Journal
GLIA
Volume 55, Issue 12, Pages 1222-1237Publisher
WILEY
DOI: 10.1002/glia.20375
Keywords
GLUT; hexokinase; mathematical modeling; blood brain barrier; hypoglycemia; GLUT1 deficiency
Categories
Funding
- FIC NIH HHS [R03 TW007024-01A1] Funding Source: Medline
- FOGARTY INTERNATIONAL CENTER [R03TW007024] Funding Source: NIH RePORTER
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While glucose is constantly being pulled into the brain by hexokinase, its flux across the blood brain barrier (BBB) is allowed by facilitative carriers of the GLUT family. Starting from the microscopic properties of GLUT carriers, and within the constraints imposed by the available experimental data, chiefly NMR spectroscopy, we have generated a numerical model that reveals several hidden features of glucose transport and metabolism in the brain, The half-saturation constant of glucose uptake into the brain (Kt) is close to 8 mM. GLUT carriers at the BBB are symmetric, show accelerated-exchange, and a K-m of zero-trans flux (K-zt) close to 5 mM, determining a ratio of 3.6 between maximum transport rate and net glucose flux (T-max/ CMRg1c). In spite of the low transporter occupancy, the model shows that for a stimulated hexokinase to pull more glucose into the brain, the number or activity of GLUT carriers must also increase, particularly at the BBB. The endothelium is therefore predicted to be a key modulated element for the fast control of energy metabolism. In addition, the simulations help to explain why mild hypoglycemia may be asymptomatic and reveal that [glucose](brain) (as measured by NMR) should be much more sensitive than glucose flux (as measured by PET) as an indicator of GLUT1 deficiency. In summary, available data from various sources has been integrated in a predictive model based on the microscopic properties of GLUT carriers. (C) 2007 Wiley-Liss, Inc.
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