Are the blood brain barrier and the availability of glucose the ONLY reasons the brain uses glucose almost exclusively?
Glucose does play a predominant role as an organic source of brain energy requirements. The importance of glucose for normal brain functioning is especially apparent in children born with chronic hyperinsulinimia. Even in children treated with a stable glucagon analog, 20% to 50% of them may develop some form of mental retardation due to breakthrough bouts of severely low levels of serum glucose. The major role that glucose plays may be due to a number of reasons. The facility with which most people are able to obtain ample sources of glucose may be a major contributor. Several experiments have shown that neurons are able to use mannose in vitro to fulfill energy requirements without any functional deficit. Neurons can convert the mannose to fructose 6-phosphate and continue with glycolysis from that point. However, this is not a physiological state as most individuals do not have significant quantities of mannose.
The blood–brain barrier (BBB) provides a molecular weight cutoff for any substance trying to gain access to the brain. For instance, lactate and pyruvate have been shown to be sufficient sources of energy for neuronal activity, but they are unable to cross the BBB. The fact that neurons are able to oxidize and use lactate as an energy source, however, contributed to the astrocyte–neuron lactate hypothesis, which states that astrocytes use glucose in the brain and provide lactate to neurons for some of their energy requirements. Incidentally, astrocytes have been shown to store small amounts of glucose in the form of glycogen, although most glycogen stores in the body are in the liver (and are usually estimated to be enough for about a 24-hour period).
The body has also developed an intricate system to regulate and maintain glucose homeostasis. The GLUT transporter system has differentially regulated glucose transporters (GLUT1 to -7) that help deliver glucose to organs in a prioritized manner. GLUT1 is enriched at the BBB and helps enable the ability of glucose to gain access to the brain. Furthermore, GLUT1 is upregulated when serum glucose concentrations fall. GLUT3, on the other hand, is found in neurons and the extremely high affinity of GLUT3 ensures that much of the glucose that makes it to the brain finds its way into neuronal cells.
While glucose is the major source of energy for the brain, other sources of energy may transiently substitute for the role of glucose in different environments. For example, someone who is on a high-protein/fat and low-carb diet, such as Atkins, will have a lower serum glucose level. In these cases, ketone bodies such as acetoacetate and beta-hydroxybutyrate (breakdown products of fat and protein) can provide an energy source for the brain.
For more information, you can check:
Lodish H, et al. Molecular Cell Biology or any introductory neuroscience textbook.
Maher F, Simpson IA. The GLUT3 glucose transporter is the predominant isoform in primary cultured neurons: assessment by biosynthetic and photoaffinity labelling. Biochem. J. (1994) 301, 379–384.