Endogenous Nutritive Support after Traumatic Brain Injury: Peripheral Lactate Production for Glucose Supply via Gluconeogenesis

Thomas C Glenn, Neil A Martin, David L McArthur, David A Hovda, Paul Vespa, Matthew L Johnson, Michael A Horning, George A Brooks, Thomas C Glenn, Neil A Martin, David L McArthur, David A Hovda, Paul Vespa, Matthew L Johnson, Michael A Horning, George A Brooks

Abstract

We evaluated the hypothesis that nutritive needs of injured brains are supported by large and coordinated increases in lactate shuttling throughout the body. To that end, we used dual isotope tracer ([6,6-(2)H2]glucose, i.e., D2-glucose, and [3-(13)C]lactate) techniques involving central venous tracer infusion along with cerebral (arterial [art] and jugular bulb [JB]) blood sampling. Patients with traumatic brain injury (TBI) who had nonpenetrating head injuries (n=12, all male) were entered into the study after consent of patients' legal representatives. Written and informed consent was obtained from healthy controls (n=6, including one female). As in previous investigations, the cerebral metabolic rate (CMR) for glucose was suppressed after TBI. Near normal arterial glucose and lactate levels in patients studied 5.7±2.2 days (range of days 2-10) post-injury, however, belied a 71% increase in systemic lactate production, compared with control, that was largely cleared by greater (hepatic+renal) glucose production. After TBI, gluconeogenesis from lactate clearance accounted for 67.1% of glucose rate of appearance (Ra), which was compared with 15.2% in healthy controls. We conclude that elevations in blood glucose concentration after TBI result from a massive mobilization of lactate from corporeal glycogen reserves. This previously unrecognized mobilization of lactate subserves hepatic and renal gluconeogenesis. As such, a lactate shuttle mechanism indirectly makes substrate available for the body and its essential organs, including the brain, after trauma. In addition, when elevations in arterial lactate concentration occur after TBI, lactate shuttling may provide substrate directly to vital organs of the body, including the injured brain.

Keywords: TBI; brain; gluconeogenesis; glucose; glucose homeostasis; glycemia; lactate; mass spectrometry.

Figures

FIG. 1.
FIG. 1.
Violin plot of arterial glucose (A) and lactate concentrations (B) in control subjects and patients with traumatic brain injury (TBI). Solid lines represent patients with TBI (n=12) while dashed lines are normal control subjects (n=6). This and subsequent figures depict the following components: median (light circle), mean (horizontal line), standard deviation (heavy vertical bar), box-plot whisker (thin vertical bar), and a kernel density estimation of the data distribution (replacing the box-plot's rectangular depiction) following Hintze and Nelson as visualized by R package “Caroline.” TBI are solid border, controls are dashed. Values were constant over time, so mean values for min 60, 90, and 120 min are shown.
FIG. 2.
FIG. 2.
Violin plot of arterial D2 glucose (A) and 13C-lactate (B) isotopic enrichments (IE). Solid lines represent patients with traumatic brain injury (TBI) (n=12) while dashed lines are normal control subjects (n=6). Panel (A) arterial glucose IE control subjects (dashed lines) compared with patients with TBI (p>0.05). Panel (B) arterial lactate IEs are significantly lower in patients with TBI than healthy control subjects (p<0.001). Values at 90, 120, and 150 min of study were shown to demonstrate constancy of arterial glucose and lactate IEs over the course of study.
FIG. 3.
FIG. 3.
Violin plot of whole-body glucose (A) and lactate production, appearance rates, Ra (B) in control subjects (dashed lines) and patients with TBI (solid lines). Glucose production tended to be higher after traumatic brain injury (TBI), but values were NSD, p>0.05. Whole body lactate production was significantly great in patients with TBI than control subjects, p<0.05.
FIG. 4.
FIG. 4.
Violin plot of incorporation of M+1 label from infused lactate tracer into glucose in healthy controls (dashed lines) and patients with traumatic brain injury (solid lines). Trauma significantly greater than control, p<0.05.
FIG. 5.
FIG. 5.
Violin plot of percent contribution of lactate to glucose production (gluconeogenesis, GNG) in healthy controls (dashed lines) and patients with traumatic brain injury (TBI) (solid lines). Values are significantly greater after TBI, p<0.05. Trauma caused a major change in GNG from lactate.
FIG. 6.
FIG. 6.
Violin plot of lactate metabolic clearance rate (MCR=Lactate Rd/[Lactate]) in healthy controls (dashed lines) and patients with traumatic brain injury (TBI) (solid lines). Typical of parameters of cerebral and body metabolism following TBI, variability in lactate MRC appeared greater following TBI, but there were no significant differences in measures of central tendency or variability in MCR following TBI.
FIG. 7.
FIG. 7.
Schematic of lactate shuttle mechanism by which the body mobilizes lactate to fuel the brain after traumatic brain injury (TBI). Lactate is the major gluconeogenic precursor, and together lactate as well as glucose formed from lactate in the liver and kidneys fuel the brain always, but especially after TBI. Hence, lactate fuels the brain directly via uptake and oxidation as well as indirectly via gluconeogenesis. Color image is available online at www.liebertpub.com/neu

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