Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.
Mol Syst Biol. 2013 May 14;9:664. doi: 10.1038/msb.2013.19.
Insulin governs systemic glucose metabolism, including glycolysis, gluconeogenesis and glycogenesis, through temporal change and absolute concentration. However, how insulin-signalling pathway selectively regulates glycolysis, gluconeogenesis and glycogenesis remains to be elucidated. To address this issue, we experimentally measured metabolites in glucose metabolism in response to insulin. Step stimulation of insulin induced transient response of glycolysis and glycogenesis, and sustained response of gluconeogenesis and extracellular glucose concentration (GLC(ex)). Based on the experimental results, we constructed a simple computational model that characterises response of insulin-signalling-dependent glucose metabolism. The model revealed that the network motifs of glycolysis and glycogenesis pathways constitute a feedforward (FF) with substrate depletion and incoherent feedforward loop (iFFL), respectively, enabling glycolysis and glycogenesis responsive to temporal changes of insulin rather than its absolute concentration. In contrast, the network motifs of gluconeogenesis pathway constituted a FF inhibition, enabling gluconeogenesis responsive to absolute concentration of insulin regardless of its temporal patterns. GLC(ex) was regulated by gluconeogenesis and glycolysis. These results demonstrate the selective control mechanism of glucose metabolism by temporal patterns of insulin.
胰岛素通过时间变化和绝对浓度来调节全身葡萄糖代谢，包括糖酵解、糖异生和糖生成。然而，胰岛素信号通路如何选择性地调节糖酵解、糖异生和糖生成仍有待阐明。为了解决这个问题，我们通过实验测量了葡萄糖代谢中对胰岛素的响应的代谢物。胰岛素的逐步刺激诱导了糖酵解和糖生成的瞬时响应，以及糖异生和细胞外葡萄糖浓度（GLC(ex)）的持续响应。基于实验结果，我们构建了一个简单的计算模型，该模型描述了胰岛素信号依赖性葡萄糖代谢的响应。该模型表明，糖酵解和糖生成途径的网络基元分别构成了具有底物耗竭的前馈（FF）和非相干前馈环（iFFL），使糖酵解和糖生成对胰岛素的时间变化而不是其绝对浓度做出响应。相比之下，糖异生途径的网络基元构成了 FF 抑制，使糖异生对胰岛素的绝对浓度做出响应，而不考虑其时间模式。GLC(ex)受糖异生和糖酵解的调节。这些结果表明了胰岛素时间模式对葡萄糖代谢的选择性控制机制。
