Center for Global Health, The Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
Center for Global Health, The Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, Guangdong, People's Republic of China.
Ecotoxicol Environ Saf. 2021 Jun 1;215:112130. doi: 10.1016/j.ecoenv.2021.112130. Epub 2021 Mar 18.
Environmental exposure to arsenic can cause a variety of health problems. Epidemiological and experimental studies have established a diabetogenic role for arsenic, but the mechanisms responsible for arsenic-induced impairment of insulin action are unclear. MicroRNAs (miRNAs) are involved in various metabolic disorders, particularly in the development of insulin resistance. The present study investigated whether arsenite, an active form of arsenic, induces hepatic insulin resistance and the mechanisms underlying it. After male C57BL/6J mice were exposed to arsenite (0 or 20 ppm) in drinking water for 12 months, intraperitoneal glucose tolerance tests (IPGTTs) and insulin tolerance tests (ITTs) revealed an arsenite-induced glucose metabolism disorder. Hepatic glycogen levels were lower in arsenite-exposed mice. Further, for livers of mice exposed to arsenite, miR-191 levels were higher, and protein levels of insulin receptor substrate 1 (IRS1), p-IRS1, and phospho-protein kinase B (p-AKT) were lower. Further, glucose transporter 4 (GLUT4) had lower levels on the plasma membrane. For insulin-treated L-02 cells, arsenite decreased glucose consumption and glycogen levels, increased miR-191 levels, and inhibited the IRS1/AKT pathway and the translocation of GLUT4 from the cytoplasm to the plasma membrane. For insulin-treated L-02 cells, the decreases of glucose consumption, glycogen levels, GLUT4 on the plasma membrane, and p-AKT levels induced by arsenite were reversed by SC79 (agonist of AKT) and an miR-191 inhibitor; these effects caused by miR-191 inhibitor were restored by IRS1 siRNA. In insulin-treated L-02 cells, miR-191, via IRS1, was involved in the arsenite-induced decreases of glucose consumption and glycogen levels and in inhibition of the translocation of GLUT4. Thus, miR-191 blocking the translocation of GLUT4 was involved in arsenite-induced hepatic insulin resistance through inhibiting the IRS1/AKT pathway. Our study reveals a mechanism for arsenite-induced hepatic insulin resistance, which provides clues for discovering biomarkers for the development of type 2 diabetes and for prevention and treatment of arsenic poisoning.
环境砷暴露会导致多种健康问题。流行病学和实验研究已经确立了砷的致糖尿病作用，但导致砷诱导胰岛素作用受损的机制尚不清楚。microRNAs (miRNAs) 参与各种代谢紊乱，特别是胰岛素抵抗的发展。本研究探讨了亚砷酸钠（砷的一种活性形式）是否会诱导肝胰岛素抵抗及其机制。雄性 C57BL/6J 小鼠经饮用水暴露于亚砷酸钠（0 或 20 ppm）12 个月后，进行腹腔内葡萄糖耐量试验（IPGTT）和胰岛素耐量试验（ITT）显示出亚砷酸钠诱导的葡萄糖代谢紊乱。亚砷酸钠暴露小鼠的肝糖原水平较低。此外，亚砷酸钠暴露小鼠的 miR-191 水平较高，胰岛素受体底物 1 (IRS1)、p-IRS1 和磷酸化蛋白激酶 B (p-AKT) 的蛋白水平较低。此外，质膜上的葡萄糖转运蛋白 4 (GLUT4) 水平较低。对于胰岛素处理的 L-02 细胞，亚砷酸钠降低葡萄糖消耗和糖原水平，增加 miR-191 水平，并抑制 IRS1/AKT 通路和 GLUT4 从细胞质向质膜的易位。对于胰岛素处理的 L-02 细胞，亚砷酸钠引起的葡萄糖消耗、糖原水平、质膜上的 GLUT4 和 p-AKT 水平的降低可被 SC79（AKT 激动剂）和 miR-191 抑制剂逆转；miR-191 抑制剂引起的这些作用可被 IRS1 siRNA 恢复。在胰岛素处理的 L-02 细胞中，miR-191 通过 IRS1 参与亚砷酸钠诱导的葡萄糖消耗和糖原水平降低以及 GLUT4 易位抑制。因此，miR-191 通过阻断 GLUT4 的易位参与了亚砷酸钠诱导的肝胰岛素抵抗，通过抑制 IRS1/AKT 通路。我们的研究揭示了亚砷酸钠诱导肝胰岛素抵抗的机制，为发现 2 型糖尿病发展的生物标志物以及砷中毒的预防和治疗提供了线索。
