Alternative glucose metabolism and glycolytic suppression after human TBI

尽管大脑葡萄糖供应正常或增加，我们已经记录了大脑葡萄糖 新陈代谢，即使超过了匹配CMRO2所需的水平，也很少会上升到超常水平 这一水平可能会导致高糖酵解，以补偿由伤害引起的能量危机。在……里面 事实上，尽管有证据表明有持续的代谢需求，但大脑对葡萄糖的摄取通常受到抑制。这 表明创伤后糖酵解可能受到抑制。此外，我们和其他调查人员已经 最近证明，在创伤性脑损伤后的最初12-24小时之后，大脑不会 释放乳酸盐，但大多数情况下会占用并明显消耗它。这一出人意料的发现意味着 过量的葡萄糖摄取量超过与摄氧量相匹配的摄氧量表示既不是高糖酵解 也不是缺氧引起的厌氧糖酵解，而是有另一种代谢命运。根据这一概念， 我们ICU最近的临床13C-葡萄糖研究表明，很大一部分创伤后 脑葡萄糖代谢支持脑外伤患者磷酸戊糖途径的激活。基座 根据这些发现，我们的中心假设是急性后阶段的生化和生理 环境行为1。)抑制糖酵解；2)将葡萄糖转向另一种代谢命运；以及3.)至 促进乳酸以及可能的其他“下游”替代燃料的新陈代谢消费，这可以 绕过糖酵解梗阻。解决这些问题的实验和方法将涉及抽样 血液、脑脊液和细胞外液，以测量葡萄糖和相关物质的浓度 生化产品。患者和正常对照组将被注入13C标记的葡萄糖和 决定了葡萄糖的代谢命运。此外，患者将接受乳酸的静脉输注。 以确定是否可以绕过对糖酵解的抑制。这一概念代表了一种实质性的 背离了目前流行的以缺血/缺氧为重点的损伤后代谢模式， 糖酵解过多，乳酸过多。如果得到证实，这些概念将影响 ICU中的代谢/营养支持，并必须纳入当前的临床方案 用于管理葡萄糖输注和胰岛素注射。

Despite normal or increased cerebral glucose delivery, we have documented that cerebral glucose metabolism, even though it exceeds the level required to match CMRO2, rarely rises to the supranormal levels that might be expected to allow hyperglycolysis to compensate for the injury-induced energy crisis. In fact, cerebral glucose uptake is generally suppressed, despite evidence of ongoing metabolic demand. This suggests that post-traumatic glycolysis may be suppressed. Furthermore, we and other investigators have recently demonstrated that beyond the first 12-24 hours following traumatic brain injury the brain does not release lactate, but most often takes up and apparently consumes it. This unexpected finding implies that the excess glucose uptake above that required to match oxygen uptake represents neither hyperglycolysis nor hypoxia-induced anaerobic glycolysis, but has an alternative metabolic fate. In line with this concept, recent clinical 13C-glucose studies in our ICU have demonstrated that a substantial fraction of post-traumatic cerebral glucose metabolism supports activation of the pentose phosphate pathway in TBI patients. Based on these findings, our central hypothesis is that the post-acute phase biochemical and physiological environment acts 1.) to suppress glycolysis; 2.) to redirect glucose to alternative metabolic fates; and 3.) to promote the metabolic consumption of lactate and possibly other "downstream" alternative fuels, which can bypass the glycolytic obstruction. Experiments and methods to address these questions will involve sampling blood, cerebral spinal fluid, and extracellular fluid to measure concentrations of glucose and related biochemical products. Patients and normal control subjects will be infused with 13C-labelled glucose and the metabolic fates of glucose determined. Additionally, patients will undergo an intravenous infusion of lactate to determine if the suppression of glycolysis can be bypassed. This concept represents a substantial departure from the prevailing post-injury metabolic paradigm, which is focused on ischemia/hypoxia, hyperglycolysis, and lactate overproduction. If confirmed, these concepts would influence metabolic/nutritional support in the ICU, and would have to be incorporated into the current clinical protocols for managing glucose infusions and insulin administration.