Mechanisms of β-cell adaptation to increased insulin demand

β-cells have various ways to adapt to stress, but in diabetes, these pathways become dysregulated, driving β-cell dysfunction, resulting in poor glucose control. Unfolded protein response (UPR) plays central roles within these pathways, cooperating to restore endoplasmic reticulum function under stress. In this study, we followed the dynamic interaction between UPR players during stress onset in response to targeted ~50% β-cell ablation in mice, using diphtheria toxin (DT) in the NSG RIP-DTR system. Importantly, these ablated mice remained normoglycemic for up to 10 weeks. By transcriptomic profiling of the islets we assessed two polarized UPR responses, with different dynamics. The first response was characterized by activation of apoptosis and clearance pathways, while the second, at a later time point, was characterized by adaptive pathways, including increased insulin processing. These findings offer potential targets for strategies aimed at promoting enhanced resistance to stress of the β-cells.