摘要
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 inβ-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 theβ-cells.In the current study,we found thatα-ENaC was expressed in human pancreatic glandule and pancreatic isletβ-cells.In the pancreas of db/db mice and high-fat diet-induced mice,and in mouse isletβ-cells(MIN6 cells)treated with palmitate,α-ENaC expression was increased.Whenα-ENaC was overexpressed in MIN6 cells,insulin content and glucose-induced insulin secretion were significantly reduced.On the other hand,palmitate injured isletβ-cells and suppressed insulin synthesis and secretion,but increasedα-ENaC expression in MIN6 cells.However,α-ENaC knockout(Scnn1a−/−)in MIN6 cells attenuatedβ-cell disorder induced by palmitate.Furthermore,α-ENaC regulated the ubiquitylation and degradation of sirtuin 2 inβ-cells.α-ENaC also modulatedβ-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 thatα-ENaC may play a novel role in insulin synthesis and secretion in theβ-cells,and the upregulation ofα-ENaC promotes isletβ-cell dysfunction.In conclusion,α-ENaC may be a key regulator involved in isletβ-cell damage and a potential therapeutic target for type 2 diabetes mellitus.
基金
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)
Postgraduate Research and Practice Innovation Program of Jiangsu Province(Grant No.KYCX21_1588 to XZhou).
