Journal
NATURE GENETICS
Volume 43, Issue 2, Pages 117-U57Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.735
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Funding
- Wellcome Trust [084726/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z]
- Diabetes UK [07/0003525]
- MRC [G0601261]
- National Institute for Health Research
- Wolfson-Royal Society Merit Award
- Henry Wellcome Post-Doctoral Fellowship
- European Commission [LSHM-CT-2004-005272]
- MRC [G0901310, G19/2, G0601261] Funding Source: UKRI
- Medical Research Council [G9817803B, G19/2, G0901310, G0601261] Funding Source: researchfish
- National Institute for Health Research [PDA/02/06/016, NF-SI-0507-10379] Funding Source: researchfish
- Wellcome Trust [084726/Z/08/Z] Funding Source: Wellcome Trust
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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 x 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.
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