THE EFFECT OF DIABETES, DIETARY PROTEIN AND TYROSINE SUPPLEMENTATION ON BRAIN AMINO ACIDS, GROWTH RATE AND HYPOTHALAMIC CATECHOLAMINE METABOLISM IN RATS

To describe alterations in amino acid metabolism and brain function induced by diabetes, four major studies were completed. The first series of experiments indicated that the brain amino acid profile in diabetic rats (streptozotocin, 65 mg/kg, ip) was related to the effect of insulin deficiency and dietary protein on plasma amino acid concentrations. Both diabetes and dietary protein consumption (evaluated over a range from 15 to 60%) markedly increased plasma levels of the branched chain amino acids (BCAA), valine, leucine and isoleucine, and as a result, plasma neutral amino acid ratios were altered. The calculated rates of brain neutral amino acid influx correlated well with the observed increase in brain methionine concentration and the reduced levels of threonine, tyrosine and tryptophan. However, BCAA influx rate and brain concentration were not associated suggesting increased catabolism by cerebral tissue. The improved growth rate observed in the second study when either 4 or 8% tyrosine was incorporated (as a percentage of protein) into the diet of diabetic rats regulating protein intake by selecting from 10 to 60% protein diets suggests that the deficit in brain tyrosine availability may be functionally significant. As demonstrated by the third study, this beneficial response to supplemental tyrosine may be related to an effect on hypothalamic catecholamine metabolism. In diabetic rats, norepinephrine turnover was suppressed below normal by a carbohydrate meal, but stimulated by a meal containing 45% protein plus 8% tyrosine. Dopamine turnover was enhanced by dietary tyrosine, but only in normal animals indicating a differential response to precursor amino acid availability. The final investigations characterized the abnormally high plasma methionine levels initially observed in the first study. It was concluded that hypermethioninemia results from the combined effects of diabetic hyperphagia (increased methionine intake) and some unidentified response to streptozotocin exposure which limits methionine disposal. The possibility of an hepatotoxic effect of streptozotocin was raised. In conclusion, brain amino acid patterns in diabetic rats represent the interactions among insulin insufficiency, dietary protein intake and metabolic adaptation. The resulting changes in brain amino acid availability, especially those influencing neurotransmitter synthesis, may explain some aspects of the neuroendocrine dysfunction which occurs in diabetic rats.