Beta cell heterogeneity: an evolving concept

Abstract

Beta cells are primarily defined by their ability to produce insulin and secrete it in response to appropriate stimuli. It has been known for some time, however, that beta cells are not functionally identical to each other and that the rates of insulin synthesis and release differ from cell to cell, although the functional significance of this variability remains unclear. Recent studies have used heterogeneous gene expression to isolate and evaluate different subpopulations of beta cells and to demonstrate alterations in these subpopulations in diabetes. In the last few years, novel technologies have emerged that permit the detailed evaluation of the proteome (e.g. time-of-flight mass spectroscopy, [CyTOF]) and transcriptome (e.g. massively parallel RNA sequencing) at the single-cell level, and tools for single beta cell metabolomics and epigenomics are quickly maturing. The first wave of single beta cell proteome and transcriptome studies were published in 2016, giving a glimpse into the power, but also the limitations, of these approaches. Despite this progress, it remains unclear if the observed heterogeneity of beta cells represents stable, distinct beta cell types or, alternatively, highly dynamic beta cell states. Here we provide a concise overview of recent developments in the emerging field of beta cell heterogeneity and the implications for our understanding of beta cell biology and pathology.

Single cell chromatin accessibility reveals pancreatic islet cell type- and state-specific regulatory programs of diabetes risk

“…Single cell accessible chromatin uncovered heterogeneity in the regulatory programs of endocrine cell types, revealing cell type- and state-resolved effects of genetic variants on fasting glucose and T2D risk. Previous studies have characterized heterogeneity in beta cell physiological function, cell surface markers, and gene expression 22,94,95 . The heterogeneity we observed in the beta cell epigenome mapped to cellular states related to insulin production and stress-related signaling response 23 , and we identified TFs likely driving cell state-specific functions.…”

Time zones of pancreatic islet metabolism

“…Accumulating evidence on distinct functional sub‐populations of β‐cells prompted the search for molecular insights of such diversity using single‐cell large‐scale transcriptome analyses, allowing for the identification and characterization of new sub‐populations among human and mouse islet cells. Interestingly, a sub‐population of proliferating β‐cells was discovered in adult mice based on their transcriptome signature .…”

“…106 Although most islet cells possess a narrow functional specialization in the adult organism, single-cell RNA sequencing analyses identified the presence of infrequent bi-or multi-hormonal cells that were often excluded from the final analysis. 106,109 At the same time, the presence of bi-hormonal cells is common in foetal islets and upon T2D development, likely representing an inter-lineage plasticity during cellular development, or dedifferentiation resulting from β-cell failure (reviewed in 101,102 ). Indeed, following a nearly total β-cell ablation in mice, αand δ-cells were reported to acquire β-cell identity.…”

Effects of proinsulin misfolding on β‐cell dynamics, differentiation and function in diabetes

“…Studies in animal models and in human subjects with diabetes provide compelling data that all these mechanisms might be involved in the pathophysiology of diabetes; however, their quantitative contribution to β‐cell loss and dysfunction is unknown . Moreover, transcriptomic analysis of single β‐cells derived from T2D patients suggests the existence of marked heterogeneity in the genetic signature of different β‐cells within the same pancreas, further illustrating the complexity of β‐cell dysfunction in diabetes β‐Cell mass is reduced in diabetes but varies markedly between patients, overlapping with normoglycemic subjects.…”

“…11,12 Moreover, transcriptomic analysis of single β-cells derived from T2D patients suggests the existence of marked heterogeneity in the genetic signature of different β-cells within the same pancreas, further illustrating the complexity of β-cell dysfunction in diabetes. 13 " β-Cell mass is reduced in diabetes but varies markedly between patients, overlapping with normoglycemic subjects. Also, transcriptomics of single β-cells indicate large heterogeneity within same pancreas.…”