ERp46 mitigates lipotoxic ER stress to preserve GLUT2 expression and insulin secretion in β‑cells

Lipotoxicity-induced β-cell dysfunction is a critical contributor to the pathogenesis of type 2 diabetes mellitus. The aim of the present study was to investigate the role of endoplasmic reticulum-resident protein 46 (ERp46) in regulating glucose transporter 2 (GLUT2) expression and insulin secretion in β-cells under palmitic acid (PA)-induced lipotoxic stress. β-TC6 cells were treated with PA to induce lipotoxicity, and ERp46 expression was silenced using specific small interfering RNA. GLUT2 expression and insulin secretion were assessed, and the involvement of protein kinase B (AKT) signaling was evaluated. The results demonstrated that PA significantly decreased GLUT2 expression and insulin secretion, while ERp46 expression was upregulated as a potential compensatory response. ERp46 knockdown exacerbated the reduction of GLUT2 expression and insulin secretion. Furthermore, PA treatment reduced phosphorylated AKT (p-AKT) levels without altering total AKT expression, and ERp46 knockdown further decreased p-AKT levels. The activation of AKT using AKT activator compound SC79 restored GLUT2 expression and insulin secretion in ERp46-depleted cells. These findings indicated that ERp46 helps preserve β-cell function under lipotoxic stress, potentially by stabilizing ER proteostasis and supporting AKT phosphorylation.