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 N6-methyladenosine (m6A) 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 (NaAsO2) for 36h. 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 m6A modification, we hypothesized that arsenic-induced SAM depletion may impair m6A methyltransferase activity, thereby disrupting m6A homeostasis and altering the expression of genes involved in insulin synthesis and secretion. Arsenic exposure significantly decreased intracellular SAM levels, global m6A abundance, and m6A 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 m6A abundance, total m6A methyltransferase activity in nuclear extracts, and attenuated the reduction in GLUT2 protein abundance. Moreover, arsenic exposure reduced m6A 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 m6A homeostasis, and altered m6A regulation of the MAFA-PDX1 regulatory network.