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 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.