Pancreatic β-cell heterogeneity in health and diabetes: classes, sources, and subtypes

Abstract

Pancreatic β-cells perform glucose-stimulated insulin secretion, a process at the center of type 2 diabetes etiology. Efforts to understand how β-cells behave in healthy and stressful conditions have revealed a wide degree of morphological, functional, and transcriptional heterogeneity. Sources of heterogeneity include β-cell topography, developmental origin, maturation state, and stress response. Advances in sequencing and imaging technologies have led to the identification of β-cell subtypes, which play distinct roles in the islet niche. This review examines β-cell heterogeneity from morphological, functional, and transcriptional perspectives, and considers the relevance of topography, maturation, development, and stress response. It also discusses how these factors have been used to identify β-cell subtypes, and how heterogeneity is impacted by diabetes. We examine open questions in the field and discuss recent technological innovations that could advance understanding of β-cell heterogeneity in health and disease.

Keywords: diabetes; insulin secretion; β-cell heterogeneity; β-cell subtype.

Graphical abstract

Figure 1.

Classes, sources, and subtypes of β-cell heterogeneity. β-Cells display variation in gene expression (red), protein level (blue), morphology (green), and function (purple). Heterogeneity is influenced by β-cell source (A), maturation state (B), topology (C), and stress response (D). A: β-cell sources include neogenesis during development, transdifferentiation of α- and ductal cells, β-cell replication, and differentiation PMPs. B: immature β-cells (B1) and mature β-cells (B2) present distinct gene expression, protein, and functional characteristics. C: topography influences β-cells through the core-mantel structure, where peripheral β-cells (C1) have more heterotypic contacts, resulting in low glucose sensitivity and insulin release compared to core β-cells (C2). D: β-cell stress response causes β-cells to cycle between states of high insulin with low UPR, low insulin with high UPR, and a period of low insulin with low UPR. Two subtypes of adult β-cells have been identified: Hub cells (E1) are characterized by very high Gck expression but low insulin expression, and high number of homotypic contacts. Extreme β-cells (E2) are located near the islet core, characterized by very high insulin expression but low mature insulin protein stores. It is unclear if hub cells and extreme β-cells stem from a mature or immature population. PMP, pancreatic multipotent progenitor; INS, insulin expression; insulin, insulin protein; UPR, unfolded protein response; FLTP, Flattop.

Figure 2.

Maturation state heterogeneity in pancreatic beta β-cells. A: following birth, neonatal β-cells are transcriptionally and functionally immature, characterized by Pax6, Hk1, Paxa, and Mafb expression, very high proliferation rates, very high basal insulin secretion, and high glucose sensitivity. Maturation is facilitated by transition to a carbohydrate-rich diet at weaning. B: mature β-cells are characterized by expression of Mafa, Ucn3, and Fltp, high expression of insulin, Glut2, and Gck. These β-cells have low proliferation rates but high glucose-stimulated insulin secretion. A subset of adult β-cells maintain an immature-like profile, including Mafb expression, low expression of insulin, Glut2, and Gck, and lack Fltp expression. These cells have elevated proliferation rates but low glucose-simulated insulin secretion. Whether these cells differ in developmental origin or can interconvert is unknown. C: in diabetes, glucotoxicity, lipotoxicity, and inflammation induces variable fates in β-cells, including dedifferentiation, apoptosis, and replication. Dedifferentiated β-cells have expression of developmental genes including Ngn3, Oc4, and Nanog, low expression of genes associated with mature β-cells including Pdx1, Mafa, Foxo1, and insulin, and low glucose-stimulated insulin secretion. Other fates for β-cells in diabetes include replication and apoptosis. The relationship among adult mature and immature cells and the three fates in diabetes remain to be described. FLTP, Flattop.