INTEGRATIVE APPROACH TO UNDERSTAND ETIOLOGY & CAUSES OF TYPE II DIABETES

葡萄糖激酶（GK）已被证明发挥作用的葡萄糖 胰腺B细胞中的传感器，凭借其作为速率的作用， 糖酵解的控制步骤。 GK也有着极高的控制力 强度对葡萄糖诱导的胰岛素分泌的影响。 这种方法导致 直到这些重要的发现是定量的和数学的 GK动力学建模。 葡萄糖必须先于胰岛素代谢 分泌被刺激，并且其之间的偶联因子 代谢和导致胞吐作用的离子事件 含有胰岛素的颗粒是细胞的能量状态， [ATP]/[ADP]。 Dukes [1994]和MacDonald [1990]提出， 作为胰岛素刺激物的ATP产生的主要来源 释放是由糖酵解衍生的NADH产生的， 穿梭进入线粒体并被氧化 这表明 三羧酸循环产生ATP的速率近似恒定， 因此，当大量丙酮酸进入克雷布斯循环后， 葡萄糖水平的上升，这是由减少抵消 乙酰辅酶A的进入来源于脂肪酸。 此夕h 控制丙酮酸进入克雷布斯循环的因素（丙酮酸 脱氢酶活性; PDH）和脂肪酸氧化，虽然 重要的是细胞的正常功能，不是机制， 细胞调节胰岛素的释放量。 我们 建议采用定量方法， GK与糖酵解、PDH与糖酵解速率的关系 丙酮酸进入克雷布斯循环。 实验方法 利用具有专门入口系统的质谱仪， 以7秒的响应时间监测 溶解的O2、12 CO2和13 CO2响应于13 C标记的底物。 通过使用O2消耗作为ATP生产的衡量标准， 在[1- 13 C]丙酮酸存在下的13 CO2作为PDH的量度， 一个基本假设，即从克雷布斯氏细胞产生的ATP是恒定的 尽管通过PDH的通量增加，但是可以测试。 两者 测量及其解释需要定量， 所以数学模型分析 将用于假设检验、参数估计、通量 估计和控制强度分析。 了解 三羧酸循环的调节机制 B细胞是了解I型和II型糖尿病病理学的先决条件。 和II型糖尿病。

Glucokinase (GK) has been shown to play the role of the glucose sensor in the pancreatic b-cell, by virtue of its role as the rate controlling step in glycolysis. GK also has a very high control strength on glucose induced insulin secretion. The approach that led up to these important discoveries was quantitative and mathematical modeling of GK kinetics. Glucose must be metabolized before insulin secretion is stimulated, and the coupling factor between its metabolism and the ionic events which lead to the exocytosis of insulin containing granules is the energy state of the cell, [ATP]/[ADP]. Dukes [1994] and MacDonald [1990] have proposed that the major source of ATP production serving as a stimulus for insulin release is that generated by glycolytically-derived NADH, which is shuttled into the mitochondria and oxidized. This suggests that the rate of ATP production from the Krebs cycle is approximately constant, so that when a greater amount of pyruvate enters the Krebs cycle after a rise in glucose levels, this is counterbalanced by a diminution of the entry of acetyl CoA derived from fatty acids. Further, the factors governing the entry of pyruvate into the Krebs cycle (pyruvate dehydrogenase activity; PDH) and fatty acid oxidation, although important to the proper functioning of the cell, are not mechanisms by which the cell regulates the amount of insulin to be released. We propose to apply the quantitative approach taken in elucidating the relation between GK and glycolysis, to that of PDH and the rate of entry of pyruvate into the Krebs cycle. The experimental approach utilizes a mass spectrometer with a specialized inlet system that can monitor with a response time of 7 seconds the concentrations of dissolved O2, 12CO2, and 13CO2 in response to 13C labeled substrates. By using O2 consumption as a measure of ATP production, and production of 13CO2 in the presence of [1-13C]pyruvate as a measure of PDH, the basic hypothesis that ATP production from the Krebs c ycle is constant despite an increase in flux thrugh PDH can be tested. Both the measurements and their interpretation need to be quantitative to allow for rigorous conclusions to be made, so mathematical modeling analysis will be used for hypothesis testing, parameter estimation, flux estimations and control strength analysis. Understanding the regulatory mechanisms of the Krebs cycle in the functioning of the b-cell is prerequisite for understanding the pathology of both Type I and II diabetes mellitus.