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).

在过去的几年中，我们开发了一个综合模型，用于在秒到分钟的时间尺度上膜电位和钙的振荡，在参考文献中进行了回顾。 #2.导致胰岛素分泌相应的波动。 该模型的基本假设是，较快（数十秒）的振荡源于钙对离子通道的反馈，可能是钙激活钾（K（Ca））通道和 ATP 依赖性钾（K（ATP））通道，而较慢（五分钟）振荡源于新陈代谢的振荡。 后者通过 K(ATP) 通道转换为电振荡。 值得注意的是，后者是胰岛素刺激药物的一线目标，例如用于治疗 2 型糖尿病的磺酰脲类药物（甲苯磺丁脲、格列本脲）。 今年，我们通过充实线粒体的描述来扩展模型（参考文献#1）。 后者作为 ATP 生成的主要位点很重要，并且在我们的模型中起到放大糖酵解的振荡输出的作用。 线粒体也受到钙的调节，向上调节是通过激活三石炭酸 (TCA) 循环酶，向下调节是通过钙进入的作用降低线粒体膜电位，从而为 ATP 合成提供驱动力。 该扩展允许模型除了像以前一样输出 ATP 和 ADP 之外，还输出线粒体膜电位、NADH 速率和耗氧量，以便与实验进行比较。 作为一项应用，我们使用该模型来应对实验提出的挑战，该实验表明，通过 K(ATP) 通道开放剂二氮嗪阻断钙进入可消除代谢振荡。 后面的实验被解释为代谢振荡继发于钙振荡的证据。 我们表明，该结果实际上与糖酵解振荡相一致，糖酵解振荡是代谢振荡以及钙振荡的主要驱动因素。 解释是，钙进入的停止减少了 ATP 将钙泵出细胞的需求，从而抑制了糖酵解振荡的主要控制酶——磷酸果糖激酶 (PFK)。