Glucose Transporter Expression in Brain: Relationship to Cerebral Glucose Utilization

Abstract

Glucose is the principle energy source for mammalian brain. Delivery of glucose from the blood to the brain requires its transport across the endothelial cells of the blood-brain barrier and across the plasma membranes of neurons and glia, which is mediated by the facilitative glucose transporter proteins. The two primary glucose transporter isoforms which function in cerebral glucose metabolism are GLUT1 and GLUT3. GLUT1 is the primary transporter in the blood-brain barrier, choroid plexus, ependyma, and glia; GLUT3 is the neuronal glucose transporter. The levels of expression of both transporters are regulated in concert with metabolic demand and regional rates of cerebral glucose utilization. We present several experimental paradigms in which alterations in energetic demand and/or substrate supply affect glucose transporter expression. These include normal cerebral development in the rat, Alzheimer's disease, neuronal differentiation in vitro, and dehydration in the rat.

Physiological and Molecular Characteristics of Rat Hypothalamic Ventromedial Nucleus Glucosensing Neurons

“…The mRNA for insulin-responsive GLUT4 was expressed in about half of all neurons, but there were no significant intergroup differences in expression (Table 3). The possibility that neuronal glucosensing might be regulated by insulin's acting on GLUT4, as it is in peripheral tissues (34,35,52), was raised by the coexpression of GLUT4 and INS-R mRNA in 40 -75% of all neurons, regardless of their glucosensing properties (Table 3). Because there were no significant intergroup differences in coexpression, it is less likely that insulin-mediated glucose uptake might serve as an alternate mechanism of glucosensing.…”

“…Although GLUT2 is expressed in the brain (3,13,22,28,33), it appears to be located predominantly in astrocytes (34). Most neurons express primarily GLUT3, a high-capacity, low-K m transporter that is largely saturated at physiological brain glucose levels (35). On the other hand, the insulin-sensitive GLUT4 (36) is expressed in neurons and has a K m within the physiological range for brain glucose (36).…”

Studies of metabolic compartmentation and glucose transport using in vivo MRS

“…5 Glutamine is released from the glia to the ECF where it is taken up by neurons and converted back to glutamate through the action of phosphate activated glutaminase (PAG). 6 Based on extensive data from isotopic labeling studies, immunohistochemical staining of cortical cells for specific enzymes, isolated cells and tissue fractionation studies it has been proposed that 66 GABAergic neurons Energy metabolism Inhibitory neurotransmission Glucose 47,50 Neurons/glia Glucose transport Glutamine 13,42 Glia Glutamate neurotransmitter cycling Ammonia detoxification Osmotic regulation Glial pH Homocarnosine 67 Subclass of GABAergic neurons pH, inhibitory neuromodulation NAA 68 Neurons Volume Mitochondrial function Myoinositol 69 Glia Osmotic regulation glutamate (as well as GABA) taken up by the glia from the synaptic cleft may be returned to the neuron in the form of glutamine. [7][8][9][10] Figure 1 shows the currently accepted model of the glutamine/glutamate cycle.…”

“…Under pathological conditions such as Alzheimer's disease, insulin-induced hypoglycemia and seizures, the transport of glucose may become ratelimiting for glucose metabolism, leading to energy failure. 47 MRS is the only noninvasive method which allows measurement of brain glucose concentration. In combination with metabolic modeling and labeled and unlabeled glucose infusions MRS has been used to determine brain glucose transport kinetics.…”

“…47 The ability to study transport kinetics of a specific cell type is based on the rate of glucose transport being kinetically determined by transporters on the capillary endothelia, often referred to as the blood-brain barrier. The transporter activity on other cell types is believed to be much higher, based upon isolated cell studies, although MRS has played an important role in establishing this phenomenon.…”