Somatostatin secretion by Na+-dependent Ca2+-induced Ca2+ release in 1 pancreatic delta-cells
<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 cells1. Somatostatin is a powerful paracrine inhibitor of insulin and glucagon secretion2. In diabetes, increased s...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Nature Research
2020
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| _version_ | 1826258614401105920 |
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| author | Vergari, E Denwood, G Salehi, A Rorsman, P Tarasov, A Adam, J Zhang, Q Chibalina, M Guida, C Ramracheya, R Hamilton, A Hill, T Briant, L et al. |
| author_facet | Vergari, E Denwood, G Salehi, A Rorsman, P Tarasov, A Adam, J Zhang, Q Chibalina, M Guida, C Ramracheya, R Hamilton, A Hill, T Briant, L et al. |
| author_sort | Vergari, E |
| collection | OXFORD |
| description | <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 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 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 vivo6. 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> |
| first_indexed | 2024-03-06T18:36:44Z |
| format | Journal article |
| id | oxford-uuid:0b80b104-324a-490b-bf2e-3df820e3c1cc |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:36:44Z |
| publishDate | 2020 |
| publisher | Nature Research |
| record_format | dspace |
| spelling | oxford-uuid:0b80b104-324a-490b-bf2e-3df820e3c1cc2022-03-26T09:29:47ZSomatostatin secretion by Na+-dependent Ca2+-induced Ca2+ release in 1 pancreatic delta-cellsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0b80b104-324a-490b-bf2e-3df820e3c1ccEnglishSymplectic Elements at OxfordNature Research2020Vergari, EDenwood, GSalehi, ARorsman, PTarasov, AAdam, JZhang, QChibalina, MGuida, CRamracheya, RHamilton, AHill, TBriant, Let al.<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 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 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 vivo6. 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> |
| spellingShingle | Vergari, E Denwood, G Salehi, A Rorsman, P Tarasov, A Adam, J Zhang, Q Chibalina, M Guida, C Ramracheya, R Hamilton, A Hill, T Briant, L et al. Somatostatin secretion by Na+-dependent Ca2+-induced Ca2+ release in 1 pancreatic delta-cells |
| title | Somatostatin secretion by Na+-dependent Ca2+-induced Ca2+ release in 1 pancreatic delta-cells |
| title_full | Somatostatin secretion by Na+-dependent Ca2+-induced Ca2+ release in 1 pancreatic delta-cells |
| title_fullStr | Somatostatin secretion by Na+-dependent Ca2+-induced Ca2+ release in 1 pancreatic delta-cells |
| title_full_unstemmed | Somatostatin secretion by Na+-dependent Ca2+-induced Ca2+ release in 1 pancreatic delta-cells |
| title_short | Somatostatin secretion by Na+-dependent Ca2+-induced Ca2+ release in 1 pancreatic delta-cells |
| title_sort | somatostatin secretion by na dependent ca2 induced ca2 release in 1 pancreatic delta cells |
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