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

Knowles, Joshua W. ; Xie, Weijia ; Zhang, Zhongyang ; Chennemsetty, Indumathi ; Assimes, Themistocles L. ; Paananen, Jussi ; Hansson, Ola LU orcid ; Pankow, James ; Goodarzi, Mark O. and Carcamo-Orive, Ivan , et al. (2015) In Journal of Clinical Investigation 125(4). p.1739-1751
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"... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Clinical Investigation
volume
125
issue
4
pages
1739 - 1751
publisher
The American Society for Clinical Investigation
external identifiers
  • wos:000352248600037
  • scopus:84926364999
ISSN
0021-9738
DOI
10.1172/JCI74692
language
English
LU publication?
yes
id
7f2aca11-6b44-4f56-967f-8402c5da3b65 (old id 5402932)
date added to LUP
2016-04-01 14:00:18
date last changed
2024-04-10 13:54:34
@article{7f2aca11-6b44-4f56-967f-8402c5da3b65,
  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.}},
  author       = {{Knowles, Joshua W. and Xie, Weijia and Zhang, Zhongyang and Chennemsetty, Indumathi and Assimes, Themistocles L. and Paananen, Jussi and Hansson, Ola and Pankow, James and Goodarzi, Mark O. and Carcamo-Orive, Ivan and Morris, Andrew P. and Chen, Yii-Der I. and Maekinen, Ville-Petteri and Ganna, Andrea and Mahajan, Anubha and Guo, Xiuqing and Abbasi, Fahim and Greenawalt, Danielle M. and Lum, Pek and Molony, Cliona and Lind, Lars and Lindgren, Cecilia and Raffel, Leslie J. and Tsao, Philip S. and Schadt, Eric E. and Rotter, Jerome I. and Sinaiko, Alan and Reaven, Gerald and Yang, Xia and Hsiung, Chao A. and Groop, Leif and Cordell, Heather J. and Laakso, Markku and Hao, Ke and Ingelsson, Erik and Frayling, Timothy M. and Weedon, Michael N. and Walker, Mark and Quertermous, Thomas}},
  issn         = {{0021-9738}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{1739--1751}},
  publisher    = {{The American Society for Clinical Investigation}},
  series       = {{Journal of Clinical Investigation}},
  title        = {{Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene}},
  url          = {{https://lup.lub.lu.se/search/files/3719090/8310667.pdf}},
  doi          = {{10.1172/JCI74692}},
  volume       = {{125}},
  year         = {{2015}},
}