Arsenic-induced SAM depletion and m6A dysregulation contribute to impaired insulin secretion in MIN6 cells

Arsenic is a widespread environmental pollutant associated with an increased risk of diabetes. However, the mechanisms by which N 6 -methyladenosine (m 6 A) RNA modification regulates insulin secretion following arsenic exposure remain largely unclear. In this study, MIN6 cells were exposed to 0–10 μmol·L⁻¹ sodium arsenite (NaAsO 2 ) for 36 h. Arsenic exposure reduced cellular metabolic activity and impaired glucose-stimulated insulin secretion (GSIS). Because S-adenosylmethionine (SAM) serves as a methyl donor for both arsenic methylation and m 6 A modification, we hypothesized that arsenic-induced SAM depletion may impair m 6 A methyltransferase activity, thereby disrupting m 6 A homeostasis and altering the expression of genes involved in insulin synthesis and secretion. Arsenic exposure significantly decreased intracellular SAM levels, global m 6 A abundance, and m 6 A methyltransferase activity. In addition, the mRNA expression of Mafa , Pdx1 , Foxa2 , and Glut2 was significantly reduced following arsenic exposure. SAM supplementation partially restored GSIS, global m 6 A abundance, total m 6 A methyltransferase activity in nuclear extracts, and attenuated the reduction in GLUT2 protein abundance. Moreover, arsenic exposure reduced m 6 A enrichment on Mafa and Pdx1 transcripts, whereas SAM supplementation attenuated these changes. Collectively, these findings suggest that arsenic exposure impairs insulin secretion in MIN6 cells, potentially through SAM depletion, disruption of m 6 A homeostasis, and altered m 6 A regulation of the MAFA–PDX1 regulatory network.