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

Lookup NU author(s): Professor Heather Cordell, Professor Mark Walker


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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.

Publication metadata

Author(s): Knowles JW, Xie WJ, Zhang ZY, Chennemsetty I, Assimes TL, Paananen J, Hansson O, Pankow J, Goodarzi MO, Carcamo-Orive I, Morris AP, Chen YDI, Makinen VP, Ganna A, Mahajan A, Guo XQ, Abbasi F, Greenawalt DM, Lum P, Molony C, Lind L, Lindgren C, Raffel LJ, Tsao PS, Schadt EE, Rotter JI, Sinaiko A, Reaven G, Yang X, Hsiung CA, Groop L, Cordell HJ, Laakso M, Hao K, Ingelsson E, Frayling TM, Weedon MN, Walker M, Quertermous T, RISC Relationship Insulin, EUGENE European Network Functional, GUARDIAN Genetics UndeRlying, SAPPHIRE Stanford Asian Pacific

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Investigation

Year: 2015

Volume: 125

Issue: 4

Pages: 1739-1751

Print publication date: 01/04/2015

Online publication date: 23/03/2015

Acceptance date: 05/02/2015

ISSN (print): 0021-9738

ISSN (electronic): 1558-8238

Publisher: American Society for Clinical Investigation


DOI: 10.1172/JCI74692


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Funder referenceFunder name
Fondation Leducq
Merck Co Inc.
Swedish Foundation for Strategic Research
Swedish Research Council
Stanford Cardiovascular Institute
Swedish Heart-Lung Foundation
10FTF3360005American Heart Association Fellow-to-Faculty Transition Award
DK072124National Institutes of Health
DK085175National Institutes of Health (GUARDIAN)
HL34659National Institutes of Health
LSHM-CT-2004-512013European Community
HL52851National Institutes of Health
M01RR00400National Institutes of Health
PH-099-PP-03National Health Research Institutes, Taiwan
QLG1CT-2001-01252European Union
PH-100-PP-03National Health Research Institutes, Taiwan
PH-101-PP-03National Health Research Institutes, Taiwan
WT098017Wellcome Trust Senior Fellow in Basic Biomedical Science
SZ-50371-GLUCOSEGENES-FP7-IDEAS-ERC: 323195European Research Council
WT064890Wellcome Trust Senior Fellow in Basic Biomedical Science