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There is growing evidence that chronic exposure of humans to inorganic arsenic(iAs),a potent environmental oxidative stressor,is associated with the incidence of Type 2 diabetes(T2D).Nuclear factor E2-related factor 2(Nrf2)is a CNC-bZIP transcription factor that is well established as a master regulator in the cellular adaptive response to oxidative stress.Although cytotoxic,reactive oxygen species(ROS)also function as important intracellular signaling molecules to activate cellular responses to a variety of physiological stimuli,including glucose-stimulated insulin secretion(GSIS)in pancreatic β-cells and insulin action in insulin responsive cells.Therefore,we propose that Nrf2-mediated antioxidant response plays paradoxical roles in β-cell function and insulin signaling transduction:(1)It protects the cells from oxidative damage and possible cell death,thus minimizing oxidative damage-related impairment in insulin secretion and action;(2)Since ROS signaling triggered by glucose and insulin could be an important component involved in insulin secretion and action,the induction of endogenous antioxidants in the presence of oxidative stress may blunt the signals,resulting in reduced GSIS and insulin resistance.iAs and its methylated trivalent metabolites are potent oxidative stressors and robustly activate Nrf2-mediated antioxidant response,but at the levels typically observed in human exposures,they are not likely to reach cytotoxic concentrations sufficient to cause overt oxidative damage,especially when endogenous antioxidant enzymes can be actively induced.Therefore,blockade of ROS signaling in premise 2 is potentially more relevant to the etiology of T2D in the context of low-level environmental iAs exposure,whereas premise 1 might be associated with protecting cells from acute toxicity induced by high doses of arsenic.