1806-P: Functional Analysis of NUPR1 in Age-Associated Changes in β-Cell Proliferation and Apoptosis

by sugaradmin



Introduction and Objective: Aging is associated with the declination of β-cell function in type 2 diabetes. However, the precise mechanisms underlying the functional changes in β cells due to aging remain unclear. In this study, we investigated the changes in β-cell functions associated with aging.Methods: We cultured islets from young (7 weeks of age) and aged (61 weeks of age) mice under low (3.9 mM) and high (11.1 mM) glucose conditions for 24 hours, then performed single-cell RNA-sequencing, histological evaluation, and qPCR.Results: In β cells from aged mice, 1344 genes were upregulated and 174 were downregulated under high glucose conditions. Pathway analysis for the differentially expressed genes in aged β cells manifested alterations in pathways associated with β-cell proliferation and apoptosis. Among these pathways, Nupr1 showed a marked 2.38-fold upregulation in aged β cells. In aged islets, β-cell proliferation significantly declined with a 98% reduction in EdU incorporation, and glucose-induced β-cell proliferation was absent. TUNEL staining showed a 4.7-fold increase in β-cell apoptosis in aged islets. Lipid droplets in β cells were highly accumulated in aged islets. qPCR confirmed elevated Nupr1 expression in aged islets, and immunofluorescence studies demonstrated a 2.2-fold increase in Nupr1 nuclear intensity in aged β cells under high glucose conditions. In young islets, glucose stimulation reduced Nupr1 expression, but this effect was absent in aged islets. Treatment with an Nupr1 inhibitor, ZZW-115, demonstrated a 1.45-fold increase in β-cell proliferation and a 55% decrease in β-cell apoptosis in non-aged islets under high glucose conditions.Conclusion: Aging reduced β-cell proliferation, exacerbated β-cell apoptosis, and increased Nupr1 expression in islets, with a loss of glucose responsiveness. Nupr1 inhibitor ameliorated β-cell proliferation and apoptosis, indicating the potential role of Nupr1 in senescence-associated β-cell dysfunctions.

Disclosure

E. Ong Yajima: None. T. Tsuno: None. J. Shirakawa: None.

Funding

JST FOREST Program ( JPMJFR234O)



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