| Autor: |
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, Rorsman, Linford J B, Briant |
| Rok vydání: |
2020 |
| Předmět: |
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| Zdroj: |
Nature metabolism |
| ISSN: |
2522-5812 |
| Popis: |
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. 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 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 intraislet paracrine network and provide a mechanistic framework for pharmacological correction of the hormone secretion defects associated with diabetes that selectively target the δ-cells. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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