The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA.
Biochem Biophys Res Commun. 2011 Apr 8;407(2):360-5. doi: 10.1016/j.bbrc.2011.03.024. Epub 2011 Mar 17.
There is growing evidence that chronic exposure of humans to inorganic arsenic, a potent environmental oxidative stressor, is associated with the incidence of type 2 diabetes (T2D). One critical feature of T2D is insulin resistance in peripheral tissues, especially in mature adipocytes, the hallmark of which is decreased insulin-stimulated glucose uptake (ISGU). Despite the deleterious effects of reactive oxygen species (ROS), they have been recognized as a second messenger serving an intracellular signaling role for insulin action. Nuclear factor erythroid 2-related factor 2 (NRF2) is a central transcription factor regulating cellular adaptive response to oxidative stress. This study proposes that in response to arsenic exposure, the NRF2-mediated adaptive induction of endogenous antioxidant enzymes blunts insulin-stimulated ROS signaling and thus impairs ISGU. Exposure of differentiated 3T3-L1 cells to low-level (up to 2 μM) inorganic arsenite (iAs³(+)) led to decreased ISGU in a dose- and time-dependent manner. Concomitant to the impairment of ISGU, iAs³(+) exposure significantly attenuated insulin-stimulated intracellular ROS accumulation and AKT S473 phosphorylation, which could be attributed to the activation of NRF2 and induction of a battery of endogenous antioxidant enzymes. In addition, prolonged iAs³(+) exposure of 3T3-L1 adipocytes resulted in significant induction of inflammatory response genes and decreased expression of adipogenic genes and glucose transporter type 4 (GLUT4), suggesting chronic inflammation and reduction in GLUT4 expression may also be involved in arsenic-induced insulin resistance in adipocytes. Taken together our studies suggest that prolonged low-level iAs³(+) exposure activates the cellular adaptive oxidative stress response, which impairs insulin-stimulated ROS signaling that is involved in ISGU, and thus causes insulin resistance in adipocytes.
越来越多的证据表明，人类长期接触无机砷这种强效的环境氧化应激物，与 2 型糖尿病（T2D）的发病率有关。T2D 的一个关键特征是外周组织（尤其是成熟脂肪细胞）的胰岛素抵抗，其标志是胰岛素刺激的葡萄糖摄取（ISGU）减少。尽管活性氧（ROS）有有害影响，但它们已被确认为细胞内信号作用的第二信使，用于胰岛素作用。核因子红细胞 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。本研究提出，在砷暴露的情况下，NRF2 介导的内源性抗氧化酶适应性诱导会削弱胰岛素刺激的 ROS 信号，从而损害 ISGU。将分化的 3T3-L1 细胞暴露于低水平（高达 2 μM）的无机亚砷酸盐（iAs³(+))会导致 ISGU 以剂量和时间依赖性的方式减少。与 ISGU 损害同时发生的是，iAs³(+)暴露显著减弱了胰岛素刺激的细胞内 ROS 积累和 AKT S473 磷酸化，这归因于 NRF2 的激活和一系列内源性抗氧化酶的诱导。此外，3T3-L1 脂肪细胞中长时间的 iAs³(+)暴露会导致炎症反应基因的显著诱导和脂肪生成基因和葡萄糖转运蛋白 4（GLUT4）的表达降低，表明慢性炎症和 GLUT4 表达减少也可能涉及砷诱导的脂肪细胞胰岛素抵抗。综上所述，我们的研究表明，长期低水平的 iAs³(+)暴露会激活细胞适应性氧化应激反应，从而损害参与 ISGU 的胰岛素刺激的 ROS 信号，导致脂肪细胞的胰岛素抵抗。
