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Intercellular communication in pseudoislets: shaping the dynamics of insulin secretion

伪胰岛的细胞间通讯：塑造胰岛素分泌的动态

基本信息

批准号：
MR/P01478X/1
负责人：
Kyle Wedgwood
金额：
$ 51.09万
依托单位：
UNIVERSITY OF EXETER
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FP01478X%2F1
关键词：
Intercellular communication pseudoislets shaping dynamics

项目摘要

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.

葡萄糖是人体能量的主要来源。当我们吃东西时，食物最终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。过高和过低的血糖水平都可能导致潜在的危及生命的疾病。血糖水平受两种关键化学物质调节：降低血糖水平的胰岛素和升高血糖水平的胰高血糖素。这两种物质都是在人体内位于胰腺内的胰岛结构中自然产生的。胰岛内的β细胞负责胰岛素的产生和分泌。胰岛素分泌依赖于胰岛内所有β细胞的同步电活动，这是通过它们之间的通信实现的。这种通信主要是由于相邻小区之间的物理连接而产生的。如果这些连接被破坏，胰岛分泌足够的胰岛素以适当调节血糖的能力可能会受到损害。这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细胞被身体自身的免疫细胞破坏。低于临界β细胞质量，身体不能再调节血糖水平，患者变得依赖于外部产生的胰岛素的管理。在2型糖尿病中，功能变化更为微妙，但可能是由胰岛上同步电反应的中断引起的。1型糖尿病的一种潜在的新疗法是将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中模拟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活动的同步性。我们还可以改变实验室培养的胰岛的大小，形状和其中细胞之间的耦合。这样，我们就可以严格地研究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有力的工具。这些模型是通过考虑β细胞内和β细胞之间发生的关键生物物理过程的数学描述来构建的。一旦开发出来，它们可用于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型糖尿病期间细胞之间通信的变化如何影响胰岛分泌胰岛素的预测。重要的是，细胞之间的连接最近被强调为治疗这两种疾病的潜在靶点。该模型的预测将通过在实验室培养的胰岛中进行类似的改变来进行测试。使用数学模型，该项目将通过考虑β细胞被破坏时细胞通讯如何中断以及这如何影响胰岛的分泌特性来研究1型糖尿病的发病情况。它还将确定与胰岛素分泌有关的胰岛的最佳大小和构型，以帮助开发1型糖尿病的移植疗法。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bump Attractors and Waves in Networks of Leaky Integrate-and-Fire Neurons

泄漏集成和激发神经元网络中的凹凸吸引子和波

DOI：
10.1137/20m1367246
发表时间：
2023
期刊：
SIAM Review
影响因子：
10.2
作者：
Avitabile D
通讯作者：
Avitabile D

Spatial distribution of heterogeneity as a modulator of collective dynamics in pancreatic beta-cell networks and beyond.

异质性的空间分布作为胰腺β细胞网络及其他区域集体动力学的调节剂。

DOI：
10.3389/fnetp.2023.1170930
发表时间：
2023
期刊：
Frontiers in network physiology
影响因子：
0
作者：
Galvis D
通讯作者：
Galvis D

Investigation of the utility of the 1.1B4 cell as a model human beta cell line for study of persistent enteroviral infection.

DOI：
10.1038/s41598-021-94878-y
发表时间：
2021-08-02
期刊：
Scientific reports
影响因子：
4.6
作者：
Chaffey JR;Young J;Leslie KA;Partridge K;Akhbari P;Dhayal S;Hill JL;Wedgwood KCA;Burnett E;Russell MA;Richardson SJ;Morgan NG
通讯作者：
Morgan NG

Mathematical Modelling in Plant Biology