Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes


Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 × 10−9, odds ratio = 1.35, 95% CI 1.22–1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Regional association plots around the ATM locus for the logistic regression analysis.
Figure 2: Effect of KU-55933 on AMPK activation by metformin.
Figure 3: A protein blot comparing the phosphorylation status of Thr172 of AMPK and Ser79 of ACC (a well characterized marker of AMPK activation).


  1. Nathan, D.M. et al. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 52, 17–30 (2009).

    CAS  Article  Google Scholar 

  2. NICE clinical guideline 87. Type 2 diabetes: the management of type 2 diabetes. (National Institute for Health and Clinical Excellence, London, UK, 2009).

  3. Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174 (2001).

    CAS  Article  Google Scholar 

  4. Owen, M.R., Doran, E. & Halestrap, A.P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 348, 607–614 (2000).

    CAS  Article  Google Scholar 

  5. Hawley, S.A. et al. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 11, 554–565 (2010).

    CAS  Article  Google Scholar 

  6. Donnelly, L.A., Doney, A.S., Hattersley, A.T., Morris, A.D. & Pearson, E.R. The effect of obesity on glycaemic response to metformin or sulphonylureas in Type 2 diabetes. Diabet. Med. 23, 128–133 (2006).

    CAS  Article  Google Scholar 

  7. Dupuis, J. et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat. Genet. 42, 105–116 (2010).

    CAS  Article  Google Scholar 

  8. Boder, E. Ataxia-telangiectasia: an overview. Kroc Found. Ser. 19, 1–63 (1985).

    CAS  PubMed  Google Scholar 

  9. Schalch, D.S., McFarlin, D.E. & Barlow, M.H. An unusual form of diabetes mellitus in ataxia telangiectasia. N. Engl. J. Med. 282, 1396–1402 (1970).

    CAS  Article  Google Scholar 

  10. Bar, R.S. et al. Extreme insulin resistance in ataxia telangiectasia: defect in affinity of insulin receptors. N. Engl. J. Med. 298, 1164–1171 (1978).

    CAS  Article  Google Scholar 

  11. Sun, Y., Connors, K.E. & Yang, D.Q. AICAR induces phosphorylation of AMPK in an ATM-dependent, LKB1-independent manner. Mol. Cell. Biochem. 306, 239–245 (2007).

    CAS  Article  Google Scholar 

  12. Fu, X., Wan, S., Lyu, Y.L., Liu, L.F. & Qi, H. Etoposide induces ATM-dependent mitochondrial biogenesis through AMPK activation. PLoS One 3, e2009 (2008).

    Article  Google Scholar 

  13. Sanli, T. et al. Ionizing radiation activates AMP-activated kinase (AMPK): a target for radiosensitization of human cancer cells. Int. J. Radiat. Oncol. Biol. Phys. 78, 221–229 (2010).

    CAS  Article  Google Scholar 

  14. Lavin, M.F. Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat. Rev. Mol. Cell Biol. 9, 759–769 (2008).

    CAS  Article  Google Scholar 

  15. Schneider, J.G. et al. ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome. Cell Metab. 4, 377–389 (2006).

    CAS  Article  Google Scholar 

  16. Miles, P.D., Treuner, K., Latronica, M., Olefsky, J.M. & Barlow, C. Impaired insulin secretion in a mouse model of ataxia telangiectasia. Am. J. Physiol. Endocrinol. Metab. 293, E70–E74 (2007).

    CAS  Article  Google Scholar 

  17. Trinklein, N.D., Aldred, S.J., Saldanha, A.J. & Myers, R.M. Identification and functional analysis of human transcriptional promoters. Genome Res. 13, 308–312 (2003).

    CAS  Article  Google Scholar 

  18. Fukao, T. et al. ATM is upregulated during the mitogenic response in peripheral blood mononuclear cells. Blood 94, 1998–2006 (1999).

    CAS  PubMed  Google Scholar 

  19. Savitsky, K. et al. Ataxia-telangiectasia: structural diversity of untranslated sequences suggests complex post-transcriptional regulation of ATM gene expression. Nucleic Acids Res. 25, 1678–1684 (1997).

    CAS  Article  Google Scholar 

  20. Gudmundsson, J. et al. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat. Genet. 39, 977–983 (2007).

    CAS  Article  Google Scholar 

  21. Libby, G. et al. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32, 1620–1625 (2009).

    CAS  Article  Google Scholar 

  22. Huang, X. et al. Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem. J. 412, 211–221 (2008).

    CAS  Article  Google Scholar 

  23. Morris, A.D. et al. The diabetes audit and research in Tayside Scotland (DARTS) study: electronic record linkage to create a diabetes register. DARTS/MEMO Collaboration. Br. Med. J. 315, 524–528 (1997).

    CAS  Article  Google Scholar 

  24. Anonymous. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352, 854–865 (1998).

  25. Kahn, S.E. et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N. Engl. J. Med. 355, 2427–2443 (2006).

    CAS  Article  Google Scholar 

  26. Barrett, J.C. et al. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat. Genet. 41, 1330–1334 (2009).

    CAS  Article  Google Scholar 

  27. Zeggini, E. et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316, 1336–1341 (2007).

    CAS  Article  Google Scholar 

  28. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

    CAS  Article  Google Scholar 

  29. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    CAS  Article  Google Scholar 

  30. Howie, B.N., Donnelly, P. & Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).

    Article  Google Scholar 

  31. Aulchenko, Y.S., Ripke, S., Isaacs, A. & van Duijn, C.M. GenABEL: an R library for genome-wide association analysis. Bioinformatics 23, 1294–1296 (2007).

    CAS  Article  Google Scholar 

  32. Hickson, I. et al. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 64, 9152–9159 (2004).

    CAS  Article  Google Scholar 

  33. Eaton, J.S., Lin, Z.P., Sartorelli, A.C., Bonawitz, N.D. & Shadel, G.S. Ataxia-telangiectasia mutated kinase regulates ribonucleotide reductase and mitochondrial homeostasis. J. Clin. Invest. 117, 2723–2734 (2007).

    CAS  Article  Google Scholar 

  34. Crescenzi, E., Palumbo, G., de Boer, J. & Brady, H.J. Ataxia telangiectasia mutated and p21CIP1 modulate cell survival of drug-induced senescent tumor cells: implications for chemotherapy. Clin. Cancer Res. 14, 1877–1887 (2008).

    CAS  Article  Google Scholar 

  35. Hardie, D.G., Salt, I.P. & Davies, S.P. Analysis of the role of the AMP-activated protein kinase in the response to cellular stress. Methods Mol. Biol. 99, 63–74 (2000).

    CAS  PubMed  Google Scholar 

  36. Dale, S., Wilson, W.A., Edelman, A.M. & Hardie, D.G. Similar substrate recognition motifs for mammalian AMP-activated protein kinase, higher plant HMG-CoA reductase kinase-A, yeast SNF1, and mammalian calmodulin-dependent protein kinase I. FEBS Lett. 361, 191–195 (1995).

    CAS  Article  Google Scholar 

Download references


We are grateful to all the participants who took part in this study, to the general practitioners, to the Scottish School of Primary Care for their help in recruiting the participants, and to the whole team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The Wellcome Trust provides support for the Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection (GoDARTS) and informatics support was provided by the Chief Scientist Office. The Wellcome Trust funds the Scottish Health Informatics Programme, provides core support for the Wellcome Trust Centre for Human Genetics in Oxford and funds the Wellcome Trust Case Control Consortium 2. This research was specifically funded by Diabetes UK (07/0003525), MRC (G0601261) and the Wellcome Trust (084726/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z). We also acknowledge support from the National Institute for Health Research award to Moorfields Eye Hospital National Health Service Foundation Trust and University College London Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology (to A.C.V.). P. Donnelly was supported in part by a Wolfson-Royal Society Merit Award. K.Z. holds a Henry Wellcome Post-Doctoral Fellowship. S.A.H. and D.G.H. were supported by the EXGENESIS consortium (LSHM-CT-2004-005272) funded by the European Commission.

Author information

Authors and Affiliations



A.D.M., C.N.A.P., E.R.P., A.S.F.D. H.C., A.T.H. and M.I.M. oversaw cohort collection for GoDARTS. R.R.H., M.I.M., R.L.C. and C.J.G. oversaw cohort collection for the UKPDS. The WTCCC2 DNA, genotyping, data quality control and informatics group (S.D., S.E., E.G., S.H. and C.L.) executed GWAS sample handling, genotyping and quality control. A.J.B., R. Tavendale, L.B., C.J.G. and F.C. performed the replication genotyping. The WTCCC2 Management Committee (P. Donnelly, J.M.B., E.B., M.A.B., J.P.C., A.C., N.C., P. Deloukas, A.D., J.J., H.S.M., C.G.M., R.P., A.R., S.J.S., N.J.S., R. Trembath, A.C.V., L.P. and N.W.W.) monitored the execution of the GWAS. K.Z., C.B., C.C.A.S., L.A.D., A.S. and C.F. performed statistical analyses. K.Z. and L.W.H. performed bioinformatic analyses. S.A.H., D.G.H., C. Schofield and C. Sutherland performed the functional studies. MAGIC investigators provided summary data on glycemic quantitative trait association. K.Z., C.B., C.C.A.S., C.N.P., A.D.M., C. Sutherland, D.G.H., R.R.H., M.I.M., P. Donnelly and E.R.P. contributed to writing the manuscript. All authors reviewed the final manuscript.

Corresponding author

Correspondence to Ewan R Pearson.

Ethics declarations

Competing interests

The author declare no competing financial interests.

Additional information

A full list of authors and affiliations is provided at the end of the paper. A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–6, Supplementary Figures 1–3 and Supplementary Note. (PDF 598 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

The GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group., The Wellcome Trust Case Control Consortium 2. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet 43, 117–120 (2011).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing