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

Elisa Vergari, Geoffrey Denwood, Albert Salehi, Quan Zhang, Julie Adam, Ahmed Alrifaiy, Ingrid Wernstedt Asterholm, Anna Benrick, Margarita V. Chibalina, Lena Eliasson, Claudia Guida, Thomas G. Hill, Alexander Hamilton, Reshma Ramracheya, Frank Reimann, Nils J.G. Rorsman, Ioannis Spilliotis, Andrei I. Tarasov, Jonathan N. Walker, Patrik RorsmanLinford J.B. Briant

Research output: Contribution to journalLetter

2 Citations (Scopus)

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 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+ 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 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+ 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.

Original languageEnglish
Pages (from-to)32-40
Number of pages9
JournalNature Metabolism
Volume2
Issue number1
DOIs
Publication statusPublished - 1 Jan 2020

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    Vergari, E., Denwood, G., Salehi, A., Zhang, Q., Adam, J., Alrifaiy, A., Wernstedt Asterholm, I., Benrick, A., Chibalina, M. V., Eliasson, L., Guida, C., Hill, T. G., Hamilton, A., Ramracheya, R., Reimann, F., Rorsman, N. J. G., Spilliotis, I., Tarasov, A. I., Walker, J. N., ... Briant, L. J. B. (2020). Somatostatin secretion by Na+-dependent Ca2+-induced Ca2+ release in pancreatic delta cells. Nature Metabolism, 2(1), 32-40. https://doi.org/10.1038/s42255-019-0158-0