Somatostatin Secreted by Islet delta-Cells Fulfills Multiple Roles as a Paracrine Regulator of Islet
Somatostatin Secreted by Islet delta-Cells Fulfills Multiple Roles as a Paracrine Regulator of Islet Function
Objective: Somatostatin (SST) is secreted by islet δ-cells and by extraislet neuroendocrine cells. SST receptors have been identified on α- and β-cells, and exogenous SST inhibits insulin and glucagon secretion, consistent with a role for SST in regulating α- and β-cell function. However, the specific intraislet function of δ-cell SST remains uncertain. We have used Sst mice to investigate the role of δ-cell SST in the regulation of insulin and glucagon secretion in vitro and in vivo.
Research Design and Methods: Islet morphology was assessed by histological analysis. Hormone levels were measured by radioimmunoassay in control and Sst mice in vivo and from isolated islets in vitro.
Results: Islet size and organization did not differ between Sst and control islets, nor did islet glucagon or insulin content. Sst mice showed enhanced insulin and glucagon secretory responses in vivo. In vitro stimulus-induced insulin and glucagon secretion was enhanced from perifused Sst islets compared with control islets and was inhibited by exogenous SST in Sst but not control islets. No difference in the switch-off rate of glucose-stimulated insulin secretion was observed between genotypes, but the cholinergic agonist carbamylcholine enhanced glucose-induced insulin secretion to a lesser extent in Sst islets compared with controls. Glucose suppressed glucagon secretion from control but not Sst islets.
Conclusions: We suggest that δ-cell SST exerts a tonic inhibitory influence on insulin and glucagon secretion, which may facilitate the islet response to cholinergic activation. In addition, δ-cell SST is implicated in the nutrient-induced suppression of glucagon secretion.
Islets of Langerhans are heterogeneous cell aggregates containing β-, α-, δ-, and PP cells, which secrete insulin, glucagon, somatostatin (SST), and pancreatic polypeptide, respectively. The different cell types within the islet are affected by changes in the extracellular glucose concentration. Thus, elevations in circulating glucose stimulate insulin secretion from islet β-cells and inhibit glucagon secretion from α-cells as part of the reciprocal regulation of blood glucose by insulin and glucagon. SST secretion from islet δ-cells is also stimulated by increased extracellular glucose, although the threshold concentration for δ-cells to respond to glucose is lower than that for β-cells, and the ionic events in stimulus-response coupling differ between β- and δ-cells.
Rodent islets have a defined architecture with a β-cell core surrounded by a mantle of non-β-cells, whereas human islets do not show such pronounced anatomical subdivisions. The anatomical organization of islets is important for their correct functioning, and there is much evidence to suggest that cell-cell interactions within islets are crucial for normal function. Interactions between islet β-cells have been investigated extensively, and we have previously demonstrated the importance of homotypic β-cell interactions in the regulation of insulin secretion. Similarly, there have been numerous studies of possible interactions between α- and β-cells within islets. Less attention has been paid to the possible intraislet roles of δ-cell-derived SST. δ-Cells comprise 5-10% of the islet endocrine cells, but the peptide hormone SST is also synthesized and secreted by neuroendocrine cells in the central nervous system and the gastrointestinal system, and the latter is the major contributor to circulating SST. SST often acts as an inhibitory regulator of endocrine systems, for example, as a hypothalamic factor to suppress growth hormone secretion from the anterior pituitary, or as a local inhibitor of the release of gastrointestinal peptide hormones. SST receptors (SSTR1-5) have been identified on both α- and β-cells, and exogenously administered SST or SST analogs inhibit glucose-induced insulin secretion and arginine-induced glucagon secretion both in vitro and in vivo. In addition, studies using SSTR-deficient mice (SSTR1, -2, or -5) revealed changes in both basal and stimulated insulin secretion. However, studies using SSTR knockout models are difficult to interpret because mouse islets express all five SSTRs and reduced expression of one receptor subtype may be compensated for by the overexpression of another. Therefore, although current data are consistent with a negative regulatory role for SST in islet secretory function, it is unclear whether this effect can be ascribed to circulating SST or to locally released δ-cell SST.
The study of δ-cell function within islets is complicated by the possibility of multiple heterotypic interactions between islet cell types in experiments using intact primary islets. Studies of islet SST have also been hampered by the lack of selective and potent SST receptor antagonists. To investigate the role of locally released δ-cell SST, we have therefore used a mouse model in which disruption of the SST gene produced a SST-deficient phenotype. Our results suggest that locally released δ-cell SST exerts a tonic inhibitory influence on insulin and glucagon secretion and that this inhibitory effect of δ-cell SST may be involved in facilitating the insulin secretory response to cholinergic activation and the nutrient-induced suppression of glucagon secretion.
Abstract and Introduction
Abstract
Objective: Somatostatin (SST) is secreted by islet δ-cells and by extraislet neuroendocrine cells. SST receptors have been identified on α- and β-cells, and exogenous SST inhibits insulin and glucagon secretion, consistent with a role for SST in regulating α- and β-cell function. However, the specific intraislet function of δ-cell SST remains uncertain. We have used Sst mice to investigate the role of δ-cell SST in the regulation of insulin and glucagon secretion in vitro and in vivo.
Research Design and Methods: Islet morphology was assessed by histological analysis. Hormone levels were measured by radioimmunoassay in control and Sst mice in vivo and from isolated islets in vitro.
Results: Islet size and organization did not differ between Sst and control islets, nor did islet glucagon or insulin content. Sst mice showed enhanced insulin and glucagon secretory responses in vivo. In vitro stimulus-induced insulin and glucagon secretion was enhanced from perifused Sst islets compared with control islets and was inhibited by exogenous SST in Sst but not control islets. No difference in the switch-off rate of glucose-stimulated insulin secretion was observed between genotypes, but the cholinergic agonist carbamylcholine enhanced glucose-induced insulin secretion to a lesser extent in Sst islets compared with controls. Glucose suppressed glucagon secretion from control but not Sst islets.
Conclusions: We suggest that δ-cell SST exerts a tonic inhibitory influence on insulin and glucagon secretion, which may facilitate the islet response to cholinergic activation. In addition, δ-cell SST is implicated in the nutrient-induced suppression of glucagon secretion.
Introduction
Islets of Langerhans are heterogeneous cell aggregates containing β-, α-, δ-, and PP cells, which secrete insulin, glucagon, somatostatin (SST), and pancreatic polypeptide, respectively. The different cell types within the islet are affected by changes in the extracellular glucose concentration. Thus, elevations in circulating glucose stimulate insulin secretion from islet β-cells and inhibit glucagon secretion from α-cells as part of the reciprocal regulation of blood glucose by insulin and glucagon. SST secretion from islet δ-cells is also stimulated by increased extracellular glucose, although the threshold concentration for δ-cells to respond to glucose is lower than that for β-cells, and the ionic events in stimulus-response coupling differ between β- and δ-cells.
Rodent islets have a defined architecture with a β-cell core surrounded by a mantle of non-β-cells, whereas human islets do not show such pronounced anatomical subdivisions. The anatomical organization of islets is important for their correct functioning, and there is much evidence to suggest that cell-cell interactions within islets are crucial for normal function. Interactions between islet β-cells have been investigated extensively, and we have previously demonstrated the importance of homotypic β-cell interactions in the regulation of insulin secretion. Similarly, there have been numerous studies of possible interactions between α- and β-cells within islets. Less attention has been paid to the possible intraislet roles of δ-cell-derived SST. δ-Cells comprise 5-10% of the islet endocrine cells, but the peptide hormone SST is also synthesized and secreted by neuroendocrine cells in the central nervous system and the gastrointestinal system, and the latter is the major contributor to circulating SST. SST often acts as an inhibitory regulator of endocrine systems, for example, as a hypothalamic factor to suppress growth hormone secretion from the anterior pituitary, or as a local inhibitor of the release of gastrointestinal peptide hormones. SST receptors (SSTR1-5) have been identified on both α- and β-cells, and exogenously administered SST or SST analogs inhibit glucose-induced insulin secretion and arginine-induced glucagon secretion both in vitro and in vivo. In addition, studies using SSTR-deficient mice (SSTR1, -2, or -5) revealed changes in both basal and stimulated insulin secretion. However, studies using SSTR knockout models are difficult to interpret because mouse islets express all five SSTRs and reduced expression of one receptor subtype may be compensated for by the overexpression of another. Therefore, although current data are consistent with a negative regulatory role for SST in islet secretory function, it is unclear whether this effect can be ascribed to circulating SST or to locally released δ-cell SST.
The study of δ-cell function within islets is complicated by the possibility of multiple heterotypic interactions between islet cell types in experiments using intact primary islets. Studies of islet SST have also been hampered by the lack of selective and potent SST receptor antagonists. To investigate the role of locally released δ-cell SST, we have therefore used a mouse model in which disruption of the SST gene produced a SST-deficient phenotype. Our results suggest that locally released δ-cell SST exerts a tonic inhibitory influence on insulin and glucagon secretion and that this inhibitory effect of δ-cell SST may be involved in facilitating the insulin secretory response to cholinergic activation and the nutrient-induced suppression of glucagon secretion.
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