Temporal Single-Cell Transcriptional Dynamics of Murine Pancreatic Islet Remodeling During Hyperglycaemia Progression

Similarly, we identified delta-cell subpopulations exhibiting beta-like transcriptional signatures and polyhormonal identity under nutritional stress, suggesting adaptive delta-cell plasticity that may partially compensate for beta-cell loss during insulin resistance. The islet microenvironment exhibited robust expansion of proinflammatory M1 macrophages, reaching a plateau by 16 weeks of HFD, indicating niche saturation.

Cell-cell communication analyses revealed disruption of key signaling pathways within endocrine and between endocrine and non-endocrine cells under HFD conditions. Notably, CCL27a–chemokine receptor signaling between beta-cells and M1 macrophages was significantly reduced in HFD islets, likely driven by reduced Ccl27a expression and chromatin accessibility in a distinct beta cell subpopulation, which we further validated using INS-1 cells exposed to HFD-like conditions.

Comparative analysis with scRNA seq of human islets confirmed conserved stress signatures. Furthermore, genetic variants at the CCL27 locus were associated with increased T2D risk and HOMA-IR in human populations, establishing a novel link between beta-cell stress and systemic inflammation. This resource provides a hierarchical framework for understanding islet failure and identifies potential therapeutic nodes for type 2 diabetes.