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Somatostatin secretion by Na+-dependent Ca2+-induced Ca2+ release in pancreatic delta-cells.

ABSTRACT: Pancreatic islets are complex micro-organs consisting of at least three different cell types: glucagon-secreting ?-, insulin-producing ?- and somatostatin-releasing ?-cells1. Somatostatin is a powerful paracrine inhibitor of insulin and glucagon secretion2. In diabetes, increased somatostatinergic signalling leads to defective counter-regulatory glucagon secretion3. This increases the risk of severe hypoglycaemia, a dangerous complication of insulin therapy4. The regulation of somatostatin secretion involves both intrinsic and paracrine mechanisms5 but their relative contributions and whether they interact remains unclear. Here we show that dapagliflozin-sensitive glucose- and insulin-dependent sodium uptake stimulates somatostatin secretion by elevating the cytoplasmic Na+ concentration ([Na+]i) and promoting intracellular Ca2+-induced Ca2+ release (CICR). This mechanism also becomes activated when [Na+]i is elevated following the inhibition of the plasmalemmal Na+-K+ pump by reductions of the extracellular K+ concentration emulating those produced by exogenous insulin in vivo 6. Islets from some donors with type-2 diabetes hypersecrete somatostatin, leading to suppression of glucagon secretion that can be alleviated by a somatostatin receptor antagonist. Our data highlight the role of Na+ as an intracellular second messenger, illustrate the significance of the intraislet paracrine network and provide a mechanistic framework for pharmacological correction of the hormone secretion defects associated with diabetes that selectively target the ?-cells.

SUBMITTER: Vergari E

PROVIDER: S-EPMC6986923 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Somatostatin secretion by Na+-dependent Ca2+-induced Ca2+ release in pancreatic delta-cells.

Vergari Elisa E Denwood Geoffrey G Salehi Albert A Zhang Quan Q Adam Julie J Alrifaiy Ahmed A Wernstedt Asterholm Ingrid I Benrick Anna A Chibalina Margarita V MV Eliasson Lena L Guida Claudia C Hill Thomas G TG Hamilton Alexander A Ramracheya Reshma R Reimann Frank F Rorsman Nils J G NJG Spilliotis Ioannis I Tarasov Andrei I AI Walker Jonathan N JN Rorsman Patrik P Briant Linford J B LJB

Nature metabolism 20200120 1

Pancreatic islets are complex micro-organs consisting of at least three different cell types: glucagon-secreting α-, insulin-producing β- and somatostatin-releasing δ-cells1. Somatostatin is a powerful paracrine inhibitor of insulin and glucagon secretion2. In diabetes, increased somatostatinergic signalling leads to defective counter-regulatory glucagon secretion3. This increases the risk of severe hypoglycaemia, a dangerous complication of insulin therapy4 ...[more]

PMID: 31993555

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Project description:ObjectiveComplex local crosstalk amongst endocrine cells within the islet ensures tight coordination of their endocrine output. This is illustrated by the recent demonstration that the negative feedback control by delta cells within pancreatic islets determines the homeostatic set-point for plasma glucose during mouse postnatal development. However, the close association of islet endocrine cells that facilitates paracrine crosstalk also complicates the distinction between effects mediated directly on beta cells from indirect effects mediated via local intermediates, such as somatostatin from delta cells.MethodsTo resolve this problem, we generated reporter mice that allow collection of pure pancreatic delta cells along with alpha and beta cells from the same islets and generated comprehensive transcriptomes for each islet endocrine cell type. These transcriptomes afford an unparalleled view of the receptors expressed by delta, alpha and beta cells, and allow the prediction of which signal targets which endocrine cell type with great accuracy.ResultsFrom these transcriptomes, we discovered that the ghrelin receptor is expressed exclusively by delta cells within the islet, which was confirmed by fluorescent in situ hybridization and qPCR. Indeed, ghrelin increases intracellular calcium in delta cells in intact mouse islets, measured by GCaMP6 and robustly potentiates glucose-stimulated somatostatin secretion on mouse and human islets in both static and perfusion assays. In contrast, des-acyl-ghrelin at the same dose had no effect on somatostatin secretion and did not block the actions of ghrelin.ConclusionsThese results offer a straightforward explanation for the well-known insulinostatic actions of ghrelin. Rather than engaging beta cells directly, ghrelin engages delta cells to promote local inhibitory feedback that attenuates insulin release. These findings illustrate the power of our approach to resolve some of the long-standing conundrums with regard to the rich feedback that occurs within the islet that is integral to islet physiology and therefore highly relevant to diabetes.

Dataset Information

Somatostatin secretion by Na+-dependent Ca2+-induced Ca2+ release in pancreatic delta-cells.

Publications

Somatostatin secretion by Na<sup>+</sup>-dependent Ca<sup>2+</sup>-induced Ca<sup>2+</sup> release in pancreatic delta-cells.

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