Abstract
Glucose is the brain's principal source of ATP, but the extent to which cerebral glucose consumption (CMRglc) is coupled with its oxygen consumption (CMRO2) remains unclear. Measurements of the brain's oxygen-glucose index OGI = CMRO2/CMRglc suggest that its oxygen uptake largely suffices for oxidative phosphorylation. Nevertheless, during functional activation and in some disease states, brain tissue seemingly produces lactate although cerebral blood flow (CBF) delivers sufficient oxygen, so-called aerobic glycolysis. OGI measurements, in turn, are method-dependent in that estimates based on glucose analog uptake depend on the so-called lumped constant (LC) to arrive at CMRglc. Capillary transit time heterogeneity (CTH), which is believed to change during functional activation and in some disease states, affects the extraction efficacy of oxygen from blood. We developed a three-compartment model of glucose extraction to examine whether CTH also affects glucose extraction into brain tissue. We then combined this model with our previous model of oxygen extraction to examine whether differential glucose and oxygen extraction might favor non-oxidative glucose metabolism under certain conditions. Our model predicts that glucose uptake is largely unaffected by changes in its plasma concentration, while changes in CBF and CTH affect glucose and oxygen uptake to different extents. Accordingly, functional hyperemia facilitates glucose uptake more than oxygen uptake, favoring aerobic glycolysis during enhanced energy demands. Applying our model to glucose analogs, we observe that LC depends on physiological state, with a risk of overestimating relative increases in CMRglc during functional activation by as much as 50%.
Highlights
Normal brain function depends critically on a constant energy supply, and on moment-to-moment regulation of oxygen and glucose availability in brain tissue
We show how cerebral metabolic rate of glucose (CMRglc) is predicted to vary between physiological conditions and compare these changes to those reported in the literature
When we consider changes in mean transit time (MTT) and capillary transit time heterogeneity (CTH) derived from Stefanovic et al (2008) and Schulte et al (2003) (Figure 5A), our model predicts that CMRglc increases by 31% (43%) from baseline condition to stimulated state, while cerebral metabolic rate of oxygen (CMRO2) is expected to increase by only 19% (18%) between baseline and stimulation, resulting in an oxygen-glucose index (OGI) decreasing by 10–20%, from 5.5 (5.8) to 5.0 (4.7)
Summary
Normal brain function depends critically on a constant energy supply, and on moment-to-moment regulation of oxygen and glucose availability in brain tissue. Lactic acid production is believed to be related to a lack of oxygen It takes place in particular in skeletal muscles when energy needs outpace the ability to transport oxygen and in solid cancer tumors, which are known to grow more rapidly than the blood vessels nourish them, and to experience hypoxia. Under these conditions, glycolysis and subsequent lactic acid fermentation becomes the primary source of ATP (Berg et al, 2012). Many aspects of aerobic glycolysis remain poorly understood, including its dependency on stimulus type, duration, and magnitude (Edvinsson and Krause, 2002)
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