Adaptation to chronic ER stress enforces pancreatic β-cell plasticity

Pancreatic beta-cells are prone to endoplasmic reticulum (ER) stress due to their role in insulin secretion. They require sustainable and efficient adaptive stress responses to cope with this stress. Whether episodes of chronic stress directly compromise beta-cell identity is unknown. We show here under reversible, chronic stress conditions beta-cells undergo transcriptional and translational reprogramming associated with impaired expression of regulators of beta-cell function and identity. Upon recovery from stress, beta-cells regain their identity and function, indicating a high degree of adaptive plasticity. Remarkably, while beta-cells show resilience to episodic ER stress, when episodes exceed a threshold, beta-cell identity is gradually lost. Single cell RNA-sequencing analysis of islets from type 1 diabetes patients indicates severe deregulation of the chronic stress-adaptation program and reveals novel biomarkers of diabetes progression. Our results suggest beta-cell adaptive exhaustion contributes to diabetes pathogenesis. Pancreatic beta-cells are naturally prone to ER stress due to their role in insulin production and secretion. Here, the authors show that chronic ER stress adaptive exhaustion results in an irreversible loss of beta-cell function leading to T1D pathogenesis