Direct measurement of brain glucose concentrations in humans by 13C NMR spectroscopy.

Abstract

Glucose is the main fuel for energy metabolism in the normal human brain. It is generally a ed that glucose transport into the brain is not rate-limiting for metabolism. Since brain glucose concentrations cannot be determined directly by radiotracer techniques, we used 13C NMR spectroscopy after infusing enriched D-[1-_3C]glucose to measure brain glucose concentrations at euglycemia and at hyperglycemia (range, 4.5-12.1 mM) in six healthy children (13-16 years old). Brain glucose concentrations averaged 1.0 ± 0.1 ,umol/ml at euglycemia (4.7 ± 0.3 mM plasma) and 1. 8-2.7 jimol/ml at hyperglycemia (7.3-12.1 mM plasma). MichaelisMenten parameters of transport were calculated to be Kt = 6.2 ± 1.7 mM and T.. = 1.2 ± 0.1 zmol/gimin from the relationship between plasma and brain glucose concentrations. The brain glucose concentrations and transport constants are consistent with transport not being rate-limiting for resting brain metabolism at plasma levels >3 mM.Under normal conditions, brain cells rely almost entirely on the availability of D-glucose for generation of energy. The lack of significant carbohydrate stores in the brain requires that a steady glucose supply from the blood be maintained. However, D-glucose cannot diffuse freely across the bloodbrain barrier but is transported by facilitated diffusion (1-4) mediated by specific transporter molecules (5-7). The importance of glucose transport to metabolism and brain function has spurred extensive research in animals (for reviews, see refs. 8 and 9), as well as in humans (10,11). Although the rate of glucose transport is considered to be rapid enough to meet the cellular energy demand under basal conditions, it may become rate-limiting during hypoglycemia (11,12). Alterations in brain glucose transport may also be involved in the central nervous system morbidity associated with diseases such as diabetes mellitus, seizures, or hypoxicischemic encephalopathy (13,14).Glucose transport into the brain can be evaluated by measuring brain glucose concentrations as a function of plasma levels (15, 16). Direct measurement of glucose concentration is possible in animal brain with rapid-freezing techniques (17,18). However, these in vitro methods cannot be applied to humans, and direct quantitation of human brain glucose concentration has thus far not been achieved.NMR spectroscopy has been shown to be a powerful noninvasive technique that can be used to determine the concentration of many metabolites in living tissue (19)(20)(21)(22)(23).Recent studies have shown that the a-and ,B-anomers of glucose can be measured in animal brain by 13C NMR, when D-[1-'3C] glucose is infused (16,24). We report here the quantitation of the glucose concentration in the human brain using localized 13C NMR spectroscopy and the determination of the kinetic parameters of D-glucose transport from the relationship between brain and plasma glucose concentration. METHODSSix nonobese healthy children (13-16 years old) were studied after written informed consent was obtained from the su...

Studies of metabolic compartmentation and glucose transport using in vivo MRS

“…The brain glucose concentration and transport constants are consistent with transport not being rate-limiting for resting brain metabolism at plasma levels >3 mM. 17,49 …”

“…[17][18][19]28,33 In 1994 it was first demonstrated that in vivo 13 C NMR may be used to measure the rate of glutamine labeling from 1-13 C glucose in human occipital/parietal cortex. 18,27 However the rate of the glutamate/glutamine cycle was not uniquely determined from these first experiments due to the inability to distinguish the glutamate/glutamine cycle from other sources of glutamine labeling in the glia.…”

“…This approach was first used with 13 C MRS in rats by Mason and coworkers 49 and in human brain by Gruetter and coworkers. 17 In the human study 13 C MRS was used to measure brain glucose concentration during an infusion of enriched 1-13 C-glucose. Brain glucose concentration was measured at euglycemia and at hyperglycemia in six healthy children (13-16 y old).…”

Effects of relative hypoglycemia on LTP and NADH imaging in rat hippocampal slices

“…In humans, a 'normal' physiological plasma glucose concentration (5-7 mM) correlates with a brain extracellular glucose concentration of approximately 2 mM, by invasive microdialysis studies [1,17,27], resulting in a linear 3:1 ratio between plasma and tissue glucose concentrations [27]. Plasma glucose concentrations of <3 mM lead to impaired cognitive function [3,4], and limitations of glycolysis [17,18].…”

“…Plasma glucose concentrations of <3 mM lead to impaired cognitive function [3,4], and limitations of glycolysis [17,18].…”