Alpha-cell paracrine signaling in the regulation of beta-cell insulin secretion

Abstract

As an incretin hormone, glucagon-like peptide 1 (GLP-1) lowers blood glucose levels by enhancing glucose-stimulated insulin secretion from pancreatic beta-cells. Therapies targeting the GLP-1 receptor (GLP-1R) use the classical incretin model as a physiological framework in which GLP-1 secreted from enteroendocrine L-cells acts on the beta-cell GLP-1R. However, this model has come into question, as evidence demonstrating local, intra-islet GLP-1 production has advanced the competing hypothesis that the incretin activity of GLP-1 may reflect paracrine signaling of GLP-1 from alpha-cells on GLP-1Rs on beta-cells. Additionally, recent studies suggest that alpha-cell-derived glucagon can serve as an additional, albeit less potent, ligand for the beta-cell GLP-1R, thereby expanding the role of alpha-cells beyond that of a counterregulatory cell type. Efforts to understand the role of the alpha-cell in the regulation of islet function have revealed both transcriptional and functional heterogeneity within the alpha-cell population. Further analysis of this heterogeneity suggests that functionally distinct alpha-cell subpopulations display alterations in islet hormone profile. Thus, the role of the alpha-cell in glucose homeostasis has evolved in recent years, such that alpha-cell to beta-cell communication now presents a critical axis regulating the functional capacity of beta-cells. Herein, we describe and integrate recent advances in our understanding of the impact of alpha-cell paracrine signaling on insulin secretory dynamics and how this intra-islet crosstalk more broadly contributes to whole-body glucose regulation in health and under metabolic stress. Moreover, we explore how these conceptual changes in our understanding of intra-islet GLP-1 biology may impact our understanding of the mechanisms of incretin-based therapeutics.

Keywords: GLP-1; alpha-cell; beta-cell; glucagon; insulin; paracrine signaling.

Figure 1

Proglucagon-derived products signal through the beta-cell glucagon-like peptide 1 (GLP-1) receptor and glucagon receptor to potentiate glucose-stimulated insulin secretion (GSIS). The triggering pathway for beta-cell insulin secretion is activated by ATP generation following the influx of glucose. The increase in intracellular ATP induces closure of ATP-dependent K⁺ (K_ATP) channels, resulting in membrane depolarization and the subsequent opening of the voltage-gated Ca²⁺ channels. The rise in intracellular Ca²⁺ concentrations triggers exocytosis of insulin-containing granules. Stimulation of the beta-cell GLP-1 receptor (GLP-1R) and glucagon receptor (GCGR) results in activation of adenylyl cyclase, leading to increase cAMP production, and the activation of EPAC and protein kinase A (PKA). EPAC and PKA further increase intracellular Ca²⁺ concentrations, allowing for the potentiation of GSIS.

Figure 2

Evidence characterizing the role of the alpha-cell in normal insulin secretory dynamics. Researchers have evaluated insulin secretion from mouse models devoid of all alpha-cell-derived proglucagon peptides (6, 19, 36) and have found that in the absence of paracrine signaling from alpha-cells, beta-cell insulin secretion is impaired. Similarly, several studies have employed mouse models with selective reactivation of Gcg expression in the gut or pancreatic islet in order to assess the relative contribution of the gut vs. the islet to whole-body glucose tolerance. These studies reveal that islet-derived proglucagon products are the predominant ligand for beta-cell glucagon-like peptide 1 receptor (GLP-1R) activation and are necessary for the glucoregulatory improvements of DPP-IV inhibitors (DPP-IVi) and vertical sleeve gastrectomy (VSG) (15, 37, 38). Furthermore, recent evidence demonstrates that glucagon-induced insulin secretion is primarily mediated by signaling at the GLP-1R. Several independent groups have demonstrated that inhibition of beta-cell GLP-1R signaling, by either Exendin 9-39 (Ex9) or through genetic knockout, impairs glucagon-induced insulin secretion, whereas pharmacological or genetic inhibition of glucagon receptor (GCGR) signaling fails to abolish this effect (5, 6, 8, 28, 36).

Figure 3

Alpha-cell glucagon-like peptide 1 (GLP-1) serves as a marker for alpha-cell heterogeneity. Several studies have identified distinct alpha-cell subpopulations that differ based on proglucagon processing (7, 12, 62) and secretory phenotype (13, 66, 67), which suggests that these distinct subpopulations can differentially regulate intra-islet paracrine signaling interactions. Similarly, recent evidence suggests that alpha-cell GLP-1 production may reflect an immature alpha-cell, as these cells have been shown to exhibit increased expression of PCSK1 (13), and increased expression of progenitor markers, NEUROD1, FEV, and ISL1 (68, 69) and decreased expression of alpha-cell maturity markers, such as ARX and DNMT1 (13, 70). Additionally, independent studies have identified a subpopulation of proliferating alpha-cells expressing TOP2A/TOP1A and CENPF (71, 72), which may be associated with maturity state and GLP-1 production. Together, these studies suggest that the heterogeneous proliferative state, maturity, and secretory phenotypes of alpha-cells prime various subpopulations for cell-type conversions. Several studies have demonstrated that under certain conditions, such as high-fat-diet (HFD) feeding (73), GLP-1R agonist treatment (13), T1DM (67), and decreased expression of alpha-cell maturity markers (67) of alpha-cells exhibit beta-cell-like characteristics.

Figure 4

Alpha-cell glucagon-like peptide 1 (GLP-1) production is upregulated in response to metabolic stress and therapeutic interventions. Metabolic dysfunction, mediated by beta-cell destruction, diet-induced obesity, and type 2 diabetes, results in a blunted incretin effect of GLP-1. Evidence suggests that the paracrine action of alpha-cell GLP-1 may compensate for this diminished peripheral incretin action of gut-derived GLP-1. In response to metabolic dysfunction, beta-cells exhibit decreased proliferation and increased apoptosis, and decreased insulin secretion and increased paracrine signaling factor secretion. In response to beta-cell paracrine signaling factors, and whole-body metabolic inputs, alpha-cells exhibit increased proliferation, PCSK1 expression, and GLP-1 production, which may reduce alpha-cell glucagon secretion. These favorable alpha-cell adaptations can then reciprocally promote beta-cell function, survival, and insulin secretion. Several studies have demonstrated that bariatric surgery and the pharmaceutical targeting of GLP-1 through GLP-1R agonists and DPP-IV inhibitors have the potential to harness and promote alpha-cell GLP-1 production.

Figure 5

Bi-directional paracrine feedback mechanisms regulate islet function in health and disease. Alpha-cell proglucagon-derived peptides (glucagon and GLP-1) signal through the beta-cell GLP-1 receptor (GLP-1R) and glucagon receptor (GCGR) to potentiate glucose-stimulated insulin secretion. Beta-cell insulin secretion then inhibits alpha-cell glucagon secretion, thereby constituting a paracrine negative feedback loop between alpha- and beta-cells under normal physiological conditions (gray arrows). In contrast, in response to beta-cell injury or metabolic stress, there is an increased reliance on GLP-1 and beta-cell GLP-1R signaling for insulin secretion. Increased beta-cell GLP-1R signaling results in the secretion of paracrine factors that can activate alpha-cell PC1/3 expression and GLP-1 production. This locally produced GLP-1 can then favorably signal at the beta-cell GLP-1R, thereby constituting a paracrine positive feedback loop between alpha- and beta-cells as an adaptation to metabolic dysfunction.