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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.
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
URL: http://dx.doi.org/10.1172/JCI74692
DOI: 10.1172/JCI74692
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