Stimulus secretion coupling in pancreatic beta-cells

胰腺β细胞的刺激分泌耦合

• 批准号: 7593401
• 负责人: Arthur Sherman
• 金额: $ 42.61万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7593401
• 关键词: ATP Synthesis Pathway; Action Potentials; Area; Back; Behavior; Beta Cell; Ca(2+)-Transporting ATPase; Calcium; Calcium Oscillations; Cells; Chemicals; Compatible; Coupled; Coupling; Cyclic AMP; Defect; Diazoxide; Endocrine; Enzymes; Equation; Feedback; Generations; Glyburide; Glycolysis; Human; Individual; Insulin; Ion Channel; Islets of Langerhans; Lead; Membrane Potentials; Metabolic; Metabolism; Mitochondria; Modeling; NADH; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Organ; Output; Oxygen Consumption; Pancreas; Pharmaceutical Preparations; Phenols; Phosphotransferases; Physiologic pulse; Physiological; Plasma; Potassium; Protein Kinase C; Pulse taking; Range; Rate; Rodent; Secondary to; Signal Pathway; Site; Stimulus; Structure of beta Cell of islet; Sulfonylurea Compounds; System; Time; Tolbutamide; driving force; glucose metabolism; insulin secretion; interest; islet; mathematical model; millisecond; mitochondrial membrane; research study; stem; tool

Over the last few years we developed a comprehensive model for oscillations of membrane potential and calcium on time scales ranging from seconds to minutes, reviewed in Ref. # 2. The lead to corresponding oscillations of insulin secretion. The basic hypothesis of the model is that the faster (tens of seconds) oscillations stem from feedback of calcium onto ion channels, likely calcium-activated potassium (K(Ca)) channels and ATP-dependent potassium (K(ATP)) channels, whereas the slower (five minutes) oscillations stem from oscillations in metabolism. The latter are transduced into electrical oscillations via the K(ATP) channels. The latter, notably, are a first-line target of insulin-stimulating drugs, such as the sulfonylureas (tolbutamide, glyburide) used in the treatment of Type 2 Diabetes. In the current year, we have extended the model by fleshing out the description of the mitochondria (Ref. # 1). The latter are important as the main sites of ATP generation, and in our model act to amplify the oscillatory output of glycolysis. The mitochondria are also modulated by calcium, both upward, through activation of tri-carbolic acid (TCA) cycle enzymes and downward, through the effect of calcium entry to reduce the mitochondrial membrane potential, which provides the driving force for ATP synthesis. The extension allows the model to output, in addition to ATP and ADP as before, mitochondrial membrane potential and rates of NADH and oxygen consumption for comparison with experiment. As an application we used the model to respond to a challenge raised by experiments showing that blockade of calcium entry by the K(ATP) channel opener diazoxide abolished metabolic oscillations. The latter experiments were interpreted as evidence that the metabolic oscillations were secondary to calcium oscillations. We showed that that result is in fact compatible with glycolytic oscillations as the primary driver of metabolic oscillations and hence the calcium oscillations. The explanation is that cessation of calcium entry reduces the need for ATP to pump the calcium back out of the cell, which inhibits the main controlling enzyme of the glycolytic oscillations, phospho-fructo kinase (PFK).

在过去的几年里，我们开发了一个全面的模型，从秒到分钟的时间尺度上的膜电位和钙的振荡，在参考文献2。 导致胰岛素分泌的相应振荡。 该模型的基本假设是，较快的振荡（数十秒）源于钙离子通道的反馈，可能是钙激活钾（K（Ca））通道和ATP依赖性钾（K（ATP））通道，而较慢的振荡（5分钟）源于代谢振荡。 后者通过K（ATP）通道转换成电振荡。 值得注意的是，后者是胰岛素刺激药物的一线靶点，例如用于治疗2型糖尿病的磺酰脲类（甲苯磺丁脲，格列本脲）。 今年，我们通过充实线粒体的描述扩展了模型（参考文献1）。 后者是重要的ATP生成的主要网站，并在我们的模型中的行为，以放大糖酵解的振荡输出。 线粒体也受到钙的调节，既通过激活三石炭酸（TCA）循环酶向上调节，又通过钙进入降低线粒体膜电位的作用向下调节，这为ATP合成提供了驱动力。 扩展允许模型输出，除了ATP和ADP之前，线粒体膜电位和速率的NADH和氧消耗与实验比较。 作为一个应用程序，我们使用该模型来应对由实验提出的挑战，该实验表明，K（ATP）通道开放剂二氮嗪阻断钙进入消除代谢振荡。 后者的实验被解释为代谢振荡是次要的钙振荡的证据。 我们发现，这一结果实际上与糖酵解振荡作为代谢振荡的主要驱动因素以及钙振荡是一致的。 解释是钙进入的停止减少了ATP将钙泵回细胞的需要，这抑制了糖酵解振荡的主要控制酶磷酸果糖激酶（PFK）。