Intercellular communication in pseudoislets: shaping the dynamics of insulin secretion

葡萄糖是人体能量的主要来源。当我们吃东西的时候，食物最终会被分解成必需的葡萄糖，因此，在一整天的过程中，血液中的葡萄糖含量会发生变化。过高或过低的血糖水平都可能导致潜在的危及生命的情况。血糖水平由两种关键的化学物质调节：降低血糖水平的胰岛素和提高血糖水平的胰高血糖素。这两种物质都是在人体中被称为朗格汉斯岛的结构中自然产生的，它位于胰腺中。在胰岛内，β细胞负责胰岛素的产生和分泌。胰岛素的分泌依赖于胰岛内所有细胞的同步电活动，这是通过它们之间的交流来实现的。这种交流主要是由于相邻细胞之间的物理连接而产生的。如果这些连接被破坏，胰岛分泌足够胰岛素来适当调节血糖的能力可能会受到损害。两种形式的糖尿病都与胰岛正常功能的丧失有关。在1型糖尿病中，β细胞被人体自身的免疫细胞破坏。低于临界的β细胞质量，身体就不能再调节血糖水平，患者就会依赖于外部产生的胰岛素。在2型糖尿病中，功能变化更为微妙，但可能是由胰岛同步电反应的中断引起的。一种潜在的1型糖尿病新疗法是将β细胞移植到患者体内，以弥补患者自身细胞的损失。我们现在有能力在实验室里模拟朗格汉斯胰岛的结构中培养人类β细胞。这使我们能够研究细胞之间的确切耦合，并观察整个胰岛的活动同步。我们还可以改变实验室培养的胰岛的大小、形状和细胞间的耦合。这样做，我们可以严格检查细胞之间的连接如何定量地影响胰岛内胰岛素的分泌。生物网络的数学模型为简化大型细胞网络的分析提供了强大的工具。这些模型是通过考虑β细胞内部和细胞之间发生的关键生物物理过程的数学描述来构建的。一旦发展起来，它们可以用来研究观察到的行为背后的机制，更重要的是，它们提供了关于1型和2型糖尿病期间细胞间通信变化如何影响胰岛胰岛素分泌的预测。重要的是，细胞之间的联系最近被强调为治疗这两种疾病的潜在靶点。然后将通过在实验室培养的胰岛上进行类似的改变来测试模型的预测。利用数学模型，该项目将研究1型糖尿病的预后，考虑细胞通讯是如何被破坏的，因为β细胞被破坏，以及这如何影响胰岛的分泌特性。它还将确定胰岛胰岛素分泌的最佳大小和配置，以帮助开发1型糖尿病的移植疗法。

Glucose is the primary source of energy for the human body. When we eat, food is ultimately broken down into the necessary glucose and so, over the course of a full day, the amount of glucose in the blood varies. Both too high and too low blood glucose levels can cause potentially life threatening conditions. Blood glucose levels are regulated by two key chemicals: insulin, which lowers the level, and glucagon, which raises it. Both of these are produced naturally in the body in structures known as the islets of Langerhans, which are located in the pancreas.Within the islets, the beta cells are responsible for the production and secretion of insulin. Insulin secretion is dependent on the synchronised electrical activity of all beta cells within an islet, which is achieved through communication between them. This communication arises primarily due to physical connections between neighbouring cells. If these connections are disrupted, the ability of the islets to secrete enough insulin to properly regulate blood glucose may become compromised.Both forms of diabetes are associated with a loss of proper functioning of the islets. In type 1 diabetes, the beta cells are destroyed by the body's own immune cells. Below a critical beta cell mass, the body can no longer regulate blood glucose levels and patients become reliant on the administration of externally produced insulin. In type 2 diabetes, the functional changes are more subtle but may be caused by disruptions to the synchronised electrical response across an islet. One potential new therapy for type 1 diabetes involves the transplantation of beta cells into patients to compensate for the loss of their own cells.We now have the capability to grow human beta cells in structures that mimic the islets of Langerhans in laboratories. This allows us to study the exact coupling between cells and observe the synchronisation of activity across the islet. We can also alter the laboratory grown islets in terms of their size, shape and the coupling between cells within them. In doing so, we can rigorously examine how how the connections between the cells quantitatively affect the secretion of insulin within an islet.Mathematical models of biological networks provide powerful tools to simplify the analysis of large networks of cells. These models are constructed by considering mathematical descriptions of key biophysical processes that occur within and between the beta cells. Once developed, they can be used to investigate the mechanisms behind observed behaviours and, more importantly, they offer predictions about how changes to the communication between cells that occur during type 1 and 2 diabetes affect the secretion of insulin from the islet. Importantly, the connections between cells have been recently been highlighted as potential target for treatment of both forms of the disease. The predictions from the model will then be tested by performing similar alterations in the lab-grown islet.Using the mathematical model, this project will investigate the prognoses of type 1 diabetes by considering how cellular communication is disrupted as the beta cells are destroyed, and how this impacts upon the secretory properties of the islets. It will also identify optimal sizes and configurations of islets with respect to insulin secretion to aid in the development of transplantation therapies for type 1 diabetes.