Effects of glucagon on glutamate metabolism in the perfused rat liver.

Early, rapid effects of glucagon on glutamate metabolism were studied in rat livers perfused with bicarbonate buffer containing bovine albumin and red cells, [14C]glutamate in tracer amounts, and physiological levels of lactate and pyruvate. Glucagon increased [Wlglucose synthesis from [W]glutamate to a greater extent than from other labeled substrates. The effect was maximal at 3 min and was not inhibited by fluoroacetate. The hormone decreased the tissue concentrations of glutamate, oc-ketoglutarate, and citrate and increased those of alanine, aspartate, and P-pyruvate. In livers perfused with [14C]glutamate for 2>$ min, glucagon increased the radioactivities of succinate, fumarate, aspartate, P-pyruvate, alanine, and glutamine, and decreased those of glutamate and or-ketoglutarate. Under these conditions, the specific radioactivities of aspartate, P-pyruvate, and alanine increased. These results are consistent with glucagon stimulation of the conversion of ar-ketoglutarate to succinate, of the synthesis of P-pyruvate, and of the transamination of oxalacetate to aspartate and of pyruvate to alanine. Tryptophan markedly inhibited the labeling of P-pyruvate and glucose in livers perfused with [Wlglutamate and increased the tissue levels of intermediates prior to P-pyruvate in the gluconeogenic pathway. Glucagon stimulation of [14C]glucose synthesis was abolished, but the hormone still produced changes in the levels and radioactivities of intermediates consistent with activation of a step between w ketoglutarate and succinate. Arsenite produced changes in metabolite levels consistent with inhibition of oc-ketoglutarate and pyruvate oxidation and abolished the effects of glucagon on [14C]glucose formation and on the levels and radioactivities of intermediates. Glucagon stimulated the release of i4COs from [1J4C]glutamate. The effect was apparently unaltered by fluoroacetate but was abolished by arsenate. Tryptophan diminished the production of r4COp in control livers slightly but did not alter the stimulation by glucagon. These data provide