Oscillation and Synchronization of Pancreatic Islet Activity

胰岛活动的振荡和同步

• 批准号: 0613179
• 负责人: Richard Bertram
• 金额: $ 19.05万
• 依托单位: Florida State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0613179&HistoricalAwards=false
• 关键词: Oscillation; Synchronization; Pancreatic; Islet; Activity

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.

这项研究的长期目标是了解β细胞分泌胰岛素的机​​制，β细胞聚集在胰腺内的朗格汉斯岛中。 β细胞以脉冲方式分泌胰岛素，脉冲周期约为五分钟。 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标是（1）更好地了解脉动胰岛素分泌的机制，以及（2）研究胰岛振荡器群体同步的潜在机制。 我们关注与细胞电活动耦合的糖酵解振荡，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显示线粒体变量振荡的合作实验室的数据。 从数学角度来看，该模型由两个相互耦合的振荡器组成，我们称之为双振荡器模型。 糖酵解是两种振荡器中最慢的，而细胞中的电爆发是更快的振荡器。 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。 胰腺含有大量胰岛，它们的活动必须同步，胰岛群释放的胰岛素才能振荡。 在该项目中，研究了两种同步机制。 一是胰内神经节周围神经夹带胰岛。 这将通过将周期性脉冲应用于双振荡器模型并识别夹带和夹带窗口的条件来进行研究。 另一种同步机制是胰岛素对β细胞上胰岛素受体的反馈。 这对模型胰岛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细胞未能根据血液中葡萄糖水平的变化分泌适量的胰岛素是导致II型糖尿病。因此，了解胰岛素分泌的生物学机制以及胰岛素分泌细胞的协调非常重要。 β细胞非常复杂，我们理解其行为的方法是将数学建模和计算机模拟与在合作实验室进行的实验研究相结合。本科生和研究生都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。 我们的目标是了解如何在细胞水平上实现适当的胰岛素分泌，然后将其扩展到了解 β 细胞功能障碍如何导致 II 型糖尿病。