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.
This project investigates novel ways in which the brain uses and needs energy fuels after traumatic brain injury. The overall goal is to develop a therapy that is based on the concept that giving the brain the right fuel at the right time after injury will lead to a better long term outcome.
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|Prins, Mayumi L; Matsumoto, Joyce (2016) Metabolic Response of Pediatric Traumatic Brain Injury. J Child Neurol 31:28-34|
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|Vespa, Paul; Tubi, Meral; Claassen, Jan et al. (2016) Metabolic crisis occurs with seizures and periodic discharges after brain trauma. Ann Neurol 79:579-90|
|Goh, S Y Matthew; Irimia, Andrei; Torgerson, Carinna M et al. (2015) Longitudinal quantification and visualization of intracerebral haemorrhage using multimodal magnetic resonance and diffusion tensor imaging. Brain Inj 29:438-45|
|Glenn, Thomas C; Martin, Neil A; Horning, Michael A et al. (2015) Lactate: brain fuel in human traumatic brain injury: a comparison with normal healthy control subjects. J Neurotrauma 32:820-32|
|Chmayssani, Mohamad; Stein, Nathan R; McArthur, David L et al. (2015) Therapeutic intravascular normothermia reduces the burden of metabolic crisis. Neurocrit Care 22:265-72|
|Glenn, Thomas C; Martin, Neil A; McArthur, David L et al. (2015) Endogenous Nutritive Support after Traumatic Brain Injury: Peripheral Lactate Production for Glucose Supply via Gluconeogenesis. J Neurotrauma 32:811-9|
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