Liu Yonglian, Wang Wenjuan, Liang Bing, Zou Zhonglan, Zhang Aihua
The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, Guizhou 550025, PR China.
The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, Guizhou 550025, PR China.
Ecotoxicol Environ Saf. 2025 Jan 1;289:117504. doi: 10.1016/j.ecoenv.2024.117504. Epub 2024 Dec 9.
Environmental exposure to arsenic is associated with significant health risks, including diabetogenic effects linked to pancreatic dysfunction. The NOD-like receptor protein 3 (NLRP3) inflammasome has been implicated in various metabolic abnormalities; however, its specific role in arsenic-induced pancreatic dysfunction remains insufficiently understood. This study aimed to elucidate the involvement and underlying mechanisms of the NLRP3 inflammasome in arsenic-induced pancreatic beta cells dysfunction through in vivo and in vitro models. In rat models, arsenic exposure was found to activate the NLRP3 inflammasome, as evidenced by pathomorphological changes and the expression of inflammasome activation markers. These pathological changes were accompanied by disruptions in the insulin signaling pathway, characterized by increased phosphorylation of insulin receptor substrate 1 (IRS-1) at Ser616, reduced expression of phosphatidylinositol 3-kinase (PI3K) and phosphorylated protein kinase B (AKT) at Ser473, and significant decreases in downstream targets, including the nuclear translocation of PDX-1, membrane translocation of glucose transporter 2 (GLUT2), and glucokinase (GCK) expression. In vitro, NaAsO-treated INS-1 cells exhibited a dose-dependent reduction in glucose-stimulated insulin secretion. Furthermore, arsenic exposure in these cells activated the NLRP3 inflammasome, suppressed the IRS-1/PI3K/AKT signaling pathway, and downregulated insulin secretion regulatory molecules (PDX-1, GLUT2, and GCK). Notably, these arsenic-induced effects were reversed by MCC950, an NLRP3 inflammasome inhibitor, and Extendin-4, an agonist of the IRS-1/PI3K/AKT signaling pathway. Collectively, these findings demonstrate that NLRP3 inflammasome activation disrupts the IRS-1/PI3K/AKT signaling pathway, contributing to arsenic-induced pancreatic beta cells dysfunction in rats.
环境砷暴露与重大健康风险相关，包括与胰腺功能障碍相关的致糖尿病作用。NOD样受体蛋白3（NLRP3）炎性小体与各种代谢异常有关；然而，其在砷诱导的胰腺功能障碍中的具体作用仍未得到充分了解。本研究旨在通过体内和体外模型阐明NLRP3炎性小体在砷诱导的胰腺β细胞功能障碍中的参与情况和潜在机制。在大鼠模型中，发现砷暴露可激活NLRP3炎性小体，病理形态学变化和炎性小体激活标志物的表达证明了这一点。这些病理变化伴随着胰岛素信号通路的破坏，其特征是胰岛素受体底物1（IRS-1）在Ser616处的磷酸化增加、磷脂酰肌醇3激酶（PI3K）和磷酸化蛋白激酶B（AKT）在Ser473处的表达降低，以及下游靶点的显著减少，包括PDX-1的核转位、葡萄糖转运蛋白2（GLUT2）的膜转位和葡萄糖激酶（GCK）的表达。在体外，经NaAsO处理的INS-1细胞表现出葡萄糖刺激的胰岛素分泌呈剂量依赖性降低。此外，这些细胞中的砷暴露激活了NLRP3炎性小体，抑制了IRS-1/PI3K/AKT信号通路，并下调了胰岛素分泌调节分子（PDX-1、GLUT2和GCK）。值得注意的是，NLRP3炎性小体抑制剂MCC950和IRS-1/PI3K/AKT信号通路激动剂艾塞那肽-4可逆转这些砷诱导的效应。总的来说，这些发现表明NLRP3炎性小体激活会破坏IRS-1/PI3K/AKT信号通路，导致大鼠砷诱导的胰腺β细胞功能障碍。
