Wilson David F, Cember Abigail T J, Matschinsky Franz M
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Physiol Rep. 2017 Jun;5(12). doi: 10.14814/phy2.13327.
A model for glucose sensing by pancreatic -cells is developed and compared with the available experimental data. The model brings together mathematical representations for the activities of the glucose sensor, glucokinase, and oxidative phosphorylation. Glucokinase produces glucose 6-phosphate (G-6-P) in an irreversible reaction that determines glycolytic flux. The primary products of glycolysis are NADH and pyruvate. The NADH is reoxidized and the reducing equivalents transferred to oxidative phosphorylation by the glycerol phosphate shuttle, and some of the pyruvate is oxidized by pyruvate dehydrogenase and enters the citric acid cycle. These reactions are irreversible and result in a glucose concentration-dependent reduction of the intramitochondrial NAD pool. This increases the electrochemical energy coupled to ATP synthesis and thereby the cellular energy state ([ATP]/[ADP][Pi]). ATP and Pi are 10-100 times greater than ADP, so the increase in energy state is primarily through decrease in ADP The decrease in ADP is considered responsible for altering ion channel conductance and releasing insulin. Applied to the reported glucose concentration-dependent release of insulin by perifused islet preparations (Doliba et al. 2012), the model predicts that the dependence of insulin release on ADP is strongly cooperative with a threshold of about 30 mol/L and a negative Hill coefficient near -5.5. The predicted cellular energy state, ADP, creatine phosphate/creatine ratio, and cytochrome c reduction, including their dependence on glucose concentration, are consistent with experimental data. The ability of the model to predict behavior consistent with experiment is an invaluable resource for understanding glucose sensing and planning experiments.
我们构建了一个胰腺β细胞葡萄糖感知模型，并将其与现有的实验数据进行比较。该模型整合了葡萄糖传感器、葡萄糖激酶和氧化磷酸化活性的数学表示。葡萄糖激酶通过不可逆反应产生6-磷酸葡萄糖（G-6-P），该反应决定糖酵解通量。糖酵解的主要产物是NADH和丙酮酸。NADH被重新氧化，还原当量通过磷酸甘油穿梭转移到氧化磷酸化，部分丙酮酸被丙酮酸脱氢酶氧化并进入柠檬酸循环。这些反应是不可逆的，导致线粒体内NAD池浓度依赖于葡萄糖的降低。这增加了与ATP合成耦合的电化学能量，从而提高了细胞能量状态（[ATP]/[ADP][Pi]）。ATP和Pi比ADP高10 - 100倍，因此能量状态的增加主要是通过ADP的减少。ADP的减少被认为是改变离子通道电导和释放胰岛素的原因。应用于报道的经灌注胰岛制剂葡萄糖浓度依赖性胰岛素释放（Doliba等人，2012年），该模型预测胰岛素释放对ADP的依赖性具有强烈的协同性，阈值约为30 μmol/L，负希尔系数接近 - 5.5。预测的细胞能量状态、ADP、磷酸肌酸/肌酸比值和细胞色素c还原，包括它们对葡萄糖浓度的依赖性，与实验数据一致。该模型预测与实验一致行为的能力是理解葡萄糖感知和规划实验的宝贵资源。
