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NLRP3 inflammasome activation and disruption of IRS-1/PI3K/AKT signaling: Potential mechanisms of arsenic-induced pancreatic beta cells dysfunction in rats

Authors :
Yonglian Liu
Wenjuan Wang
Bing Liang
Zhonglan Zou
Aihua Zhang
Source :
Ecotoxicology and Environmental Safety, Vol 289, Iss , Pp 117504- (2025)
Publication Year :
2025
Publisher :
Elsevier, 2025.

Abstract

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, NaAsO2-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.

Details

Language :
English
ISSN :
01476513
Volume :
289
Issue :
117504-
Database :
Directory of Open Access Journals
Journal :
Ecotoxicology and Environmental Safety
Publication Type :
Academic Journal
Accession number :
edsdoj.695fd119ca0142e4a19f2e54c52ada04
Document Type :
article
Full Text :
https://doi.org/10.1016/j.ecoenv.2024.117504