Previously we suggested that the early Warburg effect can be explained by the use by cancer cells the glycogen shunt during a rapid increase in glucose concentration. In analogy to the Crabtree effect in yeast, the shunt plays a critical role in maintaining homeostasis of glycolytic intermediate levels during these transitions. We extend this analysis here, and propose that the recently appreciated flexibility of cancer cell glucose and glycogen metabolism involves 4 metabolic states that we recently identified in metabolic control analysis studies of yeast. Under stable conditions of low glucose and normal O₂ yeast, and by analogy cancer, cells are in the Respiration State in which through gene expression for oxidizing non glucose substrates. When their environment changes to high glucose with reduced O₂ levels, such as occur in tumors, they transition to the Glycolysis State due to gene expression of new glycolytic enzyme isoforms such as PKM2. These isoforms optimize metabolism to sustain the Warburg effect. When the changes in glucose and O₂ levels are rapid there may be insufficient time for gene expression to adapt. The metabolic flexibility conferred by 2 states of the glycogen shunt allow the cells to survive these transitions. The model explains experimental observations in cancer such as the function of the glycogen shunt and the frequent expression of PKM2 in cells undergoing the Warburg Effect. A surprising conclusion is that the function of PKM2 is to maintain glycolytic intermediate homeostasis rather than controlling the glycolytic flux. The glycogen shunt may also have an important role in cancer metabolic reprogramming by allowing cancer cells to survive large glucose and oxygen changes during the selection of mutations that lead to the Warburg phenotype

之前我们认为早期瓦尔堡效应可以通过癌细胞在葡萄糖浓度快速增加期间使用糖原分流来解释。与酵母中的克拉布特里效应类似，分流在这些转变过程中维持糖酵解中间水平的稳态中发挥着关键作用。我们在此扩展了这一分析，并提出最近人们认识到的癌细胞葡萄糖和糖原代谢的灵活性涉及我们最近在酵母代谢控制分析研究中发现的 4 种代谢状态。在低葡萄糖和正常O ₂酵母的稳定条件下，以及类比癌症，细胞处于呼吸状态，其中通过基因表达氧化非葡萄糖底物。当它们的环境变为高葡萄糖且 O ₂水平降低时（例如在肿瘤中发生的情况），由于新的糖酵解酶亚型（例如 PKM2）的基因表达，它们会转变为糖酵解状态。这些异构体优化新陈代谢以维持瓦尔堡效应。当葡萄糖和O ₂水平快速变化时，基因表达可能没有足够的时间来适应。糖原分流的两种状态赋予的代谢灵活性使细胞能够在这些转变中生存。该模型解释了癌症中的实验观察结果，例如糖原分流的功能以及经历 Warburg 效应的细胞中 PKM2 的频繁表达。一个令人惊讶的结论是，PKM2 的功能是维持糖酵解中间稳态，而不是控制糖酵解通量。糖原分流也可能在癌症代谢重编程中发挥重要作用，因为它允许癌细胞在选择导致 Warburg 表型的突变过程中经历大量的葡萄糖和氧气变化。