Published in

American Society for Clinical Investigation, Journal of Clinical Investigation, 4(125), p. 1739-1751, 2015

DOI: 10.1172/jci74692

American Society for Clinical Investigation, Journal of Clinical Investigation, 1(126), p. 403-403

DOI: 10.1172/jci85921

Links

Tools

Export citation

Search in Google Scholar

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

Journal article published in 2015 by Knowles Jw, Weijia Xie, Zhongyang Zhang, Indumathi Chennemsetty, Themistocles L. Assimes, Indumathi Chennamsetty, Jussi Paananen ORCID, Mark O. Goodarzi, Ola Hansson ORCID, Andrew P. Morris, James Pankow ORCID, Assimes Tl, Yii-Der I. Chen, Ivan Carcamo-Orive, Ville-Petteri Mäkinen and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

Full text: Download

Red circle
Preprint: archiving forbidden
Red circle
Postprint: archiving forbidden
Green circle
Published version: archiving allowed
Upload
Policy details
Data provided by SHERPA/RoMEO

Abstract

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.