The brain constitutes only 2% of body weight, but consumes 20% of the body's oxygen and receives 15% of its cardiac output (Sokaloff, 1989). It is almost totally dependent on carbohydrate as a fuel and since it cannot store or synthesise glucose, depends on a continuous supply from circulating blood. The brain contains the enzymes needed to metabolise fuels other than glucose such as lactate, ketones and amino acids, but under physiological conditions their use is limited by insufficient quantities in the blood or slow rates of transport across the blood-brain barrier. When arterial blood glucose falls below 3 mmol/l, cerebral metabolism and function decline.
Metabolism of glucose by the brain releases energy, and also generates neurotransmitters such as gamma amino butyric acid (GABA) and acetylcholine, together with phospholipids needed for cell membrane synthesis. When blood glucose concentration falls, changes in the synthesis of these products may occur within minutes because of reduced glucose metabolism, which can alter cerebral function. This is likely to be a factor in producing the subtle changes in cerebral function detectable at blood glucose concentrations as high as 3 mmol/l, which is not sufficiently low to cause a major depletion in ATP or creatine phosphate, the brain's two main sources of energy (McCall, 1993).
Isotope techniques and Positron Emission Tomography (PET) allow the study of metabolism in different parts of the brain and show regional variations in metabolism during hypoglycaemia. The neocortex, hippocampus, hypothalamus and cerebellum are most sensitive to hypoglycaemia, whereas metabolism is relatively preserved in the thalamus and brainstem. Changes in cerebral function are initially reversible, but during prolonged severe hypoglycaemia, general energy failure (due to the depletion of ATP and creatine phosphate) can cause permanent cerebral damage. Pathologically this is caused by selective neuronal necrosis most likely due to 'excitotoxin' damage. Local energy failure induces the intrasynaptic release of glutamate or aspartate, and failure of reuptake of the neurotransmitters increases their concentrations. This leads to the activation of N-methyl-D-aspartate (NMDA) receptors causing cerebral damage. One study in rats has shown that an experimental compound called AP7, which blocks the NMDA receptor, can prevent 90% of the cerebral damage associated with severe hypoglycaemia (Wieloch, 1985). In humans with fatal hypoglycaemia, protracted neuroglycopenia causes laminar necrosis in the cerebral cortex and diffuse demyelination. Regional differences in neuronal necrosis are seen, with the basal ganglia and hippocampus being sensitive, but the hypothalamus and cerebellum being relatively spared (Auer and Siesjo, 1988; Sieber and Traysman, 1992).
The brain is very sensitive to acute hypoglycaemia, but can adapt to chronic fuel deprivation. For example, during starvation, it can metabolise ketones for up to 60% of its energy requirements (Owen et al., 1967). Glucose transport can also be increased in the face of hypoglycaemia. Normally, glucose is transported into tissues using proteins called glucose transporters (GLUT) (Bell et al., 1990). This transport occurs down a concentration gradient faster than it would by simple diffusion and does not require energy (facilitated diffusion). There are several of these transporters, with GLUT 1 being responsible for transporting glucose across the blood-brain barrier and GLUT 3 for transporting glucose into neurones (Figure 1.2). Chronic hypoglycaemia in animals (McCall et al., 1986) and in humans (Boyle et al., 1995) increases cerebral glucose uptake, which is thought to be promoted by an increase in the production and action of GLUT 1 protein. It has not been
TRANSPORT OF GLUCOSE ACROSS BLOOD BRAIN BARRIER
Figure 1.2 Transport of glucose into the brain across the blood-brain barrier established whether this adaptation is of major benefit in protecting brain function during hypoglycaemia.
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Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...