Vergari Elisa, Denwood Geoffrey, Salehi Albert, Zhang Quan, Adam Julie, Alrifaiy Ahmed, Wernstedt Asterholm Ingrid, Benrick Anna, Chibalina Margarita V, Eliasson Lena, Guida Claudia, Hill Thomas G, Hamilton Alexander, Ramracheya Reshma, Reimann Frank, Rorsman Nils J G, Spilliotis Ioannis, Tarasov Andrei I, Walker Jonathan N, Rorsman Patrik, Briant Linford J B
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, Churchill Hospital, Oxford, UK.
Department of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden.
Nat Metab. 2020 Jan;2(1):32-40. doi: 10.1038/s42255-019-0158-0. Epub 2020 Jan 20.
Pancreatic islets are complex micro-organs consisting of at least three different cell types: glucagon-secreting α-, insulin-producing β- and somatostatin-releasing δ-cells. Somatostatin is a powerful paracrine inhibitor of insulin and glucagon secretion. In diabetes, increased somatostatinergic signalling leads to defective counter-regulatory glucagon secretion. This increases the risk of severe hypoglycaemia, a dangerous complication of insulin therapy. The regulation of somatostatin secretion involves both intrinsic and paracrine mechanisms 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]) and promoting intracellular Ca-induced Ca release (CICR). This mechanism also becomes activated when [Na] is elevated following the inhibition of the plasmalemmal Na-K pump by reductions of the extracellular K concentration emulating those produced by exogenous insulin . 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.
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。生长抑素是胰岛素和胰高血糖素分泌的一种强大的旁分泌抑制剂。在糖尿病中，生长抑素能信号增加会导致反调节性胰高血糖素分泌缺陷。这增加了严重低血糖的风险，低血糖是胰岛素治疗的一种危险并发症。生长抑素分泌的调节涉及内在机制和旁分泌机制，但其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钠浓度（[Na]）和促进细胞内钙诱导的钙释放（CICR）来刺激生长抑素分泌。当通过降低细胞外钾浓度模拟外源性胰岛素产生的情况来抑制质膜钠钾泵后[Na]升高时，该机制也会被激活。一些2型糖尿病供体的胰岛生长抑素分泌过多，导致胰高血糖素分泌受到抑制，而生长抑素受体拮抗剂可缓解这种抑制。我们的数据突出了钠作为细胞内第二信使的作用，阐明了胰岛内旁分泌网络的重要性，并为选择性靶向δ细胞的糖尿病相关激素分泌缺陷的药理学纠正提供了一个机制框架。
