Quantifying the contribution of the liver to glucose homeostasis: a detailed kinetic model of human hepatic glucose metabolism.
Quantifying the contribution of the liver to glucose homeostasis: a detailed kinetic model of human hepatic glucose metabolism.
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DOI：
10.1371/journal.pcbi.1002577
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发表时间：
2012
影响因子：
4.3
通讯作者：
Holzhütter HG
中科院分区：
文献类型：
--
作者：
König M;Bulik S;Holzhütter HG
尽管肝脏在葡萄糖稳态中起着至关重要的作用，但到目前为止还缺乏人体肝脏葡萄糖代谢的详细数学模型。在这里，我们提出了一个详细的动力学模型的糖酵解，糖原合成和糖原代谢的人肝细胞与激素控制这些途径的胰岛素，胰高血糖素和肾上腺素。模型模拟与实验数据吻合良好，（i）在不同的生理状态下，糖酵解、糖原生成和糖原代谢对肝脏葡萄糖产生和肝脏葡萄糖利用的定量贡献。(ii)餐后糖原储存的时间进程以及过夜禁食和短期禁食中的糖原消耗（iii）从低血糖下的净肝葡萄糖产生到高血糖下的净肝葡萄糖利用的转换，这对于葡萄糖稳态是必需的（iv）肝葡萄糖代谢的激素扰动。响应分析揭示了肝脏抵抗低于5 mM（低血糖）和高于7.5 mM（高血糖）的血浆葡萄糖水平变化的额外高能力。我们的模型可以作为人体葡萄糖代谢的全身模型的一个重要模块，并作为一个有价值的工具，了解在正常条件下，在葡萄糖稳态的肝脏和疾病，如糖尿病或糖原贮积病的作用。葡萄糖是所有细胞和器官不可或缺的燃料，但同时在高浓度下会导致问题。因此，血糖被控制在一个狭窄的范围内，以保证恒定的供应，另一方面避免与葡萄糖水平升高相关的损害。肝脏是通过以下方式控制血糖的主要器官：（i）当血糖低时，在血流中释放新合成或储存的葡萄糖;（ii）当血糖升高时，使用和储存葡萄糖。这些过程受激素调节，特别是胰岛素、胰高血糖素和肾上腺素。我们开发了这个关键代谢系统的第一个详细的动力学模型，并将其与激素控制相结合，并根据大量实验数据验证了该模型。我们的模型使第一次能够模拟肝脏葡萄糖代谢的深度。我们的研究结果表明，由于关键酶的激素控制，肝脏代谢可以在葡萄糖的产生和利用之间切换。我们提供了一个基本的模型来分析正常状态下的葡萄糖调节和与葡萄糖稳态缺陷相关的疾病，如糖尿病。
Despite the crucial role of the liver in glucose homeostasis, a detailed mathematical model of human hepatic glucose metabolism is lacking so far. Here we present a detailed kinetic model of glycolysis, gluconeogenesis and glycogen metabolism in human hepatocytes integrated with the hormonal control of these pathways by insulin, glucagon and epinephrine. Model simulations are in good agreement with experimental data on (i) the quantitative contributions of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization under varying physiological states. (ii) the time courses of postprandial glycogen storage as well as glycogen depletion in overnight fasting and short term fasting (iii) the switch from net hepatic glucose production under hypoglycemia to net hepatic glucose utilization under hyperglycemia essential for glucose homeostasis (iv) hormone perturbations of hepatic glucose metabolism. Response analysis reveals an extra high capacity of the liver to counteract changes of plasma glucose level below 5 mM (hypoglycemia) and above 7.5 mM (hyperglycemia). Our model may serve as an important module of a whole-body model of human glucose metabolism and as a valuable tool for understanding the role of the liver in glucose homeostasis under normal conditions and in diseases like diabetes or glycogen storage diseases. Glucose is an indispensable fuel for all cells and organs, but at the same time leads to problems at high concentrations. As a consequence, blood glucose is controlled in a narrow range to guarantee constant supply and on the other hand avoid damages associated with elevated glucose levels. The liver is the main organ controlling blood glucose by (i) releasing newly synthesized or stored glucose in the blood stream when blood glucose is low (ii) using and storing glucose when blood glucose is elevated. These processes are regulated by hormones, in particular insulin, glucagon and epinephrine. We developed the first detailed kinetic model of this crucial metabolic system integrated with its hormonal control and validated the model based on a multitude of experimental data. Our model enables for the first time to simulate hepatic glucose metabolism in depth. Our results show how due to the hormonal control of key enzymes the liver metabolism can be switched between glucose production and utilization. We provide an essential model to analyze glucose regulation in the normal state and diseases associated with defects in glucose homeostasis like diabetes.
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影响因子：
7.7
作者：
FERRANNINI, E;BJORKMAN, O;DEFRONZO, RA
通讯作者：
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作者：
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