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.
Authors
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 Mäkinen, 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, The RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) Consortium, The EUGENE2 (European Network on Functional Genomics of Type 2 Diabetes) Study, The GUARDIAN (Genetics UndeRlying DIAbetes in HispaNics) Consortium, The SAPPHIRe (Stanford Asian and Pacific Program for Hypertension and Insulin Resistance) Study, 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
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