Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, and the Imperial Pancreatic Islet Biology and Diabetes Consortium, Hammersmith Hospital, Imperial College London, London, UK.
Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Edgbaston, UK.
Diabetes Obes Metab. 2017 Sep;19 Suppl 1:30-41. doi: 10.1111/dom.12990.
Ca is the key intracellular regulator of insulin secretion, acting in the β-cell as the ultimate trigger for exocytosis. In response to high glucose, ATP-sensitive K channel closure and plasma membrane depolarization engage a sophisticated machinery to drive pulsatile cytosolic Ca changes. Voltage-gated Ca channels, Ca -activated K channels and Na /Ca exchange all play important roles. The use of targeted Ca probes has revealed that during each cytosolic Ca pulse, uptake of Ca by mitochondria, endoplasmic reticulum (ER), secretory granules and lysosomes fine-tune cytosolic Ca dynamics and control organellar function. For example, changes in the expression of the Ca -binding protein Sorcin appear to provide a link between ER Ca levels and ER stress, affecting β-cell function and survival. Across the islet, intercellular communication between highly interconnected "hubs," which act as pacemaker β-cells, and subservient "followers," ensures efficient insulin secretion. Loss of connectivity is seen after the deletion of genes associated with type 2 diabetes (T2D) and follows metabolic and inflammatory insults that characterize this disease. Hubs, which typically comprise ~1%-10% of total β-cells, are repurposed for their specialized role by expression of high glucokinase (Gck) but lower Pdx1 and Nkx6.1 levels. Single cell-omics are poised to provide a deeper understanding of the nature of these cells and of the networks through which they communicate. New insights into the control of both the intra- and intercellular Ca dynamics may thus shed light on T2D pathology and provide novel opportunities for therapy.
钙是胰岛素分泌的关键细胞内调节剂，在β细胞中作为胞吐作用的最终触发因素。在高血糖的情况下，ATP 敏感性钾通道的关闭和质膜的去极化启动了一个复杂的机制，驱动脉冲式胞质钙离子变化。电压门控钙通道、钙激活钾通道和钠/钙交换都发挥着重要作用。靶向钙探针的使用表明，在每个胞质钙离子脉冲期间，线粒体、内质网（ER）、分泌颗粒和溶酶体对钙离子的摄取精细地调节了胞质钙离子动力学，并控制了细胞器的功能。例如，钙结合蛋白 Sorcin 的表达变化似乎为 ER 钙离子水平与 ER 应激之间提供了联系，影响β细胞的功能和存活。在胰岛中，高度相互连接的“中心”（作为起搏β细胞）和从属的“追随者”之间的细胞间通讯确保了有效的胰岛素分泌。在与 2 型糖尿病（T2D）相关的基因缺失后，这种连接性就会丢失，随后会发生代谢和炎症的损伤，这些损伤是这种疾病的特征。中心通常由总β细胞的 1%-10%组成，通过高葡萄糖激酶（Gck）但低 PDX1 和 NKX6.1 水平的表达，重新用于其特殊功能。单细胞组学有望更深入地了解这些细胞的性质，以及它们通过网络进行交流的方式。对细胞内和细胞间钙离子动力学的控制的新见解，可能会揭示 T2D 病理学的机制，并为治疗提供新的机会。
