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Role of AMP-activated protein kinase in mechanism of metformin action
Gaochao Zhou, … , Laurie J. Goodyear, David E. Moller
Gaochao Zhou, … , Laurie J. Goodyear, David E. Moller
Published October 15, 2001
Citation Information: J Clin Invest. 2001;108(8):1167-1174. https://doi.org/10.1172/JCI13505.
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Role of AMP-activated protein kinase in mechanism of metformin action

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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

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Figure 1

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Metformin mediates AMPK activation in primary hepatocytes. (a) Metformin...
Metformin mediates AMPK activation in primary hepatocytes. (a) Metformin (black bars) and AICAR (A; 500 μM) activate AMPK in rat primary hepatocytes. The treatments were 1 hour, 7 hours, and 39 hours, respectively. (b) Metformin (500 μM) and AICAR (500 μM) activated both AMPKα1 and AMPKα2 complexes demonstrated by immunoprecipitation-AMPK assay. DPM, disintegrations per minute. (c) Metformin (1 mM) and AICAR (500 μM) stimulated AMPK Thr172 phosphorylation. (d) Metformin does not activate partially purified rat liver AMPK in vitro. (e) Metformin and AICAR (500 μM) inactivate ACC in rat primary hepatocytes. (f) Metformin (500 μM, 4 hours) and AICAR (500 μM, 4 hours) stimulate hepatocyte fatty acid oxidation. C, vehicle control. Mean (n = 3 wells per treatment for 1 hour and 7 hours; for 39-hour treatment, n = 12–15 wells per treatment) ± SEM values are shown. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control medium (paired t test).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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