Oscillation and Synchronization of Pancreatic Islet Activity

这项研究的长期目标是了解β细胞分泌胰岛素的机制，β细胞聚集在胰腺的朗格汉斯胰岛中。β细胞以脉动的方式分泌胰岛素，脉冲周期约为5分钟。在糖尿病患者及其近亲中观察到这种振荡模式的破坏。该项目的两个主要目的是：(1)更好地了解搏动胰岛素分泌的机制；(2)研究胰岛振荡子群体同步的潜在机制。我们专注于糖酵解的振荡，与细胞的电活动耦合，作为脉动胰岛素分泌的机制。这是基于文献中的数据和来自合作实验室的数据，显示了线粒体变量的振荡。从数学角度看，该模型由两个相互耦合的振子组成，我们称之为双振子模型。糖酵解是两种振荡中最慢的，而细胞内的电破裂是较快的振荡。我们的大部分分析都集中在这个双振荡器系统的动力学上。胰腺包含大量的胰岛，它们的活动必须同步，才能使胰岛群的胰岛素释放振荡。在这个项目中，研究了两种同步机制。一种是胰腺内神经节周围神经对胰岛的夹带。这将通过将周期脉冲应用于双振荡器模型并确定夹带和夹带窗口的条件来研究。另一种同步机制是胰岛素反馈到β细胞上的胰岛素受体。这在模型小岛上提供了相对较弱的耦合效应，但它可能足够强以实现同步。β细胞分泌适量胰岛素以应对血液中葡萄糖水平的变化是II型糖尿病的一个主要因素。因此，了解胰岛素分泌的生物学机制以及胰岛素分泌细胞之间的协调是非常重要的。β细胞非常复杂，我们理解它们行为的方法是将数学建模和计算机模拟与实验研究结合起来，在合作实验室进行。本科生和研究生都将参与数学建模和计算机模拟，并将与实验合作者会面，讨论由建模驱动的数据和未来的实验。我们的目标是了解正确的胰岛素分泌是如何在细胞水平上实现的，然后扩展到了解β细胞功能障碍是如何导致II型糖尿病的。

The long-term goal of this research is to understand the mechanism of insulin secretion from beta-cells, which are clustered into islets of Langerhans within the pancreas. Beta-cells secrete insulin in a pulsatile fashion, with pulse period of approximately five minutes. Disruption of this oscillatory pattern is observed in diabetics and their near relatives. The two primary aims of this project are (1) to better understand the mechanism for pulsatile insulin secretion, and (2) to investigate potential mechanisms for the synchronization of the population of islet oscillators. We focus on oscillations in glycolysis, coupled to the electrical activity of the cell, as a mechanism for pulsatile insulin secretion. This is based on data in the literature and from a collaborating lab showing oscillations in mitochondrial variables. From a mathematical viewpoint, the model consists of two mutually coupled oscillators, which we call a dual-oscillator model. Glycolysis is the slowest of the two oscillators, while electrical bursting in the cell is the faster oscillator. Much of our analysis focuses on the dynamics of this dual-oscillator system. The pancreas contains a large number of islets, and their activity must be synchronized for the insulin release from the islet population to be oscillatory. In this project, two mechanisms for synchronization are investigated. One is the entrainment of islets by peripheral nerves in intrapancreatic ganglia. This will be investigated by applying periodic pulses to the dual-oscillator model and identifying conditions for entrainment and entrainment windows. The other synchronization mechanism is the feedback of insulin onto insulin receptors on the beta-cells. This provides a relatively weak coupling effect on the model islets, but it may be sufficiently strong to achieve synchronization.Failure of beta-cells to secrete the proper amount of insulin in response to changes in the glucose level in the blood is a major factor for type II diabetes. For this reason, it is important to understand the biological mechanism for insulin secretion, and the coordination of the insulin-secreting cells. The beta-cells are very complex, and our approach to understanding their behavior is to combine mathematical modeling and computer simulations with experimental studies, performed at a collaborating lab. Both undergraduate and graduate students are involved in the mathematical modeling and computer simulations, and will meet with experimental collaborators to discuss data and future experiments motivated by the modeling. Our goal is to understand how proper insulin secretion is achieved at the cellular level, and then extend this to understand how beta-cell disfunctions can lead to type II diabetes.