered pyruvate metabolism contribute to a dose-dependent metformin-induced lactate production of human myotubes.American journal of physiology. Cell physiology · 2023Article
- Effects of Metformin on Ischemia/Reperfusion Injury: New Evidence and Mechanisms.Pharmaceuticals (Basel, Switzerland) · 2023Review
- The potential effect of metformin on fibroblast growth factor 21 in type 2 diabetes mellitus (T2DM).Inflammopharmacology · 2023Review
- Role of the AMPK/SIRT1 pathway in non‑alcoholic fatty liver disease (Review).Molecular medicine reports · 2023Review
- Action Mechanism of Metformin and Its Application in Hematological Malignancy Treatments: A Review.Biomolecules · 2023Review
- Metformin extends the chronological lifespan of fission yeast by altering energy metabolism and stress resistance capacity.FEMS yeast research · 2023Article
59 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The mechanism for how metformin activates AMPK (AMP-activated kinase) was investigated in isolated skeletal muscle L6 cells. A widely held notion is that inhibition of the mitochondrial respiratory chain is central to the mechanism. We also considered other proposals for metformin action. As metabolic pathway markers, we focused on glucose transport and fatty acid oxidation. We also confirmed metformin actions on other metabolic processes in L6 cells. Metformin stimulated both glucose transport and fatty acid oxidation. The mitochondrial Complex I inhibitor rotenone also stimulated glucose transport but it inhibited fatty acid oxidation, independently of metformin. The peroxynitrite generator 3-morpholinosydnonimine stimulated glucose transport, but inhibited fatty acid oxidation. Addition of the nitric oxide precursor arginine to cells did not affect glucose transport. These studies differentiate metformin from inhibition of mitochondrial respiration and from active nitrogen species. Knockdown of adenylate kinase also failed to affect metformin stimulation of glucose transport. Hence, any means of increase in ADP appears not to be involved in the metformin mechanism. Knockdown of LKB1, an upstream kinase and AMPK activator, did not affect metformin action. Having ruled out existing proposals, we suggest a new one: metformin might increase AMP through inhibition of AMP deaminase (AMPD). We found that metformin inhibited purified AMP deaminase activity. Furthermore, a known inhibitor of AMPD stimulated glucose uptake and fatty acid oxidation. Both metformin and the AMPD inhibitor suppressed ammonia accumulation by the cells. Knockdown of AMPD obviated metformin stimulation of glucose transport. We conclude that AMPD inhibition is the mechanism of metformin action.
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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.