胰岛素通过CREB调节肝脏糖异生的模型化研究

Modeling study of insulin regulating hepatic gluconeogenesisby CREB

本文基于Hill动力学与Michaelis-Menten方程,建立理论模型研究胰岛素通过环磷腺苷效应元件结合蛋白(CREB)调节肝糖异生的物理机制.理论模型考虑胰岛素通过CREB调节过氧化物酶体增活化受体γ辅助活化因子(PGC)联级信号,进而调控肝脏糖异生,影响糖代谢信号通路特性.研究发现,在异常胰岛素(Ginsulin)作用下CREB表达提升,进一步刺激了磷酸烯醇式丙酮酸羧激酶1(Pck1)表达.通过Pck1的调控,柠檬酸盐酯(citrate)、α-酮戊二酸(α-keto glutarate)、苹果酸酯(Malate)、草酰乙酸盐(Oxaloacetate)出现了不同的代谢水平.高表达的CREB会上调Pck1的表达水平,通过CREB、Pck1的调节作用,磷酸烯醇式丙酮酸羧化酶(phosphoenolpyruvate)转化为白藜芦醇(Pyruvate)的水平提升,进而促使citrate、α-keto glutarate、Malate、Oxaloacetate大幅度升高,最终影响细胞葡萄糖代谢.在糖异生基因的调控作用下,较高浓度的葡萄糖(Glocose),使得phosphoenolpyruvate浓度提升,并且在Pck1的调控作用下,phosphoenolpyruvate转化为Pyruvate的量增多,也会使得citrate、α-keto glutarate、Malate、Oxaloacetate大幅度提升.理论结果进一步深刻揭示了胰岛素、CREB蛋白,以及糖异生基因对细胞糖代谢新的调控机理,可为设计阻断糖尿病转变通路的治疗方案提供理论依据.

In this paper,based on Hill kinetics and Michaelis-Menten equation,we built a theoretical model to study the physical mechanism of insulin regulating hepatic gluconeogenesis through cAMP-response element binding protein(CREB).The theoretical model considers that insulin regulates Peroxisome Proliferator-activated ReceptorγCoactivator(PGC)cascade signaling through CREB,thereby regulating hepatic gluconeogenesis and affecting the characteristics of glucose metabolism signaling pathway.We found that under the action of abnormal insulin(Ginsulin),the expression of CREB is increased,which further stimulates the expression of Pck1.By the regulation of Recombinant Phosphoenolpyruvate Carboxykinase 1(Pck1),citrate,α-keto glutarate,Malate,and Oxaloacetate show different metabolic levels.The highly expressed CREB upregulates the expression level of Pck1,and regulates the conversion of phosphoenolpyruvate to Pyruvate through regulatory factors such as CREB and Pck1.It in turn results in a significant increase in citrate,α-keto glutarate,Malate,and Oxaloacetate.The cellular glucose metabolism can be ultimately affected.Under the regulation of gluconeogenesis genes,higher Glocose concentration leads to the promotion of phosphoenolpyruvate.Under the regulation of Pck1,the conversion of phosphoenolpyruvate to Pyruvate increases,which will also greatly increase concentrations of citrate,α-keto glutarate,Malate,and Oxaloacetate.The theoretical results further reveal the new regulatory mechanism of insulin,CREB protein,and gluconeogenesis genes on cellular glucose metabolism.The results can provide a theoretical basis for designing therapeutic programs to block the diabetes transition pathway.