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 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 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.

中文翻译：

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Na+ 依赖性 Ca2+ 诱导的胰腺 δ 细胞中 Ca2+ 释放的生长抑素分泌。

胰岛是复杂的微器官，由至少三种不同的细胞类型组成：分泌胰高血糖素的 α 细胞、产生胰岛素的 β 细胞和释放生长抑素的 δ 细胞1。生长抑素是一种强大的胰岛素和胰高血糖素分泌旁分泌抑制剂2。在糖尿病中，生长抑素能信号增加会导致反调节胰高血糖素分泌缺陷 3。这会增加严重低血糖的风险，这是胰岛素治疗的一种危险并发症 4。生长抑素分泌的调节涉及内在和旁分泌机制，但它们的相对贡献以及它们是否相互作用仍不清楚。在这里，我们表明达格列净敏感的葡萄糖和胰岛素依赖性钠摄取通过提高细胞质 Na+ 浓度 ([Na+]i) 和促进细胞内 Ca2+ 诱导的 Ca2+ 释放 (CICR) 来刺激生长抑素分泌。当通过减少细胞外 K+ 浓度来抑制质膜 Na+-K+ 泵后 [Na+]i 升高时，这种机制也会被激活，这模拟了体内外源性胰岛素产生的 K+ 浓度 6. 来自一些 2 型糖尿病高分泌生长抑素的供体的胰岛，导致抑制胰高血糖素分泌，可通过生长抑素受体拮抗剂缓解。我们的数据强调了 Na+ 作为细胞内第二信使的作用，