Glucose sensing in the pancreatic beta cell: a computational systems analysis.
Glucose sensing in the pancreatic beta cell: a computational systems analysis.
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DOI：
10.1186/1742-4682-7-15
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发表时间：
2010-05-24
影响因子：
--
通讯作者：
Philipson LH
中科院分区：
文献类型：
--
作者：
Fridlyand LE;Philipson LH
胰岛β细胞对血糖升高的反应是通过增加氧化代谢，导致细胞质中的ATP/ADP比率增加。这导致KATP通道关闭，质膜去极化，钙内流，最终分泌胰岛素。这种机制表明，β细胞代谢应该具有特定于分泌的功能调节，而不是耦合到收缩。这项工作的目标是用系统生物学的方法进行数学建模，揭示细胞质和线粒体过程在这种分泌耦合机制中的作用。我们描述了一个β细胞对葡萄糖敏感性的数学模型。该模型的细胞质部分包括描述葡萄糖激酶、糖酵解、丙酮酸还原、NADH和ATP生产和消耗的方程。线粒体部分从NADH的产生开始，NADH由丙酮酸脱氢酶调节。NADH在电子传递链中被用来建立质子动力，驱动F1F0 ATPase。还模拟了氧化还原穿梭和线粒体钙离子的处理。该模型正确地预测了ATP/ADP比率、Ca~(2+)和其他代谢参数的变化，以响应在稳态和细胞质Ca~(2+)振荡期间底物输送的变化。我们对模型模拟的分析表明，与其他类型的细胞相比，β细胞的线粒体膜电位应该相对较低，以允许线粒体精确调节细胞质的ATP/ADP比率。这一关键差异可能源于呼吸活动的相对减少。该模型展示了乳酸脱氢酶、解偶联蛋白和氧化还原穿梭的活性如何协同调节β细胞的功能；细胞质钙离子的独立振荡可以导致缓慢的耦合代谢振荡；在生理条件下，β细胞中活性氧的产生速率相对较低是线粒体膜电位相对降低的结果。这一综合模型预测了线粒体控制机制在胰岛素分泌和β细胞中ROS生成中的特殊作用。该模型可用于测试和生成控制假说，并将有助于对胰腺β细胞的生理和病理中心的β细胞葡萄糖传感提供更完整的理解。
Pancreatic beta-cells respond to rising blood glucose by increasing oxidative metabolism, leading to an increased ATP/ADP ratio in the cytoplasm. This leads to a closure of KATP channels, depolarization of the plasma membrane, influx of calcium and the eventual secretion of insulin. Such mechanism suggests that beta-cell metabolism should have a functional regulation specific to secretion, as opposed to coupling to contraction. The goal of this work is to uncover contributions of the cytoplasmic and mitochondrial processes in this secretory coupling mechanism using mathematical modeling in a systems biology approach. We describe a mathematical model of beta-cell sensitivity to glucose. The cytoplasmic part of the model includes equations describing glucokinase, glycolysis, pyruvate reduction, NADH and ATP production and consumption. The mitochondrial part begins with production of NADH, which is regulated by pyruvate dehydrogenase. NADH is used in the electron transport chain to establish a proton motive force, driving the F1F0 ATPase. Redox shuttles and mitochondrial Ca2+ handling were also modeled. The model correctly predicts changes in the ATP/ADP ratio, Ca2+ and other metabolic parameters in response to changes in substrate delivery at steady-state and during cytoplasmic Ca2+ oscillations. Our analysis of the model simulations suggests that the mitochondrial membrane potential should be relatively lower in beta cells compared with other cell types to permit precise mitochondrial regulation of the cytoplasmic ATP/ADP ratio. This key difference may follow from a relative reduction in respiratory activity. The model demonstrates how activity of lactate dehydrogenase, uncoupling proteins and the redox shuttles can regulate beta-cell function in concert; that independent oscillations of cytoplasmic Ca2+ can lead to slow coupled metabolic oscillations; and that the relatively low production rate of reactive oxygen species in beta-cells under physiological conditions is a consequence of the relatively decreased mitochondrial membrane potential. This comprehensive model predicts a special role for mitochondrial control mechanisms in insulin secretion and ROS generation in the beta cell. The model can be used for testing and generating control hypotheses and will help to provide a more complete understanding of beta-cell glucose-sensing central to the physiology and pathology of pancreatic β-cells.
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影响因子：
9.8
作者：
Bordone L;Motta MC;Picard F;Robinson A;Jhala US;Apfeld J;McDonagh T;Lemieux M;McBurney M;Szilvasi A;Easlon EJ;Lin SJ;Guarente L
通讯作者：
Guarente L
影响因子：
4.1
作者：
Amo, Taku;Brand, Martin D.
通讯作者：
Brand, Martin D.
影响因子：
7.7
作者：
Ainscow, EK;Rutter, GA
通讯作者：
Rutter, GA
影响因子：
4.1
作者：
Affourtit, Charles;Brand, Martin D.
通讯作者：
Brand, Martin D.
DOI：
10.1152/ajpendo.00347.2001
发表时间：
2002-05-01
影响因子：
5.1
作者：
Arredouani, A;Henquin, JC;Gilon, P
通讯作者：
Gilon, P