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.

该奖项根据 2009 年《美国复苏和再投资法案》（公法 111-5）提供资金。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体内产生胰岛素振荡（大鼠和人类也表现出胰岛素振荡）。这些振荡对于血糖水平的正常调节至关重要，而振荡的丧失与 II 型糖尿病有关。朗格汉斯胰岛有节律的胰岛素分泌是由于β细胞中有节律的爆发性电活动以及随之而来的细胞内钙浓度的节律。 细胞内钙和三磷酸腺苷 (ATP) 都会反馈到细胞的电子系统，打开或关闭离子通道，从而影响细胞的电活动。该项目重点关注产生 ATP 的代谢子系统，并对先前开发的代谢驱动爆发模型和从胰​​岛分离的单个 β 细胞中发生的快速电爆发模型进行数学分析。 核心假设是，胰岛经常表现出的缓慢电爆发振荡和偶发爆发，并且与体内观察到的胰岛素振荡具有相同的周期，是由代谢振荡驱动的。这些振荡的一个机制是糖酵解，即葡萄糖代谢的第一阶段。然而，代谢的其他两个阶段之一（柠檬酸循环和氧化磷酸化）固有的振荡可能是驱动缓慢爆发活动的缓慢过程，并且将更快的爆发聚集在一起形成周期性发作。将使用数学建模和分析来研究这种可能性，以及柠檬酸循环中间体的周期性测量表明振荡机制。回到代谢的糖酵解部分，模型研究将与合作实验室的实验研究同时进行，以确定磷酸果糖激酶-2 (PFK-2) 如何调节糖酵解振荡。哺乳动物（包括大鼠、人类）的胰岛素分泌狗和人类都是脉动的，周期约为五分钟。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。胰岛素是由胰腺中称为胰岛的微器官分泌的，该微器官主要由分泌胰岛素的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波动的生物物理机制。这项研究涉及数学建模和分析，以及合作实验室的并行实验研究。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细胞葡萄糖代谢的振荡如何导致β细胞电活动和胰岛素分泌的振荡。此外，混合模式振荡领域的分叉分析和最新数学方法将用于了解从胰岛分离的β细胞的振荡电活动。目的是利用这种数学分析确定单细胞行为如何转化为完整胰岛中β细胞的非常不同的行为。这项研究的长期目标是更好地了解胰岛的正常功能，这最终将深入了解 II 型糖尿病中出现的胰岛功能障碍。