NAT2 plays a role in insulin sensitivity

N-acetyltransferase 2 (NAT2) has long been known to metabolize xenobiotics but the endogenous substrates of NAT2 remain unknown. A new study published in “The Journal of Clinical Investigation” provides convincing evidence that NAT2 plays a role in the regulation of insulin sensitivity. The authors of the study reported that several SNPs, including the A allele at the single nucleotide polymorphism (SNP) rs1208 (c.803G>A, p.R268K) were associated with increased likelihood of insulin resistance (IR). The authors conducted a genome wide association study (GWAS) meta-analysis using genomic data and several measures of insulin sensitivity in multiple non-diabetic cohorts, including three European, one Hispanic and one East Asian cohort totaling 5,624 individuals. Although the A allele at rs1208 was not associated with IR at the genome wide significance level (P<0.05 x10^-8) in the discovery or replication cohorts it consistently showed the strongest association (P<6.4 x 10^-7) with increased degree of IR in all cohorts studied.

The authors confirmed the role of NAT2 as a modulator of insulin sensitivity by conducting in vitro studies in mouse adipocytes (3T3-L1) and myotubes. Administration of insulin caused a 50% decrease in expression of Nat1 (the mouse ortholog of NAT2) in both 3T3 cells and myotubes and siRNA mediated silencing of Nat1 caused a decrease in insulin stimulated glucose uptake, and an increase in basal lipolysis. These effects were reversed by over-expression of Nat1. In addition, Nat1 KO (-/-) and heterozygous (-/+) mice had higher fasting plasma glucose, insulin and triglyceride levels as well as decreased response to insulin during insulin tolerance tests as compared to wild-type (+/+) mice. 

These analyses provide convincing evidence that NAT2 plays a role in mediating insulin sensitivity, even though none of the NAT2 SNPs that were identified in the GWAS were significantly associated with IR at the genome wide level. Future studies could include more detailed functional analyses of individual SNPs on NAT2 expression and function, and may provide additional clues to identify the endogenous substrates of NAT2.

Read the original paper:

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

Knowles JW, Xie W, Zhang Z, Chennemsetty I, Assimes TL, Paananen J, Hansson O, Pankow J, Goodarzi MO, Carcamo-Orive I, Morris AP, Chen YI, Mäkinen VP, Ganna A, Mahajan A, Guo X, Abbasi F, Greenawalt DM, Lum P, Molony C, Lind L, Lindgren C, Raffel LJ, Tsao PS, Schadt EE, Rotter JI, Sinaiko A, Reaven G, Yang X, Hsiung CA, Groop L, Cordell HJ, Laakso M, Hao K, Ingelsson E, Frayling TM, Weedon MN, Walker M, Quertermous T.

J Clin Invest. 2015 Mar 23. pii: 74692. doi: 10.1172/JCI74692. [Epub ahead of print]