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

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Date
2015-04-01
Author
Knowles, Joshua W.
Xie, Weijia
Zhang, Zhongyang
Chennemsetty, Indumathi
Assimes, Themistocles L.
Paananen, Jussi
Hansson, Ola
Pankow, James
Goodarzi, Mark O.
Carcamo-Orive, Ivan
Morris, Andrew P.
Chen, Yii-Der I.
Mäkinen, Ville-Petteri
Ganna, Andrea
Mahajan, Anubha
Guo, Xiuqing
Abbasi, Fahim
Greenawalt, Danielle M.
Lum, Pek
Molony, Cliona
Lind, Lars
Lindgren, Cecilia
Raffel, Leslie J.
Tsao, Philip S.
Schadt, Eric E.
Rotter, Jerome I.
Sinaiko, Alan
Reaven, Gerald
Yang, Xia
Hsiung, Chao A.
Groop, Leif
Cordell, Heather J.
Laakso, Markku
Hao, Ke
Ingelsson, Erik
Frayling, Timothy M.
Weedon, Michael N.
Walker, Mark
Quertermous, Thomas
Unique identifier
10.1172/JCI74692
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Citation
Knowles, Joshua W.. Xie, Weijia. Zhang, Zhongyang. Chennemsetty, Indumathi. Assimes, Themistocles L.. Paananen, Jussi. Hansson, Ola. Pankow, James. Goodarzi, Mark O.. Carcamo-Orive, Ivan. Morris, Andrew P.. Chen, Yii-Der I.. Mäkinen, Ville-Petteri. Ganna, Andrea. Mahajan, Anubha. Guo, Xiuqing. Abbasi, Fahim. Greenawalt, Danielle M.. Lum, Pek. Molony, Cliona. Lind, Lars. Lindgren, Cecilia. Raffel, Leslie J.. Tsao, Philip S.. Schadt, Eric E.. Rotter, Jerome I.. Sinaiko, Alan. Reaven, Gerald. Yang, Xia. Hsiung, Chao A.. Groop, Leif. Cordell, Heather J.. Laakso, Markku. Hao, Ke. Ingelsson, Erik. Frayling, Timothy M.. Weedon, Michael N.. Walker, Mark. Quertermous, Thomas. (2015). Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene.  Journal of Clinical Investigation, 125 (4) , 10.1172/JCI74692.
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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.

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https://erepo.uef.fi/handle/123456789/34
Link to the original item
http://dx.doi.org/10.1172/JCI74692
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American Society for Clinical Investigation
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