Role of AMP-activated protein kinase in mechanism of metformin action
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
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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Role of AMP-activated protein kinase in mechanism of metformin action

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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Discovery and use of a novel small-molecule AMPK inhibitor to establish ...
Discovery and use of a novel small-molecule AMPK inhibitor to establish that the effects of metformin on ACC and glucose production are AMPK dependent. (a) Inhibition of partially purified AMPK by compound C (inset shows the chemical structure) is reversible and competitive with respect to ATP. The in vitro kinase assay was performed in the presence of 5 μM ATP, 0 μM AMP (filled circles), 100 μM ATP, 0 μM AMP (filled squares), and 100 μM ATP plus 100 μM AMP (open circles). (b) Compound C inhibits the effects of AICAR and metformin on ACC in rat hepatocytes. Mean (n = 3 per treatment) ± SEM values are shown. *P < 0.05 vs. control medium (paired t test). (c) Compound C attenuates the ability of metformin to suppress glucagon-stimulated glucose production by hepatocytes from 24-hour starved rats. At time 0, compound C (40 μM) was added, and at time 30 minutes, metformin (2 mM) was added. Squares, control; diamonds, metformin; circles, metformin plus compound C. Each point represents the mean ± SEM of four replicate assays. *P < 0.05, **P < 0.01 vs. metformin alone at the same time point (paired t test). The experiment was repeated three times with similar results.