{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T18:23:28Z","timestamp":1763749408670,"version":"3.40.4"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:sec>\n            <jats:title>Objective<\/jats:title>\n            <jats:p>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 <jats:italic toggle=\"yes\">N<\/jats:italic>-hydroxylation via CYP1A2 followed by <jats:italic toggle=\"yes\">O<\/jats:italic>-acetylation via <jats:italic toggle=\"yes\">N<\/jats:italic>-acetyltransferase 2 (NAT2). <jats:italic toggle=\"yes\">NAT2<\/jats:italic> 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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>HCA treatment significantly reduced insulin-induced protein kinase B phosphorylation and significantly increased expression of genes involved in gluconeogenesis (<jats:italic toggle=\"yes\">G6PC<\/jats:italic>, <jats:italic toggle=\"yes\">PCK1<\/jats:italic>, <jats:italic toggle=\"yes\">FOXO1<\/jats:italic>, and <jats:italic toggle=\"yes\">PPARA<\/jats:italic>) in cryopreserved human hepatocytes from rapid but not from slow acetylators.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>The findings suggest that <jats:italic toggle=\"yes\">NAT2<\/jats:italic> 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.<\/jats:p>\n          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