Metabolic fuel and amino acid transport into the brain in experimental diabetes mellitus.

Abstract

We used the Oldendorf brain uptake index method to study the blood-brain barrier transport of several metabolic substrates in diabetes. Glucose transport into the brain was decreased by 1/3 in rats with moderate diabetes induced by prior injection of streptozotocin (65 mg/kg of body weight). The transports of mannose and the poorly metabolized hexoses 2-deoxyglucose and 3-0-methylglucose were similarly reduced. Likewise, brain glucose transport was decreased in rats with alloxan-induced diabetes. These alterations in brain hexose influx appeared to be related to chronic (1-2 days) hyperglycemia rather than to insulinlack per se. Thus, starvation of the diabetic rats for 48 hr restored both the plasma glucose concentration and brain hexose transport to normal. Conversely, the substitution of 10% sucrose for their drinking water both increased plasma glucose and decreased hexose transport in insulin-treated diabetic rats. The 45% decrease in maximal glucose transport rate observed and the uniformity of diminished hexose transport probably imply a decrease in the number of available high-affinity transport carriers at the blood-brain barrier. This defect was specific for hexoses in that the transports of neutral and basic amino acids and of (3-hydroxybutyrate were not similarly affected. These results suggest that chronic hyperglycemia decreases the number of hexose carrier molecules available at the blood-brain barrier. Such an adaptation could operate to decrease the net flux of glucose into the brain during sustained hyperglycemia. It also may explain the abnormal sensitivity to abrupt blood glucose lowering in patients with diabetes mellitus.Endothelial cells in brain capillaries constitute the blood-brain barrier (1-5). As such, they directly determine the transport of substrates into the brain (6), and they indirectly regulate the use ofthese substrates for such processes as fuel metabolism and neurotransmitter synthesis (7). Although the metabolism ofglucose (and probably of other substrates) may be altered within brains of rats with insulinopenic diabetes (8), the effects of diabetes on its blood-brain barrier transport remain largely undefined. To examine this question, we have compared the transports of hexoses and other substrates across the blood-brain barrier in normal and diabetic rats, using the brain uptake index (BUI) of Oldendorf (9).This report describes the effect of streptozotocin-induced diabetes of varying severity and duration on the transports of (i) glucose, (ii) two nonmetabolized hexoses (3-0-methylglucose and 2-deoxyglucose) that use the same blood-brain barrier transport system as D-glucose does, (iii) P-hydroxybutyrate, (iv) 300 mCi/mmol), and n-[1-14C]butanol 0.5 mCi/mmol). Rats were anesthetized with pentobarbital (45 mg/kg of body weight; Nembutal, Abbott) in the early afternoon, and the BUI for any particular compound was determined soon thereafter by using the singleinjection technique of Oldendorf (1,12). BUI values for all test compounds were multiplied by a ...

Modest decrements in plasma glucose concentration cause early impairment in cognitive function and later activation of glucose counterregulation in the absence of hypoglycemic symptoms in normal man.

“…However, the extent to which brain metabolism in diabetics is similar to that of normal subjects is presently unknown. Since the antecedent glycemic level influences brain glucose transport, i.e., chronic hyperglycemia reduces (39,40) and chronic hypoglycemia increases (41) glucose transport to the brain, the results of the present study in normal nondiabetic subjects do not necessarily establish the glycemic threshold for onset of neuroglycopenia, activation of counterregulatory hormones and symptoms of hypoglycemia in diabetic patients. Actually, it has been shown that the glycemic threshold for activation of counterregulation and symptoms of hypoglycemia is increased in diabetic subjects chronically hyperglycemic (42), whereas it is decreased in diabetics treated with regimens of intensive insulin therapy (42)(43)(44)(45)(46)(47) which result in chronically subnormal plasma glucose concentrations (48).…”

Experimental diabetic neuropathy: impairment of slow transport with changes in axon cross-sectional area.

“…The finding that diabetes has an effect on transport in central axons is not surprising, since there is a large body of evidence that in diabetes both metabolism and functions of the central nervous system are affected (37)(38)(39). The paucity of clinical signs of central nervous system involvement in diabetes (40,41) may be explained on the basis of a preferential vulnerability of peripheral over central axons that is also observed in certain toxic conditions (27) Another finding of the present study is that the crosssectional area of the sciatic axons in diabetic animals is increased in the proximal segments, normal in the intermediate region, and decreased distally (see Fig.…”

Adaptation in brain glucose uptake following recurrent hypoglycemia.

“…Twelve normal humans were studied over 4 days. (6). Based on the preceding series of facts, we presume that in sustained human hypoglycemia, normal increments in epinephrine and glucagon will fail to occur, reflecting a normalization ofglucose availability to the brain secondary to improved glucose uptake.…”

“…Chronic changes in the antecedent level ofglycemia (either sustained hyperglycemia or hypoglycemia) induce alterations in brain glucose metabolism in rodents. Chronically hyperglycemic animals experience low fractional extraction (and presumably reduced transport capacity), while animals with diabetes treated to reduce their glucose levels toward normal have relatively higher fractional rates of glucose extraction (6). Based on the preceding series of facts, we presume that in sustained human hypoglycemia, normal increments in epinephrine and glucagon will fail to occur, reflecting a normalization ofglucose availability to the brain secondary to improved glucose uptake.…”