Xu Shiqing, Hu Zhida, Wang Yujie, Zhang Qiyao, Wang Zhi, Ma Teng, Wang Suhua, Wang Xiaohui, Wang Li
School of Public Health, Baotou Medical College, Inner Mongolia University of Science & Technology, Baotou 014040, China.
Toxics. 2024 Dec 4;12(12):883. doi: 10.3390/toxics12120883.
Arsenic exposure can induce liver insulin resistance (IR) and diabetes (DM), but the underlying mechanisms are not yet clear. Circular RNAs (circRNAs) are involved in the regulation of the onset of diabetes, especially in the progression of IR. This study aimed to investigate the role of circRNAs in arsenic-induced hepatic IR and its underlying mechanism. Male C57BL/6J mice were given drinking water containing sodium arsenite (0, 0.5, 5, or 50 ppm) for 12 months. The results show that sodium arsenite increased circ_0000284 expression, decreased insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) and peroxisome proliferator-activated receptor-γ (PPAR-γ), and inhibited cell membrane protein levels of insulin-responsive glucose transporter protein 4 (GLUT4) in the mouse livers, indicating that arsenic exposure causes liver damage and disruptions to glucose metabolism. Furthermore, sodium arsenite reduced glucose consumption and glycogen levels, increased the expression of circ_0000284, reduced the protein levels of IGF2BP2 and PPAR-γ, and inhibited GLUT4 protein levels in the cell membranes of insulin-treated HepG2 cells. However, a circ_0000284 inhibitor reversed arsenic exposure-induced reductions in IGF2BP2, PPAR-γ, and GLUT4 levels in the plasma membrane. These results indicate that circ_0000284 is involved in arsenite-induced hepatic insulin resistance through blocking the plasma membrane translocation of GLUT4 in hepatocytes via IGF2BP2/PPAR-γ. This study provides a scientific basis for finding early biomarkers for the control of arsenic exposure and type 2 diabetes mellitus (T2DM), and discovering new prevention and control measures.
砷暴露可诱导肝脏胰岛素抵抗（IR）和糖尿病（DM），但其潜在机制尚不清楚。环状RNA（circRNAs）参与糖尿病发病的调控，尤其是在胰岛素抵抗的进展过程中。本研究旨在探讨circRNAs在砷诱导的肝脏胰岛素抵抗中的作用及其潜在机制。给雄性C57BL/6J小鼠饮用含亚砷酸钠（0、0.5、5或50 ppm）的水12个月。结果表明，亚砷酸钠增加了circ_0000284的表达，降低了胰岛素样生长因子2 mRNA结合蛋白2（IGF2BP2）和过氧化物酶体增殖物激活受体-γ（PPAR-γ），并抑制了小鼠肝脏中胰岛素反应性葡萄糖转运蛋白4（GLUT4）的细胞膜蛋白水平，表明砷暴露会导致肝脏损伤并扰乱葡萄糖代谢。此外，亚砷酸钠降低了葡萄糖消耗和糖原水平，增加了circ_0000284的表达，降低了IGF2BP2和PPAR-γ的蛋白水平，并抑制了胰岛素处理的HepG2细胞细胞膜中GLUT4蛋白水平。然而，circ_0000284抑制剂逆转了砷暴露诱导的质膜中IGF2BP2、PPAR-γ和GLUT4水平的降低。这些结果表明，circ_0000284通过IGF2BP2/PPAR-γ阻断肝细胞中GLUT4的质膜易位参与亚砷酸盐诱导的肝脏胰岛素抵抗。本研究为寻找控制砷暴露和2型糖尿病（T2DM）的早期生物标志物以及发现新的预防和控制措施提供了科学依据。
