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.

Original publication

DOI

10.1172/JCI74692

Type

Journal article

Journal

J Clin Invest

Publication Date

04/2015

Volume

125

Pages

1739 - 1751

Keywords

3T3-L1 Cells, Adipogenesis, Adolescent, Adult, Animals, Arylamine N-Acetyltransferase, Asian Continental Ancestry Group, Child, Coronary Disease, Europe, European Continental Ancestry Group, Female, Gene Frequency, Genome-Wide Association Study, Glucose, Glycated Hemoglobin A, Hispanic Americans, Humans, Hyperglycemia, Hypertriglyceridemia, Insulin Resistance, Isoenzymes, Lipolysis, Male, Mice, Mice, Knockout, Middle Aged, Mutation, Missense, Point Mutation, Polymorphism, Single Nucleotide, Prospective Studies, Taiwan, United States, Young Adult