Mathematical simulation of membrane processes and metabolic fluxes of the pancreatic β-cell
Mathematical simulation of membrane processes and metabolic fluxes of the pancreatic β-cell
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DOI：
10.1007/s11538-005-9053-9
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发表时间：
2006-10-01
影响因子：
3.5
通讯作者：
Diederichs, Frank
中科院分区：
文献类型：
--
作者：
Diederichs, Frank
开发了一种描述酶催化反应的新型方程，该方程允许描述处于或接近平衡和远离平衡的过程，因为它们都已知发生在活细胞中。这些方程将联合收割机动力学以及能量特征结合在一个单一方程中，并且它们描述了稳态以及振荡，如胰腺β细胞的葡萄糖代谢所示。可以详细描述氧化葡萄糖代谢的模拟，其允许详细分析胰腺β细胞的膜和代谢振荡是如何产生的，以及它们是如何动力学耦合的。葡萄糖代谢在静息葡萄糖浓度（[Glu]）为4 mM时表现出稳态行为。当[Glu]升高至10 mM时，葡萄糖激酶催化反应的电导首先增加，从而使稳态转变为振荡状态。事实上，这足以在胞内[Ca 2 +]恒定时降低胞浆腺苷二磷酸浓度（[ADP]（c））。ATP和ADP物质的相关变化可以降低ATP敏感性K+通道（K-ATP）的电导，从而引发细胞膜电位的爆发（三角形（c）phi），伴随着Ca 2+离子从细胞外空间流入细胞。[ADP]（c）、[Ca 2 +]（c）和所有其他变量（包括线粒体的变量）振荡的产生，一方面是由线粒体ATP产生的[Ca 2 +]（m）依赖性激活引起的，另一方面是由胞质溶胶中ATP利用的[Ca 2 +]（c）依赖性激活引起的。这两个过程必须以这样一种方式进行协调，即ATP的生产略早于其利用。振荡频率（快/慢）由通过丙酮酸脱氢酶和/或柠檬酸循环的通量的电导（分别为高/低）确定。模拟结果表明，所谓的丙酮酸悖论可能是由于相对较低的丙酮酸β细胞的膜电导。
A new type of equation to describe enzyme-catalyzed reactions was developed, which allows the description of processes both at or near equilibrium and far from equilibrium, as they are both known to occur in the living cell. These equations combine kinetic as well as energetic characteristics within one single equation, and they describe the steady state as well as oscillations, as is shown for the glucose metabolism of the pancreatic beta-cell. A simulation of oxidative glucose metabolism could be elaborated, which allows to analyse in detail, how membrane and metabolic oscillations of the pancreatic beta-cell are generated, and how they are kinetically coupled. Glucose metabolism shows steady-state behaviour at a resting glucose concentration ([Glu]) of 4 mM. The steady state is switched to the oscillatory state by a first increase of the conductance of the glucokinase-catalyzed reaction at an elevated [Glu] of 10 mM. This is in fact sufficient to decrease the cytosolic adenosine diphosphate concentration ([ADP](c)) at constant intracellular [Ca2+]. The associated changes of the ATP and ADP species can reduce the conductance of ATP-sensitive K+ channels (K-ATP), thereby initiating bursts of the cell membrane potential (triangle(c)phi) with a concomitant influx of Ca2+ ions from the extracellular space into the cell. The production of oscillations of [ADP](c), [Ca2+](c), and all other variables, including those of mitochondria, are brought about on the one hand by a [Ca2+](m) dependent activation of mitochondrial ATP production, on the other hand by a [Ca2+](c)-dependent activation of ATP utilisation in the cytosol. Both processes must be coordinated in such a way that ATP production slightly precedes its utilisation. Oscillatory frequencies (fast/slow) are determined by the conductance (high/low, respectively) of flux through pyruvate dehydrogenase and/or citric acid cycle. The simulation shows that the so-called pyruvate paradox possibly results from a relatively low membrane conductance of beta-cells for pyruvate.