The physiological role of β-cell heterogeneity in pancreatic islet function

Abstract

Endocrine cells within the pancreatic islets of Langerhans are heterogeneous in terms of transcriptional profile, protein expression and the regulation of hormone release. Even though this heterogeneity has long been appreciated, only within the past 5 years have detailed molecular analyses led to an improved understanding of its basis. Although we are beginning to recognize why some subpopulations of endocrine cells are phenotypically different to others, arguably the most important consideration is how this heterogeneity affects the regulation of hormone release to control the homeostasis of glucose and other energy-rich nutrients. The focus of this Review is the description of how endocrine cell heterogeneity (and principally that of insulin-secreting β-cells) affects the regulation of hormone secretion within the islets of Langerhans. This discussion includes an overview of the functional characteristics of the different islet cell subpopulations and describes how they can communicate to influence islet function under basal and glucose-stimulated conditions. We further discuss how changes to the specific islet cell subpopulations or their numbers might underlie islet dysfunction in type 2 diabetes mellitus. We conclude with a discussion of several key open questions regarding the physiological role of islet cell heterogeneity.

Fig. 1 |. Heterogeneity in insulin secretion by β-cells.

a | Histogram of the insulin released by dissociated human β-cells at low (2 mM) and high (22 mM) concentrations of glucose. Insulin release is measured by reverse haemolytic plaque assay. Note the high spread in release levels: at the low concentration of glucose, there are cells that secrete more insulin than the average seen at the high concentration of glucose. Conversely, at the high concentration of glucose, there are cells that secrete less insulin than the average seen at the low concentration of glucose. b | Schematic histogram for glucose sensitivity of the β-cell population when dissociated from the islet. The x-axis shows the concentration of glucose at which β-cells become activated, indicated by elevated metabolic activity measured by NAD(P)H autofluorescence, protein synthesis, insulin biosynthetic activity or elevation in calcium concentration ([Ca²⁺]). The y-axis indicates the number of cells. Cells that are activated by ≤6 mM glucose are considered activated. c | Schematic histograms for the glucose sensitivity of the β-cell populations within the islet, based on published studies^,,,. Due to intra-islet communication, β-cells that are less responsive to glucose can suppress more-responsive β-cells (solid arrow, left panel). In addition, β-cells that are more glucose responsive can recruit less-responsive β-cells (solid arrow, right panel). Further, more subtle heterogeneity exists within the islet beyond these two defined populations (not shown). We speculate that inhibitory δ-cell somatostatin release might contribute to the suppression of glucose-responsive β-cells (dashed arrow, left panel). We also speculate that stimulatory α-cell glucagon release might contribute to the recruitment of non-excitable β-cells (dashed arrow, right panel). Figure 1a is reprinted from REF., Springer Nature Limited.

Fig. 2 |. β-Cell intrinsic and extrinsic mechanisms affecting glucose-stimulated insulin release.

a | Schematic of the glucose-stimulated insulin secretion pathway in β-cells. Indicated are the mechanisms common to the mouse and human β-cell (purple) or that are specific to one species (mouse pink; human yellow). Glucokinase (GCK) phosphorylates glucose, which is further metabolized to generate ATP and alter the ATP to ADP ratio (ATP/ADP) and close ATP-sensitive potassium (K_ATP) channels. This closure prevents K⁺ export, depolarizing the cell and increasing its membrane potential (V_m), which activates voltage-gated Ca²⁺ channels (Ca_V) (and in humans, voltage-gated Na⁺ channels; Na_V). This activation leads to [Ca²⁺] influx, which drives the exocytosis of insulin granules. In addition, several G protein-coupled receptors (GPCRs) enhance (for example, glucagon receptor and glucagon-like peptide 1 (GLP1) receptor) or suppress (for example, somatostatin receptor and adrenergic receptors) granule trafficking to the plasma membrane. b | Schematic indicating the role of connexin 36 (Cx36) gap junctions in the islet in controlling islet excitability. The presence of gap junction-mediated electrical currents (indicated by the arrows in the bottom cells) between β-cells makes V_m more uniform, such that hyperpolarized β-cells depolarize more and depolarized β-cells hyperpolarize more. c | Schematic indicating how EphA receptor–ephrin-A ligand bidirectional juxtacrine signalling regulates insulin granule trafficking and exocytosis in β-cells. At basal concentrations of glucose, EphA receptor forward signalling dominates (grey cell). At elevated concentrations of glucose, ephrin-A ligand reverse signalling dominates (pink cell). d | Paracrine factors released within the islet by different endocrine cells and their effect on other endocrine cells within the islet.

Fig. 3 |. β-Cell subpopulations suppress electrical activity and basal insulin release in other β-cells across the islet.

a | Schematic of three β-cells within the islet with different ATP-sensitive potassium (K_ATP) conductance. Cell 1 has high K_ATP conductance (indicated by the thick arrow), which hyperpolarizes the cell despite an elevated level of glucose, rendering it inexcitable and maintaining a low intracellular calcium concentration ([Ca²⁺]). Cell 3 has low K_ATP conductance (indicated by the thin arrow), which depolarizes the cell at an elevated level of glucose, rendering it excitable and elevating [Ca²⁺]. Gap junction coupling causes an electrical current (indicated by arrows) to flow from cell 2 to cell 1, which hyperpolarizes cell 2, whereas gap junction coupling of cell 2 with cell 3 depolarizes cell 2. In turn, cells 1 and 3 are, respectively, depolarized and hyperpolarized. b | In the absence of gap junction coupling, cell 1 (inexcitable, hyperpolarized) secretes less insulin, whereas cell 3 (excitable, depolarized) secretes more insulin. In the presence of gap junction coupling, β-cells secrete insulin more uniformly, but are influenced more by the inexcitable cell. Cx36, connexin 36.

Fig. 4 |. Dynamics underlying different β-cell subpopulations within the islet.

a | The first-responder β-cell within the islet is that which has the earliest response to glucose (upper diagram). Ca²⁺ dynamics are differently influenced in the presence of first-responder cells (middle graph) or in their absence (lower graph). b | Ca²⁺ wave propagation and the identification and influence of leader β-cells within the islet (also referred to as the wave origin region). Wave propagation differs in the presence or absence of leader cells. c | Cell connectivity and the identification and influence of hub β-cells with the islet. Lines between cells indicate the high level of correlation between Ca²⁺ time courses in the connected cells, indicating a ‘functional connection’. Hub cells show the greatest numbers of ‘functional connections’. Connectivity differs in the presence or absence of hub cells. d | Identification of excitable β-cells in mouse islets by use of the expression of the light-activated cation channel ChR2 (an optogenetic construct). Blue light illumination over a single-cell region depolarizes the cell and elevates [Ca²⁺] (cell 1). This depolarization spreads to a number of neighbouring cells, recruiting elevated [Ca²⁺] (cell 2 but not cell 3). e | Identification of hub β-cells in mouse islets by use of the expression of the light-activated Cl⁻ pump eNpHr3 (an optogenetic construct). Yellow light illumination over a single-cell region hyperpolarizes the cell to suppress [Ca²⁺] elevation (cell 1). This hyperpolarization spreads to a number of neighbouring cells, suppressing elevated [Ca²⁺] (cell 2 but not cell 3).