The role of NAADP and the two-pore channel proteins in mediating insulin secretion in pancreatic beta cells

葡萄糖是我们身体细胞的重要燃料，使它们能够发挥许多功能。饭后，葡萄糖从我们的肠道进入血液，然后被输送到胰腺。一组被称为胰腺细胞的特殊细胞通过释放激素胰岛素来应对血液中葡萄糖水平的升高。胰岛素随后由血液运送到身体的器官，在那里它与细胞表面的特定蛋白质或受体结合，并在每个细胞内触发一系列化学反应，促进葡萄糖运输到细胞内作为燃料或储存。葡萄糖如何刺激胰岛素释放是一个关键问题，因为这一机制的缺陷是导致2型糖尿病的原因。糖尿病与细胞葡萄糖摄取减少和血液中长期高水平葡萄糖有关，导致多种病理事件。细胞周围膜上的一组关键蛋白质被称为钾通道。它们在葡萄糖的摄取和代谢反应中关闭，也在一些抗糖尿病药物治疗后关闭，导致电变化，导致β细胞内钙离子增加。钙离子作为一种信号，促进胰岛素从细胞内的储存颗粒释放到血液中。然而，现在有证据表明葡萄糖也可能通过独立于这些钾通道的机制触发胰岛素释放。我们的初步研究表明，一个重要的附加机制可能与一种叫做NAADP的分子有关，这种分子在β细胞内产生，以应对葡萄糖水平升高，然后从细胞内储存的钙中释放出来，促进胰岛素释放。最近，我们通过鉴定细胞中NAADP的靶受体是双孔通道（TPC）蛋白，取得了重大进展。我们建议研究如何在β细胞中控制NAADP的产生，并发现它作用于TPCs和其他相关信号蛋白以刺激胰岛素释放的精确方式。因此，我们的工作应该揭示参与胰岛素释放的新分子成分，这些成分可能在糖尿病中受损，并可能代表治疗这种疾病的药物的新靶点。

Glucose is an important fuel for the cells of our bodies, allowing them to carry out their many functions. After a meal, glucose passes from our gut into the blood where it is carried to the pancreas. A set of specialized cells called pancreatic beta-cells respond to the increase of glucose levels in the blood by releasing the hormone insulin. Insulin is then carried by the blood to the organs of the body where it binds to a specific protein or receptor on the surface of cells and triggers a cascade of chemical events inside each cell to promote glucose transport into the cell for use as a fuel or for storage. How glucose stimulates insulin release is a key question, since a defect in this mechanism is responsible for type 2 diabetes. Diabetes is associated with decreased glucose uptake into cells, and chronically high levels of glucose in the blood, leading to multiple pathological events. One set of key proteins in the membranes surrounding beta-cells are called potassium channels. These close in response to uptake and metabolism of glucose, and also after treatment with some anti-diabetic drugs, leading to electrical changes resulting in an increase of calcium ions inside the beta-cell. Calcium ions act as a signal to promote release of insulin from storage granules from inside the cells into the blood. However, there is now evidence that glucose may also trigger insulin release by mechanisms independent of these potassium channels. Our preliminary work has shown that an important additional mechanism may involve a molecule called NAADP, which is generated inside the beta-cell in response to raised glucose levels and then releases calcium from internal stores within the cell to promote insulin release. Recently we made a major step forward by identifying the target receptor for NAADP in the cell as being the two-pore channel (TPC) proteins. We propose to study how production of NAADP is controlled in beta-cells and discover the precise way in which it acts upon the TPCs and other connected signalling proteins to stimulate release of insulin. Our work should thus uncover new molecular components involved in insulin release which may be impaired in diabetes and may represent new targets for drugs in the treatment of this disease.