δ-Cells: The Neighborhood Watch in the Islet Community

Abstract

Simple Summary

Pancreatic islets are micro-organs composed of several endocrine cell types, including α-cells (secreting glucose-elevating glucagon), β-cells (releasing glucose-lowering insulin) and δ-cells (producing somatostatin, a potent inhibitor of insulin and glucagon secretion). Despite their low percentage within the islets (~5%), δ-cells play an important role in maintaining a balanced hormone output. This is facilitated by their complex morphology projections enabling interaction with other endocrine cells. δ-cells are electrically excitable and, like in β-cells, K _ATP channels mediate the metabolic signals by modulating δ-cell membrane potential. However, Ca ²⁺ signals amplified by mobilization of intracellular Ca ²⁺ stores play a fundamental part in the process of glucose-induced somatostatin secretion and this can be independent of δ-cell electrical activity. Apart from their intrinsic regulatory mechanisms, δ-cells’ somatostatin secretion is tightly modulated by neighboring “non-δ-cells”, fulfilling its reciprocal feedback paracrine function. In this review, we summarize the structural features of δ-cells; the intracellular signaling of δ-cells in response to nutritional stimuli; and the molecular signals mediating the paracrine crosstalk between δ- and non-δ-cells. Finally, the function of δ-cells and their intercellular interactions are impaired in diabetes. Thus, restoring δ-cell function/signaling in diabetes would be a promising approach for developing novel treatment for diabetes.

Abstract

Somatostatin-secreting δ-cells have aroused great attention due to their powerful roles in coordination of islet insulin and glucagon secretion and maintenance of glucose homeostasis. δ-cells exhibit neuron-like morphology with projections which enable pan-islet somatostatin paracrine regulation despite their scarcity in the islets. The expression of a range of hormone and neurotransmitter receptors allows δ-cells to integrate paracrine, endocrine, neural and nutritional inputs, and provide rapid and precise feedback modulations on glucagon and insulin secretion from α- and β-cells, respectively. Interestingly, the paracrine tone of δ-cells can be effectively modified in response to factors released by neighboring cells in this interactive communication, such as insulin, urocortin 3 and γ-aminobutyric acid from β-cells, glucagon, glutamate and glucagon-like peptide-1 from α-cells. In the setting of diabetes, defects in δ-cell function lead to suboptimal insulin and glucagon outputs and lift the glycemic set-point. The interaction of δ-cells and non-δ-cells also becomes defective in diabetes, with reduces paracrine feedback to β-cells to exacerbate hyperglycemia or enhanced inhibition of α-cells, disabling counter-regulation, to cause hypoglycemia. Thus, it is possible to restore/optimize islet function in diabetes targeting somatostatin signaling, which could open novel avenues for the development of effective diabetic treatments.