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

Nat Genet. 2011 Feb;43(2):117-20. doi: 10.1038/ng.735. Epub 2010 Dec 26.

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 × 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Hypoglycemic Agents
  • Tumor Suppressor Proteins
  • Metformin
  • Protein Kinases
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases