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Cellular Responses to the Metal-Binding Properties of Metformin

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Cellular Responses to the Metal-Binding Properties of Metformin. / Logie, Lisa; Harthill, Jean; Patel, Kashyap; Bacon, Sandra; Hamilton, D. Lee; Macrae, Katherine; McDougall, Gordon; Wang, Huan-Huan; Xue, Lin; Jiang, Hua; Sakamoto, Kei; Prescott, Alan R.; Rena, Graham (Lead / Corresponding author).

In: Diabetes, Vol. 61, No. 6, 06.2012, p. 1423-1433.

Research output: Contribution to journalArticle

Harvard

Logie, L, Harthill, J, Patel, K, Bacon, S, Hamilton, DL, Macrae, K, McDougall, G, Wang, H-H, Xue, L, Jiang, H, Sakamoto, K, Prescott, AR & Rena, G 2012, 'Cellular Responses to the Metal-Binding Properties of Metformin' Diabetes, vol 61, no. 6, pp. 1423-1433.

APA

Logie, L., Harthill, J., Patel, K., Bacon, S., Hamilton, D. L., Macrae, K., McDougall, G., Wang, H-H., Xue, L., Jiang, H., Sakamoto, K., Prescott, A. R., & Rena, G. (2012). Cellular Responses to the Metal-Binding Properties of Metformin. Diabetes, 61(6), 1423-1433doi: 10.2337/db11-0961

Vancouver

Logie L, Harthill J, Patel K, Bacon S, Hamilton DL, Macrae K et al. Cellular Responses to the Metal-Binding Properties of Metformin. Diabetes. 2012 Jun;61(6):1423-1433.

Author

Logie, Lisa; Harthill, Jean; Patel, Kashyap; Bacon, Sandra; Hamilton, D. Lee; Macrae, Katherine; McDougall, Gordon; Wang, Huan-Huan; Xue, Lin; Jiang, Hua; Sakamoto, Kei; Prescott, Alan R.; Rena, Graham (Lead / Corresponding author) / Cellular Responses to the Metal-Binding Properties of Metformin.

In: Diabetes, Vol. 61, No. 6, 06.2012, p. 1423-1433.

Research output: Contribution to journalArticle

Bibtex - Download

@article{8e45ac8d525141d68b60d5ff8ebf3eff,
title = "Cellular Responses to the Metal-Binding Properties of Metformin",
author = "Lisa Logie and Jean Harthill and Kashyap Patel and Sandra Bacon and Hamilton, {D. Lee} and Katherine Macrae and Gordon McDougall and Huan-Huan Wang and Lin Xue and Hua Jiang and Kei Sakamoto and Prescott, {Alan R.} and Graham Rena",
year = "2012",
volume = "61",
number = "6",
pages = "1423--1433",
journal = "Diabetes",
issn = "0012-1797",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Cellular Responses to the Metal-Binding Properties of Metformin

A1 - Logie,Lisa

A1 - Harthill,Jean

A1 - Patel,Kashyap

A1 - Bacon,Sandra

A1 - Hamilton,D. Lee

A1 - Macrae,Katherine

A1 - McDougall,Gordon

A1 - Wang,Huan-Huan

A1 - Xue,Lin

A1 - Jiang,Hua

A1 - Sakamoto,Kei

A1 - Prescott,Alan R.

A1 - Rena,Graham

AU - Logie,Lisa

AU - Harthill,Jean

AU - Patel,Kashyap

AU - Bacon,Sandra

AU - Hamilton,D. Lee

AU - Macrae,Katherine

AU - McDougall,Gordon

AU - Wang,Huan-Huan

AU - Xue,Lin

AU - Jiang,Hua

AU - Sakamoto,Kei

AU - Prescott,Alan R.

AU - Rena,Graham

PY - 2012/6

Y1 - 2012/6

N2 - <p>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 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. Diabetes 61:1423-1433, 2012</p>

AB - <p>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 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. Diabetes 61:1423-1433, 2012</p>

U2 - 10.2337/db11-0961

DO - 10.2337/db11-0961

M1 - Article

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 6

VL - 61

SP - 1423

EP - 1433

ER -

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