Increased Pentose Phosphate Pathway Flux after Clinical Traumatic Brain Injury: A [1,2-¹³C₂]glucose Labeling Study in Humans

Abstract

Patients with traumatic brain injury (TBI) routinely exhibit cerebral glucose uptake in excess of that expected by the low levels of oxygen consumption and lactate production. This brings into question the metabolic fate of glucose. Prior studies have shown increased flux through the pentose phosphate cycle (PPC) during cellular stress. This study assessed the PPC after TBI in humans.[1,2-13 C 2 ]glucose was infused for 60 mins in six consented, severe-TBI patients (GCS < 9) and six control subjects. Arterial and jugular bulb blood sampled during infusion was analyzed for 13 C-labeled isotopomers of lactate by gas chromatography/mass spectroscopy. The product of lactate concentration and fractional abundance of isotopomers was used to determine blood concentration of each isotopomer. The difference of jugular and arterial concentrations determined cerebral contribution. The formula PPC = (m1/m2)/(3 + (m1/m2)) was used to calculate PPC flux relative to glycolysis. There was enrichment of [1,2-13 C 2 ]glucose in arterial-venous blood (enrichment averaged 16.6% in TBI subjects and 28.2% in controls) and incorporation of 13 C-label into lactate, showing metabolism of labeled substrate. The PPC was increased in TBI patients relative to controls (19.6 versus 6.9%, respectively; P = 0.002) and was excellent for distinguishing the groups (AUC = 0.944, P < 0.0001). No correlations were found between PPC and other clinical parameters, although PPC was highest in patients studied within 48 h of injury (averaging 33% versus 13% in others; P = 0.0006). This elevation in the PPC in the acute period after severe TBI likely represents a shunting of substrate into alternative biochemical pathways that may be critical for preventing secondary injury and initiating recovery.

Neuron–Astrocyte Interactions, Pyruvate Carboxylation and the Pentose Phosphate Pathway in the Neonatal Rat Brain

“…In fact it was at levels comparable to those reported after stress such as traumatic brain injury in adult human and rodent brain [24,25]. Activity of the PPP was evident in neurons due to the presence of [4-C]glutamate.…”

“…These needs can be met by the PPP, which produces nucleotides and NADPH. Earlier studies have shown that the pathway accounts for approximately 2-5 % [21][22][23] of the glucose metabolism in the adult brain and can be upregulated to 9-20 % in response to injury in animal and human studies [24,25]. However, little is known about the PPP in the developing brain.…”

Dietary branched chain amino acids ameliorate injury-induced cognitive impairment

“…The largest pool is the "metabolic pool," which is approximately 1,000-fold higher than the synaptic pool, and is thought to be insular from the synaptic pool (23). However, because of greatly increased energy demand (24)(25)(26), released glutamate could be catabolized in the astrocyte for entry into the TCA cycle. Alternatively, glutamine that is returned to the neuron could be deaminated to form glutamate that is destined for energy production instead of simply replenishing the synaptic pool of glutamate.…”

Lactate Shuttling and Lactate use as Fuel after Traumatic Brain Injury: Metabolic Considerations

“…One diversion is flux through the pentose phosphate shunt pathway (Figure 1) that rises 2.8-fold from 6.9% to 19.6% of glycolytic rate in TBI patients, based on A − V differences for lactate isotopomers after intravenous infusion of [1,2-13 C]glucose. 87 This important finding establishes the global magnitude of response to enhance oxidative stress management after TBI. Another striking aspect of this study is that the analysis was based on release of labeled lactate to blood after passage of labeled glucose directly through the glycolytic pathway to generate [1,2-13 C]lactate and after detour through the pentose shunt and re-entry into the glycolytic pathway at the fructose-6-phosphate or glyceraldehyde-3-phosphate steps (Figure 1) to generate [1-13 C]lactate.…”

“…Thus, detours from the glycolytic to pentose shunt pathway may not be a serious problem owing to the probable reentry of most of the remaining 83% of glucose carbon into the glycolytic pathway upstream of the ATP-producing steps (Figure 1). Even if half of the pentose shunt flux were used for biosynthesis after TBI, only~10% of glycolytic flux is lost from energy-producing pathways (i.e., 50% × 20%, the measured pentose flux as fraction of glycolytic rate in TBI 87 ).…”