Short Communication · Volume 12, Issue 4 · December 2025
1 Department of Endocrinology, Seoul National University College of Medicine, Seoul, South Korea
2 Institute of Computational Biology, Helmholtz Zentrum München, Germany
Pancreatic islets of Langerhans contain multiple endocrine cell types essential for glucose homeostasis. While alpha, beta, delta, and PP cells are well characterized, recent advances in single-cell technologies suggest greater cellular heterogeneity than previously appreciated. Identifying novel subpopulations within islets may provide insights into diabetes pathogenesis and potential therapeutic targets.
We performed single-cell RNA sequencing (scRNA-seq) on isolated pancreatic islets from 8 human donors (4 non-diabetic, 4 with type 2 diabetes) using the 10x Genomics Chromium platform. A total of 52,847 cells passed quality control filters. We applied unsupervised clustering, trajectory analysis, and receptor-ligand interaction modeling to characterize cellular heterogeneity and intercellular communication networks.
Beyond canonical cell types, we identified two previously undescribed beta cell subpopulations: a “stress-responsive” cluster (Beta-SR, 8.3% of beta cells) enriched for unfolded protein response genes, and a “proliferation-primed” cluster (Beta-PP, 3.1%) expressing cell cycle regulators and developmental transcription factors. Beta-SR cells were significantly expanded in type 2 diabetes donors (12.7% vs. 4.1%, p=0.003). Ligand-receptor analysis revealed novel paracrine signaling between Beta-SR cells and resident macrophages mediated by the IL-33/ST2 pathway.
Our high-resolution single-cell atlas of human pancreatic islets reveals previously unrecognized beta cell heterogeneity with implications for understanding type 2 diabetes pathophysiology. The expanded Beta-SR subpopulation in diabetic islets suggests a stress-adaptive response that may represent an early marker of beta cell dysfunction.