Measurements of arteriovenous differences in the study of substrate supply to the brain.

Abstract

Less than a decade ago it was accepted biochemical dogma that the only energy-yielding substrate utilized by the brain was glucose. This belief was based on (a) the impairment of cerebral function in hypoglycaemic states, (b) the failure of potential energy-yielding substrates other than glucose to overcome the deleterious effects of hypoglycaemia and (c) measurements of arteriovenous differences across the head which indicated that glucose was the only circulating substrate taken up by the brain. Experiments which necessitated a reappraisal of the accepted view that the brain had an obligatory requirement for glucose were reported in 1967 by Cahill and his collaborators (Owen et al., 1967; Cahill et al., 1968). These experiments stemmed from calculations which suggested that in prolonged starvation sufficient glucose could not be synthesized from endogenous precursors to supply the metabolic needs of the brain and therefore other substrates must be utilized by this tissue. Measurements of arteriovenous differences in obese humans undergoing therapeutic starvation showed that the alternative substrates were ketone bodies, acetoacetate and 3-hydroxybutyrate (Owen etal., 1967). In this situation, ketonebody utilization accounted for about 60% of the oxygen consumed by the brain. This elegant experiment, with its teleological approach, renewed interest in the question of substrate supply to the brain and indicated the value of measurements of arteriovenous differences in such studies. An interesting question is why was this discovery not made earlier, because the technique of blood sampling from the internal jugular vein and an arterial site (femoral) was by no means new. At least two factors may have influenced the timing of the discovery, one being the somewhat earlier formulation of the role of free fatty acids as alternative substrates to glucose in many tissues (Fredrickson & Gordon, 1958) and the other the development of sensitive enzymic methods for the measurement of ketone bodies (Williamson et al., 1962). The discovery that ketone bodies could be utilized by brain in prolonged starvation has stimulated further work on the question whether this is due to an adaptive change within the brain or simply to the increased availability of circulating ketone bodies. One approach to this question is to measure the activities of the enzymes of ketonebody utilization in brains from animals in various physiological states. The results of such measurements in rat brain indicate that, in the adult, starvation, high-fat diets or