NLRP3 inflammasome activation and disruption of IRS-1/PI3K/AKT signaling: Potential mechanisms of arsenic-induced pancreatic beta cells dysfunction in rats
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 p...
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Elsevier
2025-01-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S014765132401580X |
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| author | Yonglian Liu Wenjuan Wang Bing Liang Zhonglan Zou Aihua Zhang |
| author_facet | Yonglian Liu Wenjuan Wang Bing Liang Zhonglan Zou Aihua Zhang |
| author_sort | Yonglian Liu |
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| description | 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. |
| format | Article |
| id | doaj-art-695fd119ca0142e4a19f2e54c52ada04 |
| institution | Kabale University |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
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| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-695fd119ca0142e4a19f2e54c52ada042025-01-23T05:25:48ZengElsevierEcotoxicology and Environmental Safety0147-65132025-01-01289117504NLRP3 inflammasome activation and disruption of IRS-1/PI3K/AKT signaling: Potential mechanisms of arsenic-induced pancreatic beta cells dysfunction in ratsYonglian Liu0Wenjuan Wang1Bing Liang2Zhonglan Zou3Aihua Zhang4The 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 ChinaThe 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 ChinaThe 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 ChinaThe 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 ChinaCorresponding author.; 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 ChinaEnvironmental 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.http://www.sciencedirect.com/science/article/pii/S014765132401580XArsenicDiabetesPancreatic beta cellsInsulin secretionNLRP3 inflammasome |
| spellingShingle | Yonglian Liu Wenjuan Wang Bing Liang Zhonglan Zou Aihua Zhang NLRP3 inflammasome activation and disruption of IRS-1/PI3K/AKT signaling: Potential mechanisms of arsenic-induced pancreatic beta cells dysfunction in rats Ecotoxicology and Environmental Safety Arsenic Diabetes Pancreatic beta cells Insulin secretion NLRP3 inflammasome |
| title | NLRP3 inflammasome activation and disruption of IRS-1/PI3K/AKT signaling: Potential mechanisms of arsenic-induced pancreatic beta cells dysfunction in rats |
| title_full | NLRP3 inflammasome activation and disruption of IRS-1/PI3K/AKT signaling: Potential mechanisms of arsenic-induced pancreatic beta cells dysfunction in rats |
| title_fullStr | NLRP3 inflammasome activation and disruption of IRS-1/PI3K/AKT signaling: Potential mechanisms of arsenic-induced pancreatic beta cells dysfunction in rats |
| title_full_unstemmed | NLRP3 inflammasome activation and disruption of IRS-1/PI3K/AKT signaling: Potential mechanisms of arsenic-induced pancreatic beta cells dysfunction in rats |
| title_short | NLRP3 inflammasome activation and disruption of IRS-1/PI3K/AKT signaling: Potential mechanisms of arsenic-induced pancreatic beta cells dysfunction in rats |
| title_sort | nlrp3 inflammasome activation and disruption of irs 1 pi3k akt signaling potential mechanisms of arsenic induced pancreatic beta cells dysfunction in rats |
| topic | Arsenic Diabetes Pancreatic beta cells Insulin secretion NLRP3 inflammasome |
| url | http://www.sciencedirect.com/science/article/pii/S014765132401580X |
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