Cellular Responses to the Metal-Binding Properties of Metformin

Lisa Logie, Jean Harthill, Kashyap Patel, Sandra Bacon, D. Lee Hamilton, Katherine Macrae, Gordon McDougall, Huan-Huan Wang, Lin Xue, Hua Jiang, Kei Sakamoto, Alan R. Prescott, Graham Rena (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    50 Citations (Scopus)

    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 p-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.
    Original languageEnglish
    Pages (from-to)1423-1433
    Number of pages11
    JournalDiabetes
    Volume61
    Issue number6
    DOIs
    Publication statusPublished - Jun 2012

    Keywords

    • Adenylate Kinase
    • Animals
    • Cell Line
    • Cells, Cultured
    • Chelating Agents
    • Copper
    • Glucose
    • Hepatocytes
    • Hypoglycemic Agents
    • Metformin
    • Oxygen Consumption
    • Phosphorylation
    • Rats
    • Ribosomal Protein S6 Kinases
    • Signal Transduction
    • Trientine

    Cite this

    Logie, L., Harthill, J., Patel, K., Bacon, S., Hamilton, D. L., Macrae, K., ... Rena, G. (2012). Cellular Responses to the Metal-Binding Properties of Metformin. Diabetes, 61(6), 1423-1433. https://doi.org/10.2337/db11-0961
    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. / Cellular Responses to the Metal-Binding Properties of Metformin. In: Diabetes. 2012 ; Vol. 61, No. 6. pp. 1423-1433.
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    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 p-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.",
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    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",
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    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. https://doi.org/10.2337/db11-0961

    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

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    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. https://doi.org/10.2337/db11-0961