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Dioxin-Induced PAI-1 Expression: A Novel Pathway to Pancreatic β-Cell Failure in Type 2 Diabetes
Exposure to environment-polluting chemicals (EPCs), which are ligands of the aryl hydrocarbon receptor (AhR), is associated with the development of type 2 diabetes (T2D). This study explores the mechanisms by which AhR ligands contribute to β-cell failure in T2D. Incubation of RINm5F rat pancreatic β-cells with low-dose 2,3,7,8-tetrachlorodibenzodioxin (TCDD), the most potent AhR ligand, inhibited glucose-stimulated insulin secretion (GSIS). A single injection of TCDD in wild type mice reduced the size of Langerhans islets, but not in AhR liver knock-out mice (AhR-LKO). RNA-seq database analysis identified Serpine1, encoding for plasminogen activator inhibitor type-1 (PAI-1) as a TCDD-mediated secretory protein that is synthesized in an AhR-dependent manner in the liver. Elevated PAI-1 levels were shown to induce Caspase-3/7-dependent apoptosis in RINm5F cells, suggesting a novel pathway through which EPCs exacerbate T2D. These findings support the hypothesis that chronic e xposure to AhR ligands may directly inhibit GSIS in pancreatic β-cells and indirectly induce β-cell apoptosis through increased PAI-1. This study provides new insights into the EPC-PAI-1 axis as a missing link between pancreatic β-cell failure and the progression of T2D and offers a potential target for therapeutic intervention. © 2024 by the authors.
Authors : Im S.; Kang S.; Son W.J.; Son M.; Oh S.J.; Yoon H.J.; Pak Y.K.
Source : Multidisciplinary Digital Publishing Institute (MDPI)
Article Information
| Year | 2024 |
| Type | Article |
| DOI | 10.3390/ijms252211974 |
| ISSN | 16616596 |
| Volume | 25 |
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