Upregulation of α-ENaC induces pancreatic β-cell dysfunction, ER stress, and SIRT2 degradation

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.

Keywords

α-ENaC / pancreatic β-cells / type 2 diabetes mellitus / endoplasmic reticulum stress / sirtuin 2

Fundings

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81870467 and 82270717 to XL, and 81970673 to FC), China Postdoctoral Science Foundation (Grant No. 2023M731630 to XZhang), and Postgraduate Research and Practice Innovation Program of Jiangsu Province (Grant No. KYCX21_1588 to XZhou).

Acknowledgments

We thank Dr. Jie Xu (Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan) for his editing and constructive comments on the manuscript.

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