Inhibition of Gluconeogenesis in Isolated Rat Kidney Tubules by Branched Chain α-Ketoacids

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Abstract

Summary

Isolated rat kidney tubules served as a model to investigate the direct effects of branched chain aminoacids, their α-ketoderivatives, and of the homolog straight chain aliphatic α-ketoacids on renal gluconeogenesis. It is demonstrated that the α-ketoderivatives, rather than the branched chain aminoacids themselves, are potent inhibitors of renal gluconeogenesis from precursors, entering the glucogenic pathway on all levels below and above triose phosphate. This inhibitory action is not specific for the branched chain α-ketoacids, since it is also observed in the presence of the homolog straight chain aliphatic α-ketoacids. The suppression of renal gluconeogenesis by α-ketoacids can not be explained by a direct inhibition of gluconeogenic reactions, by inhibition of cellular respiration, or by interference with the stimulatory action of Ca++, cAMP, and L-lysine on renal gluconeogenesis. Although the point of inhibitory attack of α-ketoacids in renal gluconeogenesis could not be localized, an impairment of the kidney to respond to metabolic acidosis with an increase of gluconeogenesis was observed, since the pH optimum of renal gluconeogenesis was shifted from pH 6.8 to pH 7.7 in the presence of α-ketoisovaleric acid.

Speculation

On the basis of well known pathophysiologic parameters in human maple syrup urine disease an in vitro model has been developed with the purpose of elucidating the pathogenesis of metabolic acidosis and hypoglycemia in this disease.

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