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    Epigenetic effects of metformin: From molecular mechanisms to clinical implications

    265919.pdf (720.6Kb)
    Access Status
    Open access
    Authors
    Bridgeman, S.
    Ellison, G.
    Melton, Phillip
    Newsholme, Philip
    Mamotte, Cyril
    Date
    2018
    Type
    Journal Article
    
    Metadata
    Show full item record
    Citation
    Bridgeman, S. and Ellison, G. and Melton, P. and Newsholme, P. and Mamotte, C. 2018. Epigenetic effects of metformin: From molecular mechanisms to clinical implications. Diabetes, Obesity and Metabolism. 20 (7): pp. 1553-1562.
    Source Title
    Diabetes, Obesity and Metabolism
    DOI
    10.1111/dom.13262
    ISSN
    1462-8902
    School
    School of Pharmacy and Biomedical Sciences
    Remarks

    This is the peer reviewed version of the following article: Bridgeman, S. and Ellison, G. and Melton, P. and Newsholme, P. and Mamotte, C. 2018. Epigenetic effects of metformin: From molecular mechanisms to clinical implications. Diabetes, Obesity and Metabolism. 20 (7): pp. 1553-1562, which has been published in final form at 10.1111/dom.13262. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving at http://olabout.wiley.com/WileyCDA/Section/id-828039.html

    URI
    http://hdl.handle.net/20.500.11937/67102
    Collection
    • Curtin Research Publications
    Abstract

    There is a growing body of evidence that links epigenetic modifications to type 2 diabetes. Researchers have more recently investigated effects of commonly used medications, including those prescribed for diabetes, on epigenetic processes. This work reviews the influence of the widely used antidiabetic drug metformin on epigenomics, microRNA levels and subsequent gene expression, and potential clinical implications. Metformin may influence the activity of numerous epigenetic modifying enzymes, mostly by modulating the activation of AMP-activated protein kinase (AMPK). Activated AMPK can phosphorylate numerous substrates, including epigenetic enzymes such as histone acetyltransferases (HATs), class II histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), usually resulting in their inhibition; however, HAT1 activity may be increased. Metformin has also been reported to decrease expression of multiple histone methyltransferases, to increase the activity of the class III HDAC SIRT1 and to decrease the influence of DNMT inhibitors. There is evidence that these alterations influence the epigenome and gene expression, and may contribute to the antidiabetic properties of metformin and, potentially, may protect against cancer, cardiovascular disease, cognitive decline and aging. The expression levels of numerous microRNAs are also reportedly influenced by metformin treatment and may confer antidiabetic and anticancer activities. However, as the reported effects of metformin on epigenetic enzymes act to both increase and decrease histone acetylation, histone and DNA methylation, and gene expression, a significant degree of uncertainty exists concerning the overall effect of metformin on the epigenome, on gene expression, and on the subsequent effect on the health of metformin users.

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