N-nitrosodimethylamine increased glucose production by promoting hyperglycemia in hepatocyte via AMPK signaling pathway

Studies have shown that exposure to N-nitrosodimethylamine (NDMA), a by-product of drinking water disinfection, increases the risk of abnormal blood glucose metabolism, although the underlying mechanism remains unclear. This study investigated the effects of NDMA on glucose metabolism and related molecular pathways through in vivo and in vitro models. The research found that mice exposed to 12.5 mg/L NDMA had elevated fasting blood glucose, impaired glucose tolerance and decreased insulin sensitivity. In mouse and human MIHA hepatocytes, NDMA exposure enhances hepatic gluconeogenesis while inhibiting glycolysis. Mechanism, NDMA inhibits the phosphorylation of AMPK and FoxO1, down-regulates the expression of GLUT2 protein to reduce liver glucose uptake, and increases the level of PGC-1α protein. Dephosphorylated fox01 may translocate to the nucleus and bind to the promoters of gluconeogenesis enzymes PEPCK and G6Pase to upregulate its expression. PGC-1α can also stimulate the expression of PEPCK and G6Pase. The AMPK agonist AICAR reversed the alterations in the expressions of p-fox01, PGC-1α, GLUT2, PEPCK and G6Pase in NDMA-exposed MIHA cells, restoring glycolysis and glucose uptake capabilities. In conclusion, NDMA in drinking water leads to elevated fasting blood glucose, impaired glucose tolerance and insulin sensitivity, and increased liver gluconeogenesis through the AMPK signaling pathway.