Abstract
Type 2 Diabetes (T2D) is characterized by hyperglycemia due to pancreatic beta cell failure and the development of insulin resistance. Although high carbohydrate intake and arsenic exposure increase the risk of developing T2D, their interactions and mechanisms associated with changes in insulin signaling pathways that lead to beta-cell apoptosis remain unknown. We determined the effects of in vitro exposure for 48 and 72 h to arsenic (As, 2 µM), glucose (Gluc, 22 mM), and their interaction (As + Gluc) on the apoptosis in RINm5F insulinoma beta-cells and explored the possible mechanisms dependent on alterations in insulin signaling pathways. We found that arsenic induced early apoptosis, while glucose co-treatment reduced arsenic-induced apoptosis. Mechanistically, co-treatment with As + Gluc deregulates the PI3K/Akt pathway, increasing the activation of Akt and S6K1, whereas in the MAPK pathway decreases arsenic-induced ERK1/2 activation. Furthermore, in these cells we observed an increased calpain proteolytic activity and down-regulation of the pro-apoptotic Bax/Caspase-3 pathway, compared to the effects of arsenic alone. Overall, our results suggest that 48 and 72 h of glucose co-treatment mitigates the pro-apoptotic effect of arsenic in RINm5F cells. Notably, calpains appear to play a critical role in this response, whereas the Akt/S6K1 signaling axis shows significant changes compared to the control.