Role of AMP-activated protein kinase in mechanism of metformin action.
Journal: 2001/December - Journal of Clinical Investigation
ISSN: 0021-9738
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.
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J Clin Invest 108(8): 1167-1174

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

+5 authors
Departments of Molecular Endocrinology, Metabolic Disorders, and Comparative Medicine, Merck Research Laboratories, Rahway, New Jersey, USAJoslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, USA
Address correspondence to: Gaochao Zhou, Merck Research Laboratories, Rahway, New Jersey 07065, USA. Phone: (732) 594-4782; Fax: (732) 594-5700; E-mail: moc.kcrem@uohz;f5000x#&oahcoag.
Address correspondence to: Gaochao Zhou, Merck Research Laboratories, Rahway, New Jersey 07065, USA. Phone: (732) 594-4782; Fax: (732) 594-5700; E-mail: moc.kcrem@uohz;f5000x#&oahcoag.
Received 2001 Jun 13; Accepted 2001 Aug 28.

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.

Abstract

Acknowledgments

We thank Shiying Chen for characterizing anti-AMPK Ab’s, Marcie Donnelly for technical support related to animal studies, Mark Fraley for compound synthesis, and Georgianna Harris and Denis McGarry for helpful discussions and intellectual support.

Acknowledgments

Footnotes

See the related Commentary beginning on page 1105.

Footnotes

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