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细胞的胰岛素分泌机制，这些机制被聚集在胰腺内的兰格汉斯胰岛中。 β细胞以脉动的方式分泌胰岛素，脉搏周期约为五分钟。 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的是（1）更好地了解脉冲胰岛素分泌的机制，以及（2）研究胰岛振荡器种群同步的潜在机制。 我们专注于糖酵解中的振荡，耦合到细胞的电活动，作为脉冲胰岛素分泌的一种机制。这是基于文献中的数据和协作实验室，显示了线粒体变量中的振荡。 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。 糖酵解是两个振荡器中最慢的，而电池中电爆裂的速度更快。 我们的大部分分析都集中在此双振荡器系统的动态上。 胰腺包含大量胰岛，其活性必须同步，以使胰岛素从胰岛群体释放，才能具有振荡性。 在该项目中，研究了两种用于同步的机制。 一种是外周神经中神经内神经节中胰岛的夹带。 这将通过将定期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研究。 另一个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，但是实现同步可能足够强。β细胞的效果分泌适当的胰岛素，以响应血液中葡萄糖水平的变化，这是II型糖尿病型的主要因素。因此，重要的是要了解胰岛素分泌的生物学机制以及分泌胰岛素分泌细胞的协调。 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协作实验室进行的实验研究结合在一起。本科生和研究生都参与了数学建模和计算机模拟，并将与实验合作者会面，讨论由建模动机的数据和未来实验。 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，然后扩展以了解β细胞的失调如何导致II型糖尿病。