Integrated meta-analysis of public human pancreatic single-cell transcriptomes reveals distinct beta-cell state trajectories across aging and diabetes

SUMMARY Human pancreas single-cell RNA sequencing (scRNA-seq) studies have revealed extensive islet heterogeneity, yet cross-study integration remains limited by cohort- and platform-specific effects. Here, we assembled a unified atlas of >266,000 human pancreatic cells by harmonizing 18 publicly available scRNA-seq datasets spanning diverse technologies and donor phenotypes. Trajectory-based analyses resolved three beta-cell state trajectories associated with distinct stress axes. One trajectory reflects aging-associated transcriptional drift with progressive ER stress activation. A second captures diabetes-associated remodeling characterized by combined ER stress and induction of exocrine-like gene programs. A third highlights a metabolic-stress-associated program linked to lipid metabolism and polyhormonal transcriptional signatures in non-diabetic donors with elevated metabolic burden. In contrast to the relative stability of alpha-cell states, beta-cell identity programs eroded along specific trajectories, often preceding marked reductions in INS expression. Together, this integrated resource provides a scalable framework for dissecting human beta-cell plasticity and dysfunction using public single-cell transcriptomic data. HIGHLIGHTS Integrated atlas of >266,000 human pancreatic cells from 18 public scRNA-seq datasets spanning aging and diabetes Three beta-cell state trajectories associated with aging-related stress, diabetes-linked stress with exocrine-like program induction, and lipid-associated polyhormonal dedifferentiation Alpha-cell states are comparatively stable, whereas beta-cell identity programs erode along trajectory-specific paths, often preceding INS loss Diabetes-associated beta-cell subsets exhibit endocrine-exocrine transcriptional plasticity inferred from transcriptomic programs JUND identified as a candidate transcription factor associated with stress-linked exocrine gene expression in T2D beta cells Competing Interest Statement The authors have declared no competing interest. Footnotes Updated Data Availability statement to include Zenodo DOI for integrated atlas dataset.