INTEGRATIVE APPROACH TO UNDERSTAND ETIOLOGY & CAUSES OF TYPE II DIABETES

葡萄糖激酶(GK)已被证明起到葡萄糖的作用 感受器在胰腺b细胞中，由于其作为速率的作用。 糖酵解的控制步骤。GK也有非常高的控制力 对葡萄糖诱导的胰岛素分泌的强度。这种方法导致了 这些重要的发现是定量的和数学的 GK动力学模型。在胰岛素之前必须先代谢葡萄糖 分泌受到刺激，其之间的偶联因子 新陈代谢和导致胞吐的离子事件 含胰岛素颗粒是细胞的能量状态， [ATP]/[ADP]。杜克斯[1994]和麦克唐纳[1990]提出了 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，即 穿梭到线粒体并被氧化。这表明， 从克雷布斯循环产生的ATP的速率几乎是恒定的， 因此，当更多的丙酮酸进入克雷布斯循环后 血糖水平的上升，这被血糖水平的下降所抵消 从脂肪酸衍生的乙酰辅酶A的条目。此外， 影响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，尽管 对细胞的正常运作很重要，并不是由 该细胞调节胰岛素的释放量。我们 建议采用量化的方法来澄清 GK与糖酵解、PDH与糖酵解的关系 丙酮酸进入克雷布斯循环。实验方法 利用带有专门进气系统的质谱仪，可以 以7秒的响应时间进行浓度监测 溶解O2、12CO2和13CO2以响应13C标记的底物。 通过使用氧气消耗作为衡量ATP产生和生产的指标 在[1-13C]丙酮酸存在下的~(13)CO2作为PDH的量度， 从Krebs循环产生ATP的基本假设是恒定的 尽管流量有所增加，但仍可测试PDH。这两个 测量和它们的解释需要是定量的，以便 为了得出严格的结论，所以数学建模分析 将用于假设检验、参数估计、通量 评估和控制强度分析。了解 克雷布斯循环中的调节机制 B细胞是了解这两种I型疾病病理的先决条件 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.