Cellular Responses to the Metal-Binding Properties of Metformin
- Lisa Logie1,
- Jean Harthill1,
- Kashyap Patel2,
- Sandra Bacon1,3,
- D. Lee Hamilton1,
- Katherine Macrae4,
- Gordon McDougall3,
- Huan-Huan Wang5,
- Lin Xue5,
- Hua Jiang5,
- Kei Sakamoto2,
- Alan R. Prescott4 and
- Graham Rena1⇓
- 1Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, U.K.
- 2Medical Research Council Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee, Scotland, U.K.
- 3James Hutton Institute, Dundee, Scotland, U.K.
- 4Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee, Scotland, U.K.
- 5Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Photochemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing, People’s Republic of China
- Corresponding author: Graham Rena, .
In recent decades, the antihyperglycemic biguanide metformin has been used extensively in the treatment of type 2 diabetes, despite continuing uncertainty over its direct target. In this paper, using two independent approaches, we demonstrate that cellular actions of metformin are disrupted by interference with its metal-binding properties, which have been known for over a century but little studied by biologists. We demonstrate that copper sequestration opposes known actions of metformin not only on AMP-activated protein kinase (AMPK)-dependent signaling, but also on S6 protein phosphorylation. Biguanide/metal interactions are stabilized by extensive pi-electron delocalization and by investigating analogs of metformin; we provide evidence that this intrinsic property enables biguanides to regulate AMPK, glucose production, gluconeogenic gene expression, mitochondrial respiration, and mitochondrial copper binding. In contrast, regulation of S6 phosphorylation is prevented only by direct modification of the metal-liganding groups of the biguanide structure, supporting recent data that AMPK and S6 phosphorylation are regulated independently by biguanides. Additional studies with pioglitazone suggest that mitochondrial copper is targeted by both of these clinically important drugs. Together, these results suggest that cellular effects of biguanides depend on their metal-binding properties. This link may illuminate a better understanding of the molecular mechanisms enabling antihyperglycemic drug action.
- Received July 11, 2011.
- Accepted February 7, 2012.
- © 2012 by the American Diabetes Association.
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