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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 × 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.

Original publication




Journal article


Nature genetics

Publication Date





117 - 120


Biomedical Research Institute, University of Dundee, Dundee, UK.


GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group, Wellcome Trust Case Control Consortium 2, MAGIC investigators, Animals, Humans, Rats, Carcinoma, Hepatocellular, Liver Neoplasms, Diabetes Mellitus, Type 2, Metformin, Protein Kinases, Protein-Serine-Threonine Kinases, Cell Cycle Proteins, DNA-Binding Proteins, Tumor Suppressor Proteins, Hypoglycemic Agents, Dose-Response Relationship, Drug, Polymorphism, Single Nucleotide, Scotland, Genome-Wide Association Study, Ataxia Telangiectasia Mutated Proteins