Metabolic effects of heterocyclic amines on insulin‑induced AKT phosphorylation and gluconeogenic gene expression are modified by N-acetyltransferase 2 genetic polymorphism.

Objective: Heterocyclic amines (HCAs) are mutagens and carcinogens primarily generated when cooking meat at high temperatures or until well-done, and their major metabolic pathway includes hepatic N-hydroxylation via CYP1A2 followed by O-acetylation via N-acetyltransferase 2 (NAT2). NAT2 expresses a well-defined genetic polymorphism in humans resulting in rapid and slow acetylators. Recent epidemiological studies reported significant associations between dietary HCA exposure and insulin resistance and type II diabetes.

Methods: We assessed the effect of some of the most common HCAs found in cooked meat, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, on insulin signaling and gluconeogenic gene expression in cryopreserved human hepatocytes characterized by their NAT2 genotype and phenotype to investigate the role of NAT2 genetic polymorphism in HCA-induced metabolic dysregulation.

Results: HCA treatment significantly reduced insulin-induced protein kinase B phosphorylation and significantly increased expression of genes involved in gluconeogenesis (G6PC, PCK1, FOXO1, and PPARA) in cryopreserved human hepatocytes from rapid but not from slow acetylators.

Conclusion: The findings suggest that NAT2 genetic polymorphism modifies HCA-induced insulin resistance and gluconeogenic gene expression, implying that individuals with rapid acetylator phenotype may be at greater risk of dysregulated glucose homeostasis following exposure to HCAs.