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. Epithelial sodium channel alpha subunit (α-ENaC), a voltage-independent sodium ion channel, is also expressed in human pancreatic endocrine cells. However, there has not been much study done on ENaC's function in β-cells. In the current work, we found that human pancreatic glandule and pancreatic islet β-cells expressed α-ENaC. In the pancreas of db/db mice, high-fat diet-induced obesity, 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 markedly reduced. On the other hand, palmitate injured islet β-cells, suppressed insulin synthesis and secretion, and increased α-ENaC expression in Min6 cells. However, α-ENaC knockout (Scnn1a^-/-) in Min6 cells attenuated β-cells disorder induced by palmitate. Furthermore, we revealed that α-ENaC regulated the ubiquitylation and degradation of Sirtuin 2 in β-cells. α-ENaC also modulated β-cell function related to inositol-requiring enzyme 1alpha/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 plays a novel role in insulin synthesis and secretion in β-cells. Upregulation of α-ENaC promotes islet β-cell dysfunction. As a result, α-ENaC is a key regulator involved in islet β-cell damage and a potential therapeutic target for type 2 diabetes mellitus.