Introduction: Greater than 200 million people are estimated to be exposed to unsafe levels of arsenic (As3+) worldwide leading to pathology of various diseases including type 2 diabetes (T2DM) and cancer. Experimental evidence in in vitro (cell culture) and in vivo (rodents and humans) models suggest a tight correlation between As3+ exposure and the onset of T2DM. In addition to consumption of food (rice and seafood) and drinking water contaminated with high levels of As3+, compelling evidence also suggests that exposure of our military personnel to As3+ via jet fuel combustion, burn pits, and contaminated dust (e.g., in desert conflicts) manifests in the onset of various chronic health problems, including T2DM. At this backdrop, we undertook the current investigation to determine effects of As3+ exposure on the pancreatic β-cell with a goal to understand potential alterations in its function at the cellular level, including physiological insulin secretion. Methods: Insulin secreting clonal β (INS-1 832/13)-cells were cultured under basal (2.5mM glucose); high (20mM glucose) or As3+ (at different concentrations and time intervals) conditions. Western blotting was used to determine total and phosphorylated forms of candidate signaling proteins. Insulin secretion and Rac1 activation were quantified using commercially available kits. Results: Exposure of INS-1 832/13 cells to As3+ (20µM; 12 hr.) induced the expression of ER stress markers (p-PERK and CHOP). A marked increase in the phosphorylation of p53 and cleaved caspase-3 expression (caspase-3 activation) was also observed in As3+ exposed β-cells. Furthermore, As3+exposure promoted activation of other pro-apoptotic signaling steps, including phosphorylation of JNK, STAT3 (S727 and Y705) and Akt in INS-1 832/13 cells. Co-provision of N-acetyl cysteine, a known antioxidant, markedly attenuated As3+ induced phosphorylation of JNK, STAT3 and Akt, suggesting critical roles for oxidative stress-induced by As3+. Sustained activation of Rac1, which has been implicated in the onset of high glucose-induced oxidative stress, was not observed in these cells following exposure to As3+ (10-20 µM; 12-24 hrs.) implicating additional sources for As3+ -derived ROS. Lastly, As3+ (20 µM; 12 hrs.) markedly inhibited glucose-induced (physiological) insulin secretion from INS-1 832/13 cells, highlighting significant abnormalities in cellular metabolic events in As3+ exposed β-cells, leading to impaired physiological insulin secretion. Discussion: As3+ exposure of islet β-beta cells leads to severe metabolic abnormalities including activation of oxidative and ER stress pathways and mitochondrial dysregulation (caspase activation) culminating in the loss of physiological insulin secretion. Funding: AK is supported by an Institutional grant and the Distinguished Professor award from Wayne State University, and a Senior Research Career Scientist (K6 BX005383) award from the U.S. Department of Veterans Affairs. FC is supported by R01 ES031822, R01 ES028335, R01 ES028263, and Research Start-up fund of the Stony Brook University. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
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