β-cell adaptation to increased insulin demand is a swift and dynamic process orchestrated by unfolded protein response.

Pancreatic β-cells adapt to increased insulin demand through coordinated functional and molecular responses. However, in diabetes, these adaptive pathways eventually fail, driving β-cell dysfunction and demise. One of these pathways is unfolded protein response (UPR), a complex network of sensors and effectors that cooperate to restore endoplasmic reticulum (ER) function under stress. To define the early UPR programs engaged during β-cell adaptation, we employed a murine model of partial β-cell ablation that preserves normoglycemia while imposing an increased secretory workload on the remaining β-cells. Integrating bulk islet transcriptomics with imaging, ultrastructural and physiological analyses, we identified dynamic molecular and functional adaptations during the compensatory phase. The initial transcriptional response was characterised by induction of apoptosis genes and a stress response. This was later replaced by activation of adaptive UPR pathways accompanied by increased insulin processing. Nuclear Atf4 and Xbp1 increased transiently, consistent with engagement of multiple UPR branches through different mechanisms to restore homeostasis. Functionally, partially ablated islets displayed enhanced secretory competence during an acute secondary ER stress challenge, although this adaptive advantage was lost during prolonged stress. Together, these findings define a transient adaptive UPR program that sustains β-cell function during the early response to β-cell loss and provide insight into mechanisms that may be leveraged to enhance β-cell resilience in diabetes.