A Mathematical Study of the Biochemical and Electrical Dynamics of Pancreatic Islets

胰岛生化和电动力学的数学研究

• 批准号: 0917664
• 负责人: Richard Bertram
• 金额: $ 23.75万
• 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: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0917664&HistoricalAwards=false
• 关键词: Mathematical; Study; Biochemical; Electrical; Dynamics

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5). The long-term goal of this research project is to understand how the many subsystems of the pancreatic beta-cell interact to produce insulin oscillations in mice (rats and humans also exhibit oscillations). These oscillations are crucial for the normal regulation of blood glucose levels, and loss of oscillations is linked to type II diabetes. Rhythmic insulin secretion from pancreatic islets of Langerhans is due to rhythmic bursting electrical activity in the beta-cells, and a consequent rhythm in the intracellular calcium concentration. Both the intracellular calcium and adenosine triphosphate (ATP) feed back onto the cell's electrical subsystem, opening or closing ion channels and thus affecting the cell's electrical activity. This project focuses on the metabolic subsystem that produces ATP, and on a mathematical analysis of previously-developed models of metabolismdriven bursting and the fast electrical bursting that occurs in single beta-cells that are isolated from the islet. The central hypothesis is that the slow electrical bursting oscillations and episodic bursting that are often exhibited by pancreatic islets, and that have the same period as insulin oscillations observed in vivo, are driven by oscillations in metabolism. One mechanism for these oscillations is in glycolysis, the first stage of glucose metabolism. However, it is possible that oscillations inherent in one of the other two stages of metabolism, the citric acid cycle and oxidative phosphorylation, could be the slow process that drives slow bursting activity and that clusters faster bursts together into periodic episodes. This possibility will be investigated using mathematical modeling and analysis, as will what measurements of periodicity in citric acid cycle intermediates indicate about the mechanism of the oscillations. Returning to the glycolytic component of metabolism, modeling studies will be conducted in parallel with experimental studies in a collaborating laboratory to determine how the enzyme phosphosphofructokinase-2 (PFK-2) may modulate glycolytic oscillations.Insulin secretion in mammals, including rats, humans, dogs, and humans, is pulsatile, with a period of about five minutes. These insulin oscillations, which can be measured in the blood, are important for normal glucose homeostasis, since disruption of the oscillations is linked to type II diabetes. Insulin is secreted from micro-organs in the pancreas called Islets of Langerhans, composed largely of insulin-secreting beta-cells. For more than a decade now, the principal investigator has been investigating the biophysical mechanism for the oscillations in insulin secretion. This research involves mathematical modeling and analysis, and parallel experimental studies in a collaborating laboratory. It is thus a truly multidisciplinary project. The current project uses a current mathematical model of pancreatic beta-cells to understand how oscillations in the metabolism of glucose by the beta-cells can lead to oscillations in the electrical activity and insulin secretion from the beta-cells. In addition, bifurcation analysis and recent mathematical methods in the area of Mixed Mode Oscillations will be used to understand the oscillatory electrical activity of beta-cells that have been isolated from an islet. The intention is to determine, using this mathematical analysis, how single-cell behavior is converted to the very different behavior of beta-cells in an intact islet. The long-term goal of this research is to better understand the normal functioning of islets, which will ultimately provide insights into the dysfunction of islets that occurs in type II diabetes.

该奖项是根据2009年《美国复苏与再投资法》（公法111-5）资助的。该研究项目的长期目标是了解胰腺β细胞的许多子系统如何相互作用以在小鼠中产生胰岛素振荡（大鼠和人类也表现出振荡）。这些振荡对于血糖水平的正常调节至关重要，振荡的丧失与II型糖尿病有关。 Langerhans胰岛的节奏胰岛素分泌是由于β细胞中的节奏爆发电活动引起的，因此在细胞内钙浓度中产生了节奏。 细胞内钙和三磷酸腺苷（ATP）都反馈到细胞的电源子系统，打开或关闭离子通道，从而影响细胞的电活动。该项目的重点是产生ATP的代谢子系统，以及对先前开发的代谢驱动爆发模型的数学分析以及在与小岛分离的单个β细胞中发生的快速电爆发。 中心假设是，胰岛通常表现出的缓慢的电爆发振荡和情节爆发，并且与体内观察到的胰岛素振荡相同的时期是由代谢中的振荡驱动的。这些振荡的一种机制是糖酵解，这是葡萄糖代谢的第一阶段。然而，在其他两个代谢之一，柠檬酸周期和氧化磷酸化的其他两个阶段之一中固有的振荡可能是驱动缓慢爆发活性的慢速过程，并且该促进速度更快地爆发成周期性发作。这种可能性将使用数学建模和分析进行研究，柠檬酸循环中间体中周期性的测量值也表明了振荡的机理。返回代谢的糖酵解成分，将与合作实验室中的实验研究并行进行建模研究，以确定磷酸果果酶动物酶-2（PFK-2）如何调节糖酵解振荡，可能会在包括大鼠，狗，人类和人类的pulss pulssakiles，unsakiles，unsakiles，unsakiles，unsakiles，unsakiles，unsakiles，unsakiles，unsakiles，unsakiles，unsakiles，unsakit，usats pulssats pulssats pulssats pulssats pulssatike中。这些可以在血液中测量的胰岛素振荡对于正常的葡萄糖稳态很重要，因为振荡的破坏与II型糖尿病有关。胰岛素是从兰格汉胰岛中的微孔分泌的，该胰岛在很大程度上由分泌胰岛素的β细胞组成。十多年来，主要研究人员一直在研究胰岛素分泌振荡的生物物理机制。这项研究涉及数学建模和分析，以及合作实验室中的平行实验研究。因此，这是一个真正的多学科项目。当前的项目使用胰腺β细胞的当前数学模型来了解β细胞在葡萄糖代谢中的振荡如何导致电活动的振荡和β细胞的胰岛素分泌。此外，混合模式振荡区域中的分叉分析和最近的数学方法将用于了解已从胰岛分离的β细胞的振荡电活动。目的是使用此数学分析确定单细胞行为如何转换为完整胰岛中β细胞的完全不同的行为。这项研究的长期目标是更好地了解胰岛的正常功能，这最终将提供有关II型糖尿病中胰岛功能障碍的见解。