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Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene

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Author

  • Joshua W. Knowles
  • Weijia Xie
  • Zhongyang Zhang
  • Indumathi Chennemsetty
  • Themistocles L. Assimes
  • Jussi Paananen
  • Ola Hansson
  • James Pankow
  • Mark O. Goodarzi
  • Ivan Carcamo-Orive
  • Andrew P. Morris
  • Yii-Der I. Chen
  • Ville-Petteri Maekinen
  • Andrea Ganna
  • Anubha Mahajan
  • Xiuqing Guo
  • Fahim Abbasi
  • Danielle M. Greenawalt
  • Pek Lum
  • Cliona Molony
  • Lars Lind
  • Cecilia Lindgren
  • Leslie J. Raffel
  • Philip S. Tsao
  • Eric E. Schadt
  • Jerome I. Rotter
  • Alan Sinaiko
  • Gerald Reaven
  • Xia Yang
  • Chao A. Hsiung
  • Leif Groop
  • Heather J. Cordell
  • Markku Laakso
  • Ke Hao
  • Erik Ingelsson
  • Timothy M. Frayling
  • Michael N. Weedon
  • Mark Walker
  • Thomas Quertermous
Show all

Summary, in English

Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.

Publishing year

2015

Language

English

Pages

1739-1751

Publication/Series

Journal of Clinical Investigation

Volume

125

Issue

4

Document type

Journal article

Publisher

The American Society for Clinical Investigation

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Translational Muscle Research

ISBN/ISSN/Other

  • ISSN: 0021-9738