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

Journal article

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.

Authors: Zhou, K; Bellenguez, C; Spencer, C; Bennett, A; Coleman, R

• Journal: Nature genetics
• Volume: 43
• Issue: 2
• Pages: 117-120
• Publication date: 2011-02-01
• DOI: 10.1038/ng.735
• EISSN: 1546-1718
• ISSN: 1061-4036
• Language: English
• Keywords: Humans; Protein Kinases; Diabetes Mellitus, Type 2; Carcinoma, Hepatocellular; Hypoglycemic Agents; Dose-Response Relationship, Drug; Ataxia Telangiectasia Mutated Proteins; Rats; MAGIC investigators; Wellcome Trust Case Control Consortium 2; Cell Cycle Proteins; GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group; Scotland; Polymorphism, Single Nucleotide; Genome-Wide Association Study; Liver Neoplasms; Tumor Suppressor Proteins; Protein-Serine-Threonine Kinases; Animals; Metformin; DNA-Binding Proteins