Real-Time Detection of Somatostatin Release From Single Pancreatic Islets Reveals δ-Cell Dysfunction in Type 2 Diabetes

Abstract

Pancreatic δ-cells are endocrine cells located within the islets of Langerhans and are primarily responsible for secreting somatostatin. Although δ-cells represent a minority population within the islets—approximately 5% of the total islet cells—they play an important role in modulating glucagon and insulin secretion through paracrine regulatory effects of somatostatin on neighboring α- and β-cells. Classically, somatostatin has been well recognized as a potent inhibitor of glucagon and insulin secretion. Recent research, however, has underscored that δ-cells mediate these inhibitory effects not only through diffusible paracrine signaling but also via direct cell-to-cell contacts, facilitated by δ-cell processes extending toward neighboring α- and β-cells [1]. Moreover, advanced imaging techniques and patch-clamp electrophysiological recordings have revealed synchronized calcium oscillations between δ- and β-cells, [2, 3] highlighting tightly coordinated secretory dynamics within the islet microenvironment. A recent study in Acta Physiologica by Yang et al. [4] significantly advances our understanding by introducing a novel method for the real-time visualization of somatostatin secretion, revealing δ-cell dysfunction in type 2 diabetes.

Abnormalities in these δ-cell-mediated interactions have been reported in pathological conditions such as diabetes. Dysfunctional communication among δ-, α-, and β-cells, [2, 5] along with impaired or dysregulated somatostatin secretion, [1] disrupts hormonal balance and compromises glucose homeostasis. Accurate visualization of these δ-cell-mediated intercellular interactions, including real-time imaging of somatostatin secretion dynamics at the single islet level, is therefore critical not only for elucidating the overall mechanisms governing hormone secretion within islets but also for advancing our understanding of diabetes pathophysiology and identifying novel therapeutic targets. However, traditional immunoassays used to measure somatostatin have limited sensitivity and temporal resolution, which obscures accurate evaluation of somatostatin secretion dynamics at the single islet level.

To overcome the limitations associated with conventional immunoassays, Yang et al. developed an innovative real-time reporter cell assay to analyze somatostatin secretion dynamics at the single islet level. Specifically, the authors engineered HeLa cells to serve as highly sensitive reporter cells expressing somatostatin receptor subtype 2 (SSTR2), which is functionally coupled via the G-protein subunit Gα15 to phospholipase C-dependent intracellular calcium signaling pathways (Figure 1). Upon binding of somatostatin to SSTR2, the receptor cells exhibit a measurable intracellular calcium oscillation via fluorescence emitted by the genetically encoded calcium indicator R-GECO1, enabling precise real-time detection and quantification of somatostatin secretion. Simultaneously, intraislet calcium responses were visualized using the calcium-sensitive dye Cal-520, allowing direct monitoring of overall islet cell activity. Thus, this innovative approach allows simultaneous visualization of somatostatin secretion dynamics and intraislet calcium signaling, providing deeper insights into islet hormone secretion kinetics at unprecedented single islet resolution.

Employing this novel real-time reporter assay, Yang et al. demonstrated robust glucose-induced somatostatin secretion from both mouse and human pancreatic islets, frequently occurring as coordinated pulses synchronized with intracellular calcium fluctuations within the islets. They also found that glucose-induced somatostatin secretion was not fully replicated by the ATP-sensitive potassium (K_ATP) channel blocker tolbutamide alone. Specifically, the tolbutamide-induced somatostatin secretion was weaker compared to not only glucose stimulation but also direct membrane depolarization with high potassium, suggesting that additional signaling pathways beyond simple K_ATP channel closure are involved in glucose-dependent somatostatin secretion.

In addition, the authors demonstrated significant enhancement of glucose-induced somatostatin secretion by glucagon-like peptide-1 (GLP-1) and glucagon, suggesting that somatostatin secretion is modulated by multiple hormonal factors in a glucose-dependent manner. Notably, ghrelin was also identified as a robust stimulator of somatostatin secretion, adding another layer of complexity to the intraislet communication networks by implicating ghrelin-producing ε-cells in the modulation of δ-cell function. Only in human islets, insulin selectively stimulated somatostatin secretion at low glucose levels, further suggesting potential species-specific regulatory mechanisms.

A particularly noteworthy observation in this study was a higher glucose-induced somatostatin secretion in islets from donors with type 2 diabetes (T2D), despite a reduced number of δ-cells, compared with islets from nondiabetic donors. This paradoxical hypersecretion suggests intrinsic functional changes within δ-cells that may contribute to the dysregulated hormonal balance and impaired glucose homeostasis in T2D. Previous research has yielded conflicting results, with studies showing decreased somatostatin secretion in islets from high-fat-fed mice [6] and those undergoing lipotoxicity [7], whereas others have documented increased secretion in islets from a nonobese diabetic mouse model and from donors with T2D [8]. The findings of Yang et al. robustly support the existence of a hypersecretory δ-cell phenotype in T2D, prompting reconsideration of the role of δ-cells in the pathophysiology of diabetes.

Based on these findings, future research should focus on elucidating the precise molecular mechanisms underlying the paradoxical hypersecretion of somatostatin from δ-cells in T2D. It will be important to investigate whether δ-cell hypersecretion represents an adaptive protective response aimed at mitigating hyperglucagonemia or whether it negatively contributes to diabetes progression by exacerbating hormonal imbalances and worsening glucose homeostasis. In addition, exploration of the additional signaling pathways beyond K_ATP channel closure involved in glucose-dependent somatostatin secretion may identify novel therapeutic targets. Understanding these mechanisms could significantly inform therapeutic strategies targeting δ-cell function, potentially improving diabetes management by restoring hormonal balance.

In summary, the innovative assay developed by Yang et al. represents a substantial technological advance for islet research, enabling precise, real-time measurement of somatostatin secretion dynamics at single-islet resolution. By uncovering key alterations in δ-cell function associated with T2D, particularly paradoxical hypersecretion despite reduced δ-cell populations, this assay provides essential insights into the pathophysiology of diabetes. Ultimately, this methodology and the knowledge derived from it will facilitate deeper investigations into islet biology and may pave the way for novel targeted therapeutic interventions aimed at restoring proper islet function and hormone regulation in diabetes.

Mototsugu Nagao: writing – original draft, writing – review and editing.

This work was supported by the Japan Society for the Promotion of Science.

The author declares no conflicts of interest.