Fu Jingqi, Woods Courtney G, Yehuda-Shnaidman Einav, Zhang Qiang, Wong Victoria, Collins Sheila, Sun Guifan, Andersen Melvin E, Pi Jingbo
Division of Translational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709 , USA.
Environ Health Perspect. 2010 Jun;118(6):864-70. doi: 10.1289/ehp.0901608. Epub 2010 Jan 25.
Chronic exposure of humans to inorganic arsenic, a potent environmental oxidative stressor, is associated with incidence of type 2 diabetes (T2D). A key driver in the pathogenesis of T2D is impairment of pancreatic beta-cell function, with the hallmark of beta-cell function being glucose-stimulated insulin secretion (GSIS). Reactive oxygen species (ROS) derived from glucose metabolism serve as one of the metabolic signals for GSIS. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a central transcription factor regulating cellular adaptive response to oxidative stress.
We tested the hypothesis that activation of Nrf2 and induction of antioxidant enzymes in response to arsenic exposure impedes glucose-triggered ROS signaling and thus GSIS.
Exposure of INS-1(832/13) cells to low levels of arsenite led to decreased GSIS in a dose- and time-dependent fashion. Consistent with our hypothesis, a significantly enhanced Nrf2 activity, determined by its nuclear accumulation and induction of its target genes, was observed in arsenite-exposed cells. In keeping with the activation of Nrf2-mediated antioxidant response, intracellular glutathione and intracellular hydrogen peroxide-scavenging activity was dose dependently increased by arsenite exposure. Although the basal cellular peroxide level was significantly enhanced, the net percentage increase in glucose-stimulated intracellular peroxide production was markedly inhibited in arsenite-exposed cells. In contrast, insulin synthesis and the consensus GSIS pathway, including glucose transport and metabolism, were not significantly reduced by arsenite exposure.
Our studies suggest that low levels of arsenic provoke a cellular adaptive oxidative stress response that increases antioxidant levels, dampens ROS signaling involved in GSIS, and thus disturbs beta-cell function.
人类长期暴露于强效环境氧化应激源无机砷中，与2型糖尿病（T2D）的发病率相关。T2D发病机制的一个关键驱动因素是胰腺β细胞功能受损，β细胞功能的标志是葡萄糖刺激的胰岛素分泌（GSIS）。葡萄糖代谢产生的活性氧（ROS）是GSIS的代谢信号之一。核因子红系2相关因子2（Nrf2）是调节细胞对氧化应激适应性反应的核心转录因子。
我们检验了以下假设，即Nrf2的激活以及砷暴露诱导的抗氧化酶可阻碍葡萄糖触发的ROS信号传导，进而阻碍GSIS。
将INS-1(832/13)细胞暴露于低水平亚砷酸盐中，导致GSIS呈剂量和时间依赖性降低。与我们的假设一致，在暴露于亚砷酸盐的细胞中观察到Nrf2活性显著增强，这通过其核积累及其靶基因的诱导来确定。与Nrf2介导的抗氧化反应激活一致，亚砷酸盐暴露使细胞内谷胱甘肽和细胞内过氧化氢清除活性呈剂量依赖性增加。尽管基础细胞过氧化物水平显著升高，但在暴露于亚砷酸盐的细胞中，葡萄糖刺激的细胞内过氧化物产生的净百分比增加受到明显抑制。相比之下，亚砷酸盐暴露并未显著降低胰岛素合成以及包括葡萄糖转运和代谢在内的共同GSIS途径。
我们的研究表明，低水平砷引发细胞适应性氧化应激反应，增加抗氧化剂水平，抑制GSIS中涉及的ROS信号传导，从而扰乱β细胞功能。
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