Pancreatic islet cells continuously synthesize and secrete large quantities of peptide hormones, making them uniquely dependent on robust proteostasis networks to maintain cellular function. Traditionally, the unfolded protein response (UPR) is considered a stress-responsive pathway that protects cells from endoplasmic reticulum (ER) dysfunction or triggers apoptosis when ER stress is excessive. Here, we propose that proteostasis functions as an active physiological signaling network that governs islet cell adaptation, plasticity, and long-term homeostasis, extending beyond its conventional role in the response to cellular damage. In pancreatic β cells, glucose signaling suppresses the expression of the proapoptotic factor CHOP through both IRS2-dependent and IRS2-independent pathways, indicating that metabolic signaling directly remodels the ER stress response. In contrast, the CHOP-GADD34-eIF2α dephosphorylation axis constitutes a negative feedback mechanism that fine-tunes translational recovery and determines the balance between adaptation and cell death. Moreover, 4E-BP1-mediated inhibition of mRNA translation and modulation of mTOR signaling alleviate proteotoxic stress and promote β-cell survival under conditions of increased secretory demand. In addition to translational control, IGF2 receptor-mediated signaling has recently been implicated in the regulation of autophagy, further linking lysosomal quality control to β-cell proteostasis. Importantly, proteostasis also affects α-cell biology, where UPR signaling regulates glucagon secretion and contributes to α-to-β cell transdifferentiation, highlighting a previously unrecognized role of ER homeostasis in endocrine cell identity. Finally, recent findings indicate that progressive impairment of proteostasis is a hallmark of islet aging, integrating defects in protein folding, translation, autophagy, and stress adaptation into the pathogenesis of diabetes.
