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- Title
Upregulation of α-ENaC induces pancreatic β-cell dysfunction, ER stress, and SIRT2 degradation.
- Authors
Xue Zhang; Dan Zhang; Lei Huo; Xin Zhou; Jia Zhang; Min Li; Dongming Su; Peng Sun; Fang Chen; Xiubin Liang
- Abstract
Islet beta cells (β-cells) produce insulin in response to high blood glucose levels, which is essential for preserving glucose homeostasis. Voltage-gated ion channels in β-cells, including Na+, K+, and Ca2+ channels, aid in the release of insulin. The epithelial sodium channel alpha subunit (α-ENaC), a voltage-independent sodium ion channel, is also expressed in human pancreatic endocrine cells. However, there is no reported study on the function of ENaC in the β-cells. In the current study, we found that α-ENaC was expressed in human pancreatic glandule and pancreatic islet β-cells. In the pancreas of db/db mice and high-fat diet-induced mice, and in mouse islet β-cells (MIN6 cells) treated with palmitate, α-ENaC expression was increased. When α-ENaC was overexpressed in MIN6 cells, insulin content and glucose-induced insulin secretion were significantly reduced. On the other hand, palmitate injured islet β-cells and suppressed insulin synthesis and secretion, but increased α-ENaC expression in MIN6 cells. However, α-ENaC knockout (Scnn1a−/−) in MIN6 cells attenuated β-cell disorder induced by palmitate. Furthermore, α-ENaC regulated the ubiquitylation and degradation of sirtuin 2 in β-cells. α-ENaC also modulated β-cell function in correlation with the inositol-requiring enzyme 1 alpha/X-box binding protein 1 (IRE1α/XBP1) and protein kinase RNA-like endoplasmic reticulum kinase/C/EBP homologous protein (PERK/CHOP) endoplasmic reticulum stress pathways. These results suggest that α-ENaC may play a novel role in insulin synthesis and secretion in the β-cells, and the upregulation of α-ENaC promotes islet β-cell dysfunction. In conclusion, α-ENaC may be a key regulator involved in islet β-cell damage and a potential therapeutic target for type 2 diabetes mellitus.
- Subjects
SIRTUINS; VOLTAGE-gated ion channels; TYPE 2 diabetes; INSULIN synthesis; CARRIER proteins; ENDOCRINE cells
- Publication
Journal of Biomedical Research, 2024, Vol 38, Issue 3, p241
- ISSN
1674-8301
- Publication type
Article
- DOI
10.7555/JBR.37.20230128