Review Article | Published:

Metformin—mode of action and clinical implications for diabetes and cancer

Nature Reviews Endocrinology volume 10, pages 143156 (2014) | Download Citation

Abstract

Metformin has been the mainstay of therapy for diabetes mellitus for many years; however, the mechanistic aspects of metformin action remained ill-defined. Recent advances revealed that this drug, in addition to its glucose-lowering action, might be promising for specifically targeting metabolic differences between normal and abnormal metabolic signalling. The knowledge gained from dissecting the principal mechanisms by which metformin works can help us to develop novel treatments. The centre of metformin's mechanism of action is the alteration of the energy metabolism of the cell. Metformin exerts its prevailing, glucose-lowering effect by inhibiting hepatic gluconeogenesis and opposing the action of glucagon. The inhibition of mitochondrial complex I results in defective cAMP and protein kinase A signalling in response to glucagon. Stimulation of 5′-AMP-activated protein kinase, although dispensable for the glucose-lowering effect of metformin, confers insulin sensitivity, mainly by modulating lipid metabolism. Metformin might influence tumourigenesis, both indirectly, through the systemic reduction of insulin levels, and directly, via the induction of energetic stress; however, these effects require further investigation. Here, we discuss the updated understanding of the antigluconeogenic action of metformin in the liver and the implications of the discoveries of metformin targets for the treatment of diabetes mellitus and cancer.

Key points

  • The glucose-lowering, insulin-sensitizing agent metformin works mainly by reducing gluconeogenesis and opposing glucagon-mediated signalling in the liver and, to a lesser extent, by increasing glucose uptake in skeletal muscle

  • The primary site of metformin action is the mitochondrion

  • The antihyperglycaemic effect of metformin is probably owing to defective protein kinase A signalling

  • Metformin affects lipid metabolism primarily via 5′-AMP-activated protein kinase (AMPK) activation

  • Antitumourigenic effects of metformin, which require further study, might be partially due to systemic metabolic alterations, including the reduced availability of insulin

  • In cancer cells, metformin acts as an inducer of energetic stress; AMPK-driven inhibition of mTOR seems to be required for much of its antimitotic activity

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Acknowledgements

We would like to thank Professor A. B. Grossman, Oxford Centre for Diabetes, Endocrinology and Metabolism, for his expert review of this manuscript. I. Pernicova is supported by a Project Grant from the Barts Charity.

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  1. Department of Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1A 6BQ, UK.

    • Ida Pernicova
    •  & Márta Korbonits

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Contributions

The authors contributed equally to all aspects of the manuscript.

Competing interests

The authors have received an educational research grant from Merck.

Corresponding author

Correspondence to Márta Korbonits.

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DOI

https://doi.org/10.1038/nrendo.2013.256

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