Cellular Heterogeneity and Plasticity in Pancreatic Islets: Implications for Diabetes

The pancreatic islet has long been described as a set of well-defined endocrine cell types – β, α, δ, ε, and PP cells – each with a fixed identity and a single hormonal output. Single-cell and single-nucleus technologies have made that picture untenable. Within every major islet cell type there are transcriptionally and functionally distinct subpopulations, and their proportions shift with age, sex, environmental stress, metabolic demand, and disease. β cells differ in maturation state, secretory competence, stress-response signature, and proliferative capacity; α cells display comparable heterogeneity, including subsets positioned along trajectories towards β cell like states.Alongside this diversity sits plasticity. Islet cells are not locked into their identity: under metabolic stress, inflammation, genetic predisposition, aging, or pharmacological stimulation they can dedifferentiate, adopt progenitor-like or polyhormonal states, and in some settings transdifferentiate. Loss of β cell identity is now recognized as a major contributor to β cell failure in type 2 diabetes, and potentially a reversible one – which makes the molecular control of cell state a therapeutic target in its own right, distinct from the classical goals of protecting β cell mass or enhancing secretion.Progress has been rapid but fragmented. Studies differ in species, tissue source, dissociation and nuclei-isolation protocols, sequencing modality, and the computational definition of a “cell state”, which makes subpopulations difficult to reconcile across datasets. Spatial context – where a cell sits within the islet, which neighbors it signals to, and how the microenvironment and immune infiltrate shape its state – is only beginning to be integrated. And the translation of this biology into regenerative and immunomodulatory therapies, including β cell regenerative drugs and stem-cell derived islet products, requires a shared framework for describing which cells are being targeted and what states they occupy.This Research Topic aims to bring together molecular, cellular, computational, and translational research on islet cell heterogeneity and plasticity, and to move the field towards a consistent, mechanistically grounded, and clinically useful description of islet cell states in health and diabetes. We welcome Original Research, Review, Mini Review, Systematic Review, Hypothesis and Theory, Methods and Perspective articles. Human islet studies, animal and in vitro models, stem-cell-derived islets, methodological and computational work, and dataset-driven reanalyses are all in scope. Themes of interest include, but are not limited to:• Islet-cell subpopulations: transcriptional, epigenetic, and proteomic definition of β, α, δ, and other islet cell subtypes, and the gene sets that distinguish them• Functional and disease-associated cell states: maturation, senescence, stress and unfolded-protein responses, secretory competence, and proliferative capacity, and how these states change in type 1 and type 2 diabetes• Cellular plasticity and lineage transitions: dedifferentiation, transdifferentiation, polyhormonal and progenitor-like states, α-to-β conversion, and the molecular switches that govern them• Spatial organization and cell–cell communication: islet architecture, paracrine and juxtacrine signaling, vascular, neural, and immune interactions within the islet niche• Single-cell and spatial multi-omics: scRNA-seq, snRNA-seq, multiome and ATAC approaches, spatial transcriptomics and proteomics, and the technical and computational challenges of integrating them• Methodology and reproducibility: tissue and nuclei isolation protocols, batch and donor effects, benchmarking of clustering and trajectory-inference approaches, and standards for defining and naming cell states• Implications for pathogenesis: how heterogeneity and plasticity contribute to β-cell failure, autoimmunity, and disease progression• Therapeutic development: β cell regenerative and redifferentiation strategies, immunomodulation, stem-cell-derived islets and transplantation, and the use of cell-state signatures as biomarkers or drug targets• Sex as a biological variable: Sex-specific islet architecture, endocrine-cell state distributions, hormonal regulation, immune interactions, and differential responses to metabolic or inflammatory stress.• Exocrine–endocrine interface: Effects of acinar, ductal, stellate, endothelial, neural, and adipose-associated cells on endocrine-cell states in normal pancreas, obesity, pancreatitis, and diabetes.• Mitochondrial and metabolic state heterogeneity: Relationships among mitochondrial dynamics, oxidative phosphorylation, nutrient sensing, redox balance, metabolite flux, and the maintenance or loss of endocrine identity.By integrating molecular, functional, metabolic, spatial, temporal, and disease-associated heterogeneity, this Research Topic seeks to establish a more comprehensive framework for understanding how pancreatic islet cells adapt, interact, fail, and potentially recover during diabetes. Topic editors: Geming Lu, Yingfeng Deng, Fahd Qadir Source: https://www.frontiersin.org/research-topics/84853/cellular-heterogeneity-and-plasticity-in-pancreatic-islets-implications-for-diabetes