Please use this identifier to cite or link to this item: http://hdl.handle.net/1893/16516
Appears in Collections:Faculty of Health Sciences and Sport Journal Articles
Peer Review Status: Refereed
Title: Cellular Responses to the Metal-Binding Properties of Metformin
Authors: Logie, Lisa
Harthill, Jean
Patel, Kashyap
Bacon, Sandra
Hamilton, David Lee
Macrae, Katherine
McDougall, Gordon
Wang, Huan-Huan
Xue, Lin
Jiang, Hua
Sakamoto, Kei
Prescott, Alan R
Rena, Graham
Contact Email: d.l.hamilton@stir.ac.uk
Issue Date: Jun-2012
Publisher: American Diabetes Association
Citation: Logie L, Harthill J, Patel K, Bacon S, Hamilton DL, Macrae K, McDougall G, Wang H, Xue L, Jiang H, Sakamoto K, Prescott AR & Rena G (2012) Cellular Responses to the Metal-Binding Properties of Metformin, Diabetes, 61 (6), pp. 1423-1433.
Abstract: 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 article, 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 π-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.
Type: Journal Article
URI: http://hdl.handle.net/1893/16516
DOI Link: http://dx.doi.org/10.2337/db11-0961
Rights: The publisher does not allow this work to be made publicly available in this Repository. Please use the Request a Copy feature at the foot of the Repository record to request a copy directly from the author. You can only request a copy if you wish to use this work for your own research or private study.
Affiliation: University of Dundee
University of Dundee
University of Dundee
University of Dundee
Sport
University of Dundee
The James Hutton Institute
Chinese Academy of Sciences
Chinese Academy of Sciences
Chinese Academy of Sciences
University of Dundee
University of Dundee
University of Dundee

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