ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2019
Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 96 citations in OpenAlex.
- Combined effect of metformin and ezetimibe on PPAR-γ and adiponectin gene expression and biochemical parameters in MAFLD patients with type 2 diabetes.Scientific reports · 2025 · on this mapTrial
- Small Molecule Insulin Sensitisers: New Leads and Targets for Next-Generation Insulin Sensitising Strategies.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Review
- Discovery and Characterization of a Selective Inhibitor of Synaptojanin1 5‑Phosphatase Activity.ACS pharmacology & translational science · 2025Article
- Long-term effects of metformin on offspring health: A review of current evidence and future directions.Diabetes, obesity & metabolism · 2025Review
- Integrin Trafficking, Fibronectin Architecture, and Glomerular Injury upon Adiponectin Receptor 1 Depletion.Journal of the American Society of Nephrology : JASN · 2025Article
- New Perspectives on the Molecular Action of Metformin in the Context of Cellular Transduction and Adipogenesis.International journal of molecular sciences · 2025Review
- The direct targets of metformin in diabetes and beyond.Trends in endocrinology and metabolism: TEM · 2025Review
- Metformin's Effects on Cognitive Function from a Biovariance Perspective: A Narrative Review.International journal of molecular sciences · 2025Review
- Role of Metformin in Preventing New-Onset Chronic Kidney Disease in Patients with Type 2 Diabetes Mellitus.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Evaluating the Prophylactic and Nephroprotective Effects of Vitamin D and Metformin in Diabetic Nephropathy.Oxidative medicine and cellular longevity · 2025Article
- Metformin Effects on SHIP2, AMPKs and Gut Microbiota: Recent Updates on Pharmacology.Current medicinal chemistry · 2025Review
- Aerobic Exercise and Metformin: A Dual Approach to Enhancing Glycemic Maintenance in Type 2 Diabetes Mellitus.Chonnam medical journal · 2025Review
- Mechanisms to medicines: navigating drug repurposing strategies in Alzheimer's disease.Frontiers in aging neuroscience · 2025Review
- TangNaikang Formula Alleviates Podocyte Injury in Diabetic Nephropathy by Modulating the SHIP2/PI3K/AKT Pathway.Journal of diabetes research · 2025Article
- Pharmacokinetic and Pharmacodynamic Interaction of Metformin and Ojeok-san in Healthy Volunteers.Drug design, development and therapy · 2025Article
- Treatment of acromegaly-induced diabetes: an updated proposal.Pituitary · 2024Review
- Diverse Applications of the Anti-Diabetic Drug Metformin in Treating Human Disease.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Article
- Discovery of aurones bearing two amine functionalities as SHIP2 inhibitors with insulin-sensitizing effect in rat myotubes.RSC medicinal chemistry · 2024Article
- Empagliflozin alone and in combination with metformin mitigates diabetes-associated renal complications.Journal of medicine and life · 2024Article
Corrections and comments
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Authors and funding
16 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Metformin, the first-line drug to treat type 2 diabetes (T2D), inhibits mitochondrial glycerolphosphate dehydrogenase in the liver to suppress gluconeogenesis. However, the direct target and the underlying mechanisms by which metformin increases glucose uptake in peripheral tissues remain uncharacterized. Lipid phosphatase Src homology 2 domain-containing inositol-5-phosphatase 2 (SHIP2) is upregulated in diabetic rodent models and suppresses insulin signaling by reducing Akt activation, leading to insulin resistance and diminished glucose uptake. Here, we demonstrate that metformin directly binds to and reduces the catalytic activity of the recombinant SHIP2 phosphatase domain in vitro. Metformin inhibits SHIP2 in cultured cells and in skeletal muscle and kidney of db/db mice. In SHIP2-overexpressing myotubes, metformin ameliorates reduced glucose uptake by slowing down glucose transporter 4 endocytosis. SHIP2 overexpression reduces Akt activity and enhances podocyte apoptosis, and both are restored to normal levels by metformin. SHIP2 activity is elevated in glomeruli of patients with T2D receiving nonmetformin medication, but not in patients receiving metformin, compared with people without diabetes. Furthermore, podocyte loss in kidneys of metformin-treated T2D patients is reduced compared with patients receiving nonmetformin medication. Our data unravel a novel molecular mechanism by which metformin enhances glucose uptake and acts renoprotectively by reducing SHIP2 activity.-Polianskyte-Prause, Z., Tolvanen, T. A., Lindfors, S., Dumont, V., Van, M., Wang, H., Dash, S. N., Berg, M., Naams, J.-B., Hautala, L. C., Nisen, H., Mirtti, T., Groop, P.-H., Wähälä, K., Tienari, J., Lehtonen, S. Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity.
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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 Socratic graph.