Heterogeneity of human pancreatic β-cells

Background: Human pancreatic beta-cells are heterogeneous. This has been known for a long time and is based on various functional and morphological readouts. beta-Cell heterogeneity could reflect fixed subpopulations with distinct functions. However, recent pseudotime analysis of large-scale RNA sequencing data suggest that human beta-cell subpopulations may rather reflect dynamic interchangeable states characterized by low expression of genes involved in the unfolded protein response (UPR) and low insulin gene expression, low UPR and high insulin expression or high UPR and low insulin expression. Scope of review: This review discusses findings obtained by single-cell RNA sequencing combined with pseudotime analysis that human beta-cell heterogeneity represents dynamic interchangeable functional states. The physiological significance and potential implications of beta-cell heterogeneity in the development and progression of diabetes is highlighted. Major conclusions: The existence of dynamic functional states allow beta-cells to transition between periods of high insulin production and UPR-mediated stress recovery. The recovery state is important since proinsulin is a misfolding-prone protein, making its biosynthesis in the endoplasmic reticulum a stressful event. The transition of beta-cells between dynamic states is likely controlled at multiple levels and influenced by the microenvironment within the pancreatic islets. Disturbances in the ability of the beta-cells to transition between periods of high insulin biosynthesis and UPR-mediated stress recovery may contribute to diabetes development. Diabetes medications that restore the ability of the beta-cells to transition between the functional states should be considered. (C) 2019 Published by Elsevier GmbH.