TY - JOUR
T1 - Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene
AU - Knowles, Joshua W.
AU - Xie, Weijia
AU - Zhang, Zhongyang
AU - Chennemsetty, Indumathi
AU - Assimes, Themistocles L.
AU - Paananen, Jussi
AU - Hansson, Ola
AU - Pankow, James
AU - Goodarzi, Mark O.
AU - Carcamo-Orive, Ivan
AU - Morris, Andrew P.
AU - Chen, Yii Der I
AU - Mäkinen, Ville Petteri
AU - Ganna, Andrea
AU - Mahajan, Anubha
AU - Guo, Xiuqing
AU - Abbasi, Fahim
AU - Greenawalt, Danielle M.
AU - Lum, Pek
AU - Molony, Cliona
AU - Lind, Lars
AU - Lindgren, Cecilia
AU - Raffel, Leslie J.
AU - Tsao, Philip S.
AU - Schadt, Eric E.
AU - Rotter, Jerome I.
AU - Sinaiko, Alan
AU - Reaven, Gerald
AU - Yang, Xia
AU - Hsiung, Chao A.
AU - Groop, Leif
AU - Cordell, Heather J.
AU - Laakso, Markku
AU - Hao, Ke
AU - Ingelsson, Erik
AU - Frayling, Timothy M.
AU - Weedon, Michael N.
AU - Walker, Mark
AU - Quertermous, Thomas
AU - The RISC (Relationship between Insulin 1Sensitivity and Cardiovascular Disease) Consortium The EUGENE2 (European Network on Functional Genomics of Type 2 Diabetes) Study The GUARDIAN (Genetics UndeRlying DIAbetes in HispaNics) Consortium
PY - 2015/4/1
Y1 - 2015/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84926364999&partnerID=8YFLogxK
U2 - 10.1172/JCI74692
DO - 10.1172/JCI74692
M3 - Article
C2 - 25798622
AN - SCOPUS:84926364999
VL - 125
SP - 1739
EP - 1751
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 4
ER -