GLYCEROL AND LACTATE INDUCE RECIPROCAL CHANGES IN GLUCOSE FORMATION AND GLUTAMINE PRODUCTION IN ISOLATED RABBIT KIDNEY-CORTEX TUBULES INCUBATED WITH ASPARTATE

In renal tubules isolated from fed rabbits, 1 mM aspartate is mainly u tilized for production of glutamine, glutamate, alanine, and serine, w hile it is not used for glucose synthesis. However, the addition of ei ther 2 mM glycerol or 2 mM lactate, which are poor gluconeogenic subst rates in renal tubules, results in acceleration of both glucose format ion and incorporation of [C-14]aspartate into glucose by several fold, accompanied by about a twofold decrease in glutamine synthesis and ma rked accumulation of glutamate and alanine. Ammonium release in renal tubules incubated with aspartate in the presence of methionine sulfoxi mine, an inhibitor of glutamine synthetase, is also decreased on the a ddition of glycerol and lactate by about two- and threefold, respectiv ely. Since intracellular [glyceraldehyde 3-phosphate]/[3-phosphoglycer ate] [glycerol 3-phosphate]/[dihydroxyacetone phosphate], [lactate]/[p yruvate], and intramitochondrial [glutamate]/[2-oxoglutarate] x [NH4+] ratios are increased in comparison with control values determined wit h aspartate alone, it is likely that the stimulatory effect of lactate and glycerol on glucose formation from aspartate may be due to (i) an increased availability of reducing equivalents in the cytosol resulti ng in an enhancement of glyceraldehyde-3-phosphate dehydrogenase activ ity and (ii) elevation of the mitochondrial NADH/NAD(+) ratio causing a decrease in glutamate dehydrogenase activity resulting in a diminish ed glutamine synthesis and enhanced provision of carbon skeleton of as partate for gluconeogenesis. Stimulation of glucose formation in the p resence of 1 mM aspartate + glycerol is not related to cell volume cha nges. However, an increase for about 30% of intracellular water space induced by 10 mM aspartate + glycerol is accompanied by both diminishe d gluconeogenesis and enhanced glutamine synthesis, compared with valu es measured with 1 mM aspartate plus glycerol. (C) 1995 Academic Press , Inc.