Glucose is the primary energy source for mammalian brain and its uptake across the blood-brain barrier (BBB) and into the neurons and glia that make up the brain is mediated by a family of glucose transporters (GLUTs). The 55kDa isoform of GLUT1 facilitates the transcytosis of glucose across the endothelial cells that constitute the BBB. It has been proposed that this transporter is asymmetrically distributed between the luminal and abluminal membranes. The luminal concentration of GLUT1 was quantitated in control and diabetic animals by perfusion and subsequent photolysis of an impermeant photolabel [3H] ATB-BMPA. The ration of luminal : total transporter was reduced in the microvessels of diabetic animals suggesting a mechanism of redistribution may account for the observed reduction of glucose flux. GLUT3 is the primary neuronal transporter and in cultured cerebellar granule neurons it exhibits both a high affinity (Km approximately 2.8 mM for 3-O-methylglucose) and the highest transport rate (turnover number = 853-1) of all the GLUT isoforms measured. Thus the kinetic capacity of GLUT3 provides the neuron a survival advantage under conditions of metabolic stress such as hypoxia or hypoglycemia. Glucose consumption is enhanced when cultured hippocampal neurons are exposed to nitric oxide (NO), however GLUT1 and GLUT3 expression is suppressed. bFGF and EGF both protect against NO toxicity and restore GLUT1 and GLUT3 expression to normoxic levels suggesting a relationship between fuel supply and neuronal survival. In vivo studies of hypoxia-ischemia in the 7 day old neonatal rat have revealed that dramatic increases in the levels of GLUT1 mRNA and protein occur very rapidly following the insult and persist in the ischemic hemisphere at 24h of recovery. Over a period of 24-48 h GLUT3 mRNA levels decline in a manner consistent with neuronal necrosis. In contrast, GLUT5 expression in microglia is unchanged at 24h but by 48h a dramatic increase is observed in the area of the infarct. Similar observations have now been made in an adult rat model of focal ischemia. In a clinical setting, a small group of children have recently been identified with a deficiency in GLUT1 glucose transporter which results in an impaired ability to transport glucose across the BBB. This defect is manifested by infantile-onset seizures and persistent hypoglycorrachia. A screening system has been devised to identify other children with defects in either GLUT1 or GLUT3 transporters which might induce seizure activity. Such children have been found to respond positively tot he Ketogenic Diet which effectively provides ketone bodies as an alternative energy source to glucose.
