Curriculum in Toxicology and Environmental Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7325, USA.
National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, 27709, USA.
Arch Toxicol. 2019 Sep;93(9):2525-2533. doi: 10.1007/s00204-019-02526-2. Epub 2019 Jul 22.
Chronic exposure to inorganic arsenic (iAs), a common drinking water and food contaminant, has been associated with an increased risk of type 2 diabetes in population studies worldwide. Several mechanisms underlying the diabetogenic effects of iAs have been proposed through laboratory investigations. We have previously shown that exposure to arsenite (iAs(III)) or its methylated trivalent metabolites, methylarsonite (MAs(III)) and dimethylarsinite (DMAs(III)), inhibits glucose-stimulated insulin secretion (GSIS) in pancreatic islets, without significant effects on insulin expression or insulin content. The goal of the present study was to determine if iAs(III) and/or its metabolites inhibit Ca influx, an essential mechanism that regulates the release of insulin from β cells in response to glucose. We found that in vitro exposures for 48 h to non-cytotoxic concentrations of iAs(III), MAs(III), and DMAs(III) impaired Ca influx in isolated murine pancreatic islets stimulated with glucose. MAs(III) and DMAs(III) were more potent inhibitors of Ca influx than iAs(III). These arsenicals also inhibited Ca influx and GSIS in islets treated with depolarizing levels of potassium chloride in the absence of glucose. Treatment with Bay K8644, a Ca1.2 channel agonist, did not restore insulin secretion in arsenical-exposed islets. Tolbutamide, a K channel blocker, prevented inhibition of insulin secretion in MAs(III)- and DMAs(III)-exposed islets, but only marginally in islets exposed to iAs(III). Our findings suggest that iAs(III), MAs(III), and DMAs(III) inhibit glucose-stimulated Ca influx in pancreatic islets, possibly by interfering with K and/or Ca1.2 channel function. Notably, the mechanisms underlying inhibition of GSIS by iAs(III) may differ from those of its trivalent methylated metabolites.
长期接触无机砷（iAs），一种常见的饮用水和食物污染物，与全世界人群研究中 2 型糖尿病风险增加有关。通过实验室研究提出了 iAs 致糖尿病作用的几种机制。我们之前已经表明，暴露于亚砷酸盐（iAs(III)）或其甲基化三价代谢物，甲基砷酸盐（MAs(III)）和二甲基砷酸盐（DMAs(III)），会抑制胰岛的葡萄糖刺激胰岛素分泌（GSIS），而对胰岛素表达或胰岛素含量没有显著影响。本研究的目的是确定 iAs(III)及其代谢物是否抑制 Ca 内流，这是调节β细胞响应葡萄糖释放胰岛素的基本机制。我们发现，在体外暴露于非细胞毒性浓度的 iAs(III)、MAs(III)和 DMAs(III) 48 小时，会损害葡萄糖刺激的分离的鼠胰岛中的 Ca 内流。MAs(III)和 DMAs(III)比 iAs(III)更能抑制 Ca 内流。这些砷化物还抑制了在没有葡萄糖的情况下用高浓度氯化钾处理的胰岛中的 Ca 内流和 GSIS。用 Ca1.2 通道激动剂 Bay K8644 处理不能恢复暴露于砷化物的胰岛中的胰岛素分泌。甲苯磺丁脲，一种 K 通道阻滞剂，可防止 MAs(III)和 DMAs(III)暴露的胰岛中胰岛素分泌受到抑制，但对暴露于 iAs(III)的胰岛仅有轻微影响。我们的研究结果表明，iAs(III)、MAs(III)和 DMAs(III)抑制胰岛的葡萄糖刺激的 Ca 内流，可能通过干扰 K 和/或 Ca1.2 通道功能。值得注意的是，iAs(III)抑制 GSIS 的机制可能与三价甲基化代谢物的机制不同。
