Alternative glucose metabolism and glycolytic suppression after human TBI

尽管脑葡萄糖输送正常或增加，我们已经证明，脑葡萄糖 代谢，即使它超过了匹配CMRO 2所需的水平，很少上升到超正常水平， 这可能是预期允许糖酵解过度以补偿损伤引起的能量危机的水平。在 事实上，尽管有持续代谢需求的证据，脑葡萄糖摄取通常受到抑制。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 最近证明，在创伤性脑损伤后的第一个12-24小时内，大脑不会 释放乳酸，但大多数情况下会吸收并消耗它。这一意外发现意味着， 超过与氧摄取相匹配所需的过量葡萄糖摄取既不代表糖酵解过度 也不是缺氧诱导的无氧糖酵解，但具有替代的代谢命运。根据这一概念， 最近在我们ICU的临床13 C-葡萄糖研究表明， 脑葡萄糖代谢支持TBI患者戊糖磷酸途径的激活。基于 根据这些发现，我们的中心假设是，急性期后的生化和生理 环境法1.）抑制糖酵解; 2.）将葡萄糖重定向到替代的代谢命运;以及3.）到 促进乳酸盐和可能的其他“下游”替代燃料的代谢消耗， 绕过糖酵解障碍解决这些问题的实验和方法将涉及采样 血液、脑脊液和细胞外液，以测量葡萄糖和相关的 生化产品。患者和正常对照受试者将输注13 C标记的葡萄糖， 确定葡萄糖的代谢命运。此外，患者将接受乳酸盐静脉输注 以确定是否可以绕过糖酵解的抑制。这一概念代表了一个实质性的 偏离了主要的损伤后代谢范例，其集中于缺血/缺氧， 糖酵解过度和乳酸盐过量产生。如果得到证实，这些概念将影响 代谢/营养支持在ICU，并将纳入目前的临床协议 用于管理葡萄糖输注和胰岛素给药。

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.