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The role of ATM in response to metformin treatment and activation of AMPK

Nature Genetics volume 44, pages 359–360 (2012)Cite this article

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To the Editor:

The GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group & The Wellcome Trust Case Control Consortium 2 (WTCCC2) recently reported the first genome-wide association study (GWAS) for treatment response to the anti-diabetic drug metformin in European populations1. The rs11212617 SNP was found to reach the genome-wide level of significance in the discovery cohort (n = 1,024; P = 1.9 × 10−7; odds ratio = 1.64, 95% confidence interval (CI) = 1.37–1.99) and was also shown to be significant (P < 0.008) in two replication cohorts (UKPDS and WTCCC2). Among several genes in a 340-kb linkage disequilibrium block containing rs11212617, the authors proposed that ATM, encoding a member of the phosphatidylinositol 3/phosphatidylinositol 4 (PI3/PI4)-kinase family, was the causative gene due to its reported function. In particular, AMP-activated protein kinase (AMPK), the energy sensor widely considered to be involved in the pharmacologic action of metformin, is one of the downstream targets of ATM2,3,4. The authors showed that an inhibitor of ATM, KU-55933, reduced metformin-stimulated phosphorylation of AMPK in H4IIE rat hepatoma cells, suggesting that ATM has a role in the therapeutic action of metformin.

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Figure 1: Cellular metformin uptake in H4IIE and HEK293 cells.

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Acknowledgements

We acknowledge funding from the US National Institutes of Health and the US National Institute of General Medical Sciences (GM61390 and GM36780).

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  1. Sook Wah Yee and Ligong Chen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA

    Sook Wah Yee, Ligong Chen & Kathleen M Giacomini

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  1. Sook Wah Yee
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  2. Ligong Chen
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Correspondence to Kathleen M Giacomini.

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Yee, S., Chen, L. & Giacomini, K. The role of ATM in response to metformin treatment and activation of AMPK. Nat Genet 44, 359–360 (2012). https://doi.org/10.1038/ng.2236

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