Comments for:
Abstract
Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformin’s beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Here we report that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed. Activation of AMPK by metformin or an adenosine analogue suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; activity of the AMPK target, ACC, is also reduced. Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin’s inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of this drug; these results also suggest that alternative means of modulating AMPK should be useful for the treatment of metabolic disorders.
Authors
Gaochao Zhou, Robert Myers, Ying Li, Yuli Chen, Xiaolan Shen, Judy Fenyk-Melody, Margaret Wu, John Ventre, Thomas Doebber, Nobuharu Fujii, Nicolas Musi, Michael F. Hirshman, Laurie J. Goodyear, David E. Moller
Metformin's primary site of action is the respiratory chain
Submitter: Andrew P Halestrap | A.Halestrap@Bristol.ac.uk
Department of Biochemistry, University of Bristol
Published January 17, 2002
The recent paper by Zhou et al (1) elegantly demonstrates that metformin may exert some of its anti-diabetic actions on metabolism and gene expression through activation of AMP-activated protein kinase (AMPK). The authors recognise that this is consistent with the drug inhibiting complex I of the respiratory chain as demonstrated in this laboratory (2) and by El-Mir et al. (3). However, our own data have shown that the inhibition of hepatic gluconeogenesis by metformin does not necessarily require AMPK activation. A modest inhibition of the respiratory chain leads to an increase in NADH/NAD+ ratio and a decrease in ATP/ADP ratio without a significant effect on total ATP content. As the authors point out, it is this decrease in ATP/ADP ratio that will lead to an increase in tissue [AMP] and hence activation of AMPK. However, changes in these critical metabolite ratios will also cause inhibition of pyruvate carboxylase and activation of pyruvate kinase sufficient to account for the decreased rates of hepatic gluconeogenesis (2). Whatever the exact contributions of AMPK activation and direct metabolic effects of metformin are to its anti-diabetic action, a surprising conclusion suggests itself. The pharmacological actions of metformin may all be secondary to its inhibition of hepatic mitochondrial respiration (2). This might appear unlikely, since metformin is a remarkably safe drug, whereas excessive inhibition of the respiratory chain would lead to catastrophic tissue ATP depletion, such as occurs with cyanide poisoning. This apparent paradox can be reconciled in light of metformin 's unusual characteristics as a respiratory chain inhibitor (2). The drug is an extremely weak inhibitor of complex I (K0.5 of about 80mM) compared to most respiratory chain inhibitors (K0.5 values in the micromolar range or less). However, because of its positive charge, metformin accumulates to high concentrations within the mitochondrial matrix, driven by the membrane potential. This occurs extremely slowly (over several hours) because the drug is very hydrophilic and does not readily permeate biological membranes. As the drug accumulates, the increasing inhibition of the respiratory chain leads to a decrease in membrane potential that in turn prevents further drug uptake. Thus inhibition of respiration is self-limiting and excessive inhibition is avoided, ensuring that side effects such as lactic acidosis are minimal. Contrast this with the more lipid soluble phenformin that enters mitochondria much more rapidly (2) and is more likely to induce lactic acidosis.
1. Zhou, G.C., Myers, R., Li, Y., Chen, Y.L., Shen, X.L., FenykMelody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N. et al. 2001. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108:1167-1174.
2. Owen, M.R., Doran, E., and Halestrap, A.P. 2000. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 348:607-614.
3. El-Mir, M.Y., Nogueira, V., Fontaine, E., Averet, N., Rigoulet, M., and Leverve, X. 2000. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 275:223-228.
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