Somatostatin Secretion by Na+-dependent Ca2+-induced Ca2+ Release in Pancreatic Delta-Cells.

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 1 . Somatostatin is a powerful paracrine inhibitor of insulin and glucagon secretion 2 . In diabetes, increased somatostatinergic signalling leads to defective counter-regulatory glucagon secretion 3 . This increases the risk of severe hypoglycaemia, a dangerous complication of insulin therapy 4 . The regulation of somatostatin secretion involves both intrinsic and paracrine mechanisms 5 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 Ca 2+ -induced Ca 2+ 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 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 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.