Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain.
Top Cited Papers
- 15 June 2000
- journal article
- Vol. 348, 607-14
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.This publication has 33 references indexed in Scilit:
- Hypoxia and Mitochondrial Inhibitors Regulate Expression of Glucose Transporter-1 via Distinct Cis-acting SequencesJournal of Biological Chemistry, 1995
- Translocation of two glucose transporters in heart: effects of rotenone, uncouplers, workload, palmitate, insulin and anoxiaBiochimica et Biophysica Acta (BBA) - Biomembranes, 1994
- Studies on the Characterization of the Inhibitory Mechanism of 4′‐Alkylated 1‐Methyl‐4‐Phenylpyridinium and Phenylpyridine Analogues in Mitochondria and Electron Transport ParticlesJournal of Neurochemistry, 1994
- Accumulation of metformin by tissues of the normal and diabetic mouseXenobiotica, 1994
- Metformin Increases Glucose Transporter Protein and Gene Expression in Human FibroblastsBiochemical and Biophysical Research Communications, 1993
- Metformin decreases gluconeogenesis by enhancing the pyruvate kinase flux in isolated rat hepatocytesEuropean Journal of Biochemistry, 1993
- The mechanisms by which mild respiratory chain inhibitors inhibit hepatic gluconeogenesisBiochimica et Biophysica Acta (BBA) - Bioenergetics, 1993
- Biguanide-associated lactic acidosis. Case report and review of the literatureArchives of Internal Medicine, 1992
- Energetics of Ehrlich ascites mitochondria: Membrane potential of isolated mitochondria and mitochondria within digitonin-permeabilized cellsBiochimica et Biophysica Acta (BBA) - Bioenergetics, 1990
- The mechanism of action of phenformin in starved ratsBiochemical Pharmacology, 1983