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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

DOI

10.1038/ng.735

Type

Journal article

Journal

Nat Genet

Publication Date

02/2011

Volume

43

Pages

117 - 120

Keywords

Animals, Ataxia Telangiectasia Mutated Proteins, Carcinoma, Hepatocellular, Cell Cycle Proteins, DNA-Binding Proteins, Diabetes Mellitus, Type 2, Dose-Response Relationship, Drug, Genome-Wide Association Study, Humans, Hypoglycemic Agents, Liver Neoplasms, Metformin, Polymorphism, Single Nucleotide, Protein Kinases, Protein-Serine-Threonine Kinases, Rats, Scotland, Tumor Suppressor Proteins