SUMMARY1. By measurement of the rate of disappearance of injected tracer thiamine from the bloodstream, a programme for the continuous injection of thiamine at a variable rate has been devised by which a steady raised level can be achieved rapidly and maintained in the circulation. By this means the flux of radioactive thiamine across the blood-brain barrier has been measured.2. In separate experiments progressively higher levels ofthiamine were maintained in the bloodstream. Evidence was obtained that the transport of thiamine across the blood-brain barrier is a carrier-mediated process which can be saturated by raised levels of thiamine.3. The saturation of the transport process was incomplete: kinetic analysis showed that there was a non-saturable component of the transport which was probably due to passive diffusion.4. The contribution of the non-saturable component was normally small and is probably insufficient to meet the needs of the brain for the vitamin unless the concentration of the vitamin in the blood is raised considerably above normal.5. This two-component transport process had substantially similar kinetic parameters in different regions of the brain.
SUMMARY1. Rats aged from 2 to 116 weeks were studied. 2. Influx of glucose into the brain is low in suckling rats but rises after weaning, to reach its highest level in the young adult, thenceforward declining slowly as age increases.3. The blood-brain barrier for glucose is fully developed in the rat by the age of 18 days and glucose enters the brain, at this stage, by carrier-mediated transport, as in the adult.4. The results show that the low influx of glucose into the brain of the suckling animal is due to a low maximum rate of transport of glucose rather than to a low affinity of the carrier-molecule for glucose.5. In the young adult rat, efflux of glucose back from the brain into the blood is greater than in either the suckling or the old animals. Thus the margin of safety, i.e. the extent to which the blood glucose can be reduced without affecting the utilization of glucose by the brain, is highest in the young adult.6. The lower margin of safety in the suckling animals is compensated for by the high influx of the ketone bodies which provide an alternative source of energy at this age. In the old animals there is no alternative source of energy, so that the older brain is at greatest risk in hypoglycaemia.
—In living rats the concentration of insulin in the circulating blood was raised and independently of this the glucose concentration in the blood plasma was varied from hyperglycaemic to hypoglycaemic levels. Hyperglycaemia increased the influx of glucose into the brain and it also, for a limited period, increased the glucose gain by the brain. Insulin, on the other hand, did not affect influx but significantly increased the gain of glucose by the brain. It is suggested that although both hyperglycaemia and insulin can increase glucose gain by the brain they do so in entirely different ways.
SUMMARY1. The entry of glucose into the pectorals major muscle of living rats was measured over a wide range of plasma glucose concentrations. A technique was used by which steady concentrations of substances are maintained in the circulation throughout the experiments.2. Raising the concentration of glucose in the plasma caused saturation of the mechanism by which it is transported into muscle. Estimates of the values of the kinetic constants for this transport system were: Kt, 34,mole ml.-' and V, 1P2 ,mole min-' g-' muscle.3. When the plasma glucose concentration was raised up to at least twelve times normal, there was no sign of saturation of the transport system in insulin-treated animals. This finding could be explained if insulin increased greatly both V and Kt for glucose transport.4. Insulin increased the rate of entry of glucose into muscle over the entire range of plasma glucose concentrations studied (4-80 Iumole ml.-').There was evidence that endogenous insulin produced a similar increase. in entry rate some 10 min after the injection of glucose. Fasting, which is associated with a decrease in insulin level, depressed the rate of entry. In hyperglycaemia insulin caused a rise in the concentration of glucose within the muscle cells.
SUMMARY1. The effect of hyperinsulinaemia upon the influx of tryptophan into the brain was determined. A raised level of insulin was maintained in the circulation of rabbits for periods of up to 120 min by means of a continuous, programmed intravenous injection of the hormone, given by an electronically controlled variable-drive syringe. A similar, appropriately programmed, intravenous injection of glucose, given simultaneously with the insulin, maintained the concentration of the blood glucose within normal limits throughout each experiment, so that the results were not vitiated by the development of hypoglyeaemia.2. Raised levels of insulin in the blood affect the supply of tryptophan to the brain in two opposing ways: (a) by increasing the binding of tryptophan to the albumin in the blood, thereby reducing the level of the free tryptophan in the circulation by about a half, which would decrease the influx of tryptophan into the brain; (b) by simultaneously reducing the levels in the blood of six or more ofthe amino acids which compete with tryptophan for transport carriers into the brain, which would increase the influx of tryptophan. The net result of these two opposing effects is that insulin causes only a slight increase in the influx of tryptophan into the brain.3. To account in quantitative terms for the effect of insulin upon the influx of tryptophan into the brain it proved necessary to make one assumption. This assumption was that a predictable proportion of the tryptophan which is loosely bound to blood albumin is being stripped off this protein by the transport carrier located on the luminal surface membranes of the endothelial cells during the passage of the blood through the cerebral capillaries. If this assumption is accepted the work reported here explains adequately the effect of insulin on the influx of tryptophan into the brain.
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