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Epigenetic effects of metformin: From molecular mechanisms to clinical implications

Citation

Bridgeman, SC and Ellison, GC and Melton, PE and Newsholme, P and Mamotte, CDS, Epigenetic effects of metformin: From molecular mechanisms to clinical implications, Diabetes Obesity & Metabolism, 20, (7) pp. 1553-1562. ISSN 1462-8902 (2018) [Substantial Review]


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DOI: doi:10.1111/dom.13262

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.

Item Details

Item Type:Substantial Review
Keywords:antidiabetic drug, cellular research, drug mechanism, metformin, type 2 diabetes, epigenetics
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Epigenetics (incl. genome methylation and epigenomics)
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Melton, PE (Dr Phillip Melton)
ID Code:141392
Year Published:2018
Web of Science® Times Cited:63
Deposited By:Menzies Institute for Medical Research
Deposited On:2020-10-19
Last Modified:2021-05-17
Downloads:0

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