title: Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene.
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
authors: JW
authors: Knowles
authors: Weijia
authors: W
authors: Xie
authors: Zhongyang
authors: Z
authors: Zhang
authors: Indumathi
authors: I
authors: Chennamsetty
authors: Indumathi
authors: I
authors: Chennemsetty
authors: Themistocles L
authors: TL
authors: Assimes
authors: Jussi
authors: J
authors: Paananen
authors: Ola
authors: O
authors: Hansson
authors: James
authors: J
authors: Pankow
authors: Mark O
authors: MO
authors: Goodarzi
authors: Ivan
authors: I
authors: Carcamo-Orive
authors: Andrew P
authors: AP
authors: Morris
authors: Yii-Der I
authors: YD
authors: Chen
authors: Ville-Petteri
authors: VP
authors: Mäkinen
authors: Andrea
authors: A
authors: Ganna
authors: Anubha
authors: A
authors: Mahajan
authors: Xiuqing
authors: X
authors: Guo
authors: Fahim
authors: F
authors: Abbasi
authors: Danielle M
authors: DM
authors: Greenawalt
authors: Pek
authors: P
authors: Lum
authors: Cliona
authors: C
authors: Molony
authors: Lars
authors: L
authors: Lind
authors: Cecilia
authors: C
authors: Lindgren
authors: Leslie J
authors: LJ
authors: Raffel
authors: Philip S
authors: PS
authors: Tsao
authors: Eric E
authors: EE
authors: Schadt
authors: Jerome I
authors: JI
authors: Rotter
authors: Alan
authors: A
authors: Sinaiko
authors: Gerald
authors: G
authors: Reaven
authors: Xia
authors: X
authors: Yang
authors: Chao A
authors: CA
authors: Hsiung
authors: Leif
authors: L
authors: Groop
authors: Heather J
authors: HJ
authors: Cordell
authors: Markku
authors: M
authors: Laakso
authors: Ke
authors: K
authors: Hao
authors: Erik
authors: E
authors: Ingelsson
authors: Timothy M
authors: TM
authors: Frayling
authors: Michael N
authors: MN
authors: Weedon
authors: Mark
authors: M
authors: Walker
authors: Thomas
authors: T
authors: Quertermous
mesh_terms: D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects / Q000502:physiology; D000293:Adolescent; D000328:Adult; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D044466:Asian People / Q000235:genetics; D002648:Child; D003327:Coronary Disease / Q000201:enzymology / Q000235:genetics; D005060:Europe / Q000453:epidemiology; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005947:Glucose / Q000378:metabolism; D006442:Glycated Hemoglobin / Q000032:analysis; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D006943:Hyperglycemia / Q000201:enzymology / Q000235:genetics; D015228:Hypertriglyceridemia / Q000201:enzymology / Q000235:genetics; D007333:Insulin Resistance / Q000502:physiology*; D007527:Isoenzymes / Q000172:deficiency / Q000502:physiology; D008066:Lipolysis / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D020125:Mutation, Missense; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D013624:Taiwan / Q000453:epidemiology; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D001191:Arylamine N-Acetyltransferase; D005947:Glucose; D006442:Glycated Hemoglobin; D007527:Isoenzymes; C089384:N-acetyltransferase 1; C478900:NAT2 protein, human