Year: 2020
Type: article
Abstract: Metformin is a first-line therapy for the treatment of type 2 diabetes, due to its robust glucose-lowering effects, well-established safety profile, and relatively low cost. While metformin has been shown to have pleotropic effects on glucose metabolism, there is a general consensus that the major glucose-lowering effect in patients with type 2 diabetes is mostly mediated through inhibition of hepatic gluconeogenesis. However, despite decades of research, the mechanism by which metformin inhibits this process is still highly debated. A key reason for these discrepant effects is likely due to the inconsistency in dosage of metformin across studies. Widely studied mechanisms of action, such as complex I inhibition leading to AMPK activation, have only been observed in the context of supra-pharmacological (>1 mM) metformin concentrations, which do not occur in the clinical setting. Thus, these mechanisms have been challenged in recent years and new mechanisms have been proposed. Based on the observation that metformin alters cellular redox balance, a redox-dependent mechanism of action has been described by several groups. Recent studies have shown that clinically relevant (50-100 μM) concentrations of metformin inhibit hepatic gluconeogenesis in a substrate-selective manner both in vitro and in vivo, supporting a redox-dependent mechanism of metformin action. Here, we review the current literature regarding metformin's cellular and molecular mechanisms of action.
Source: Endocrine Reviews
Authors: Traci E LaMoia, Gerald I Shulman
Institution: Yale University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,750
Funders: AstraZeneca, Gilead Sciences, National Institutes of Health, U.S. Public Health Service, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Advancing Translational Sciences
Awards: G1044130170, G1236451951, Development of Controlled Release Mitochondrial Protonophore (CRMP) as a Novel Treatment for Type-2 Diabetes and Non-Alcoholic Steatohepatitis in Dysmetabolic Non-Human Primates, G2490750684, G2641931136, Microbiome origins and insulin regulatory responses of the short chain fatty acid acetate, G2816320713, Institutional National Research Service Award, Glucagon Regulation of Hepatic Mitochondrial Activity and Glucose Metabolism by InsP3R-1, G4928300808, G5153427240, G5530890406, G7126574865, G7314688813, G73615776, G7476218225, Dual-specificity phosphatase action in muscle disease, Yale Clinical and Translational Science Award
OpenAlex ID: W3084144806