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

Vergari, Elisa ; Denwood, Geoffrey ; Salehi, Albert LU orcid ; Zhang, Quan LU ; Adam, Julie ; Alrifaiy, Ahmed ; Wernstedt Asterholm, Ingrid ; Benrick, Anna ; Chibalina, Margarita V. and Eliasson, Lena LU orcid , et al. (2020) In Nature Metabolism 2(1). p.32-40
Abstract

Pancreatic islets are complex micro-organs consisting of at least three different cell types: glucagon-secreting alpha, insulin-producing beta and somatostatin-releasing delta cells. Somatostatin is a powerful paracrine inhibitor of insulin and glucagon secretion. In diabetes, increased somatostatinergic signalling leads to defective counter-regulatory glucagon secretion. This increases the risk of severe hypoglycaemia, a dangerous complication of insulin therapy. The regulation of somatostatin secretion involves both intrinsic and paracrine mechanisms but their relative contributions and whether they interact remain unclear. Here we show that dapagliflozin-sensitive glucose- and insulin-dependent sodium uptake stimulates somatostatin... (More)

Pancreatic islets are complex micro-organs consisting of at least three different cell types: glucagon-secreting alpha, insulin-producing beta and somatostatin-releasing delta cells. Somatostatin is a powerful paracrine inhibitor of insulin and glucagon secretion. In diabetes, increased somatostatinergic signalling leads to defective counter-regulatory glucagon secretion. This increases the risk of severe hypoglycaemia, a dangerous complication of insulin therapy. The regulation of somatostatin secretion involves both intrinsic and paracrine mechanisms but their relative contributions and whether they interact remain unclear. Here we show that dapagliflozin-sensitive glucose- and insulin-dependent sodium uptake stimulates somatostatin secretion by elevating the cytoplasmic Na+ concentration (intracellular [Na+]; [Na+]i) and promoting intracellular Ca2+-induced Ca2+ release. 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. 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 intra-islet paracrine network and provide a mechanistic framework for pharmacological correction of the hormone secretion defects associated with diabetes that selectively target the delta cells.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Metabolism
volume
2
issue
1
pages
9 pages
publisher
Springer Nature
external identifiers
  • scopus:85078074463
  • pmid:31993555
ISSN
2522-5812
DOI
10.1038/s42255-019-0158-0
language
English
LU publication?
yes
id
c5d5f180-7bcc-4357-abd4-d493aa623495
date added to LUP
2020-02-06 13:45:27
date last changed
2024-04-17 03:05:31
@article{c5d5f180-7bcc-4357-abd4-d493aa623495,
  abstract     = {{<p>Pancreatic islets are complex micro-organs consisting of at least three different cell types: glucagon-secreting alpha, insulin-producing beta and somatostatin-releasing delta cells. Somatostatin is a powerful paracrine inhibitor of insulin and glucagon secretion. In diabetes, increased somatostatinergic signalling leads to defective counter-regulatory glucagon secretion. This increases the risk of severe hypoglycaemia, a dangerous complication of insulin therapy. The regulation of somatostatin secretion involves both intrinsic and paracrine mechanisms but their relative contributions and whether they interact remain unclear. Here we show that dapagliflozin-sensitive glucose- and insulin-dependent sodium uptake stimulates somatostatin secretion by elevating the cytoplasmic Na<sup>+</sup> concentration (intracellular [Na<sup>+</sup>]; [Na<sup>+</sup>]<sub>i</sub>) and promoting intracellular Ca<sup>2+</sup>-induced Ca<sup>2+</sup> release. This mechanism also becomes activated when [Na<sup>+</sup>]<sub>i</sub> is elevated following the inhibition of the plasmalemmal Na<sup>+</sup>-K<sup>+</sup> pump by reductions of the extracellular K<sup>+</sup> concentration emulating those produced by exogenous insulin in vivo. 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<sup>+</sup> as an intracellular second messenger, illustrate the significance of the intra-islet paracrine network and provide a mechanistic framework for pharmacological correction of the hormone secretion defects associated with diabetes that selectively target the delta cells.</p>}},
  author       = {{Vergari, Elisa and Denwood, Geoffrey and Salehi, Albert and Zhang, Quan and Adam, Julie and Alrifaiy, Ahmed and Wernstedt Asterholm, Ingrid and Benrick, Anna and Chibalina, Margarita V. and Eliasson, Lena and Guida, Claudia and Hill, Thomas G. and Hamilton, Alexander and Ramracheya, Reshma and Reimann, Frank and Rorsman, Nils J.G. and Spilliotis, Ioannis and Tarasov, Andrei I. and Walker, Jonathan N. and Rorsman, Patrik and Briant, Linford J.B.}},
  issn         = {{2522-5812}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  pages        = {{32--40}},
  publisher    = {{Springer Nature}},
  series       = {{Nature Metabolism}},
  title        = {{Somatostatin secretion by Na<sup>+</sup>-dependent Ca<sup>2+</sup>-induced Ca<sup>2+</sup> release in pancreatic delta cells}},
  url          = {{http://dx.doi.org/10.1038/s42255-019-0158-0}},
  doi          = {{10.1038/s42255-019-0158-0}},
  volume       = {{2}},
  year         = {{2020}},
}