Authors:
Zhou, K.; Bellenguez, C.; Spencer, C. C. A.; ...: Blackwell, J. M.; et al.
Authors notes:
Nature Genetics. 2011;43(2):117-20
Keywords:
2 morpholino 6 (1 thianthrenyl) 4 pyranone, ATM protein, hydroxymethylglutaryl coenzyme A reductase kinase, metformin, animal cell, cancer cell culture, drug mechanism
Abstract:
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 P× -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.