Effects of glucagon on gluconeogenesis from lactate and propionate in the perfused rat liver.
Quinolinic acid (Q.A.) which inhibits gluconeogenesis at the site of phosphoenolpyruvate (PEP) synthesis, reduced the content of PEP while elevating that of aspartate and malate in rat livers perfused with a medium containing 10 mM L-lactate. Glucagon at 10(-9) M did not affect Q.A. inhibition of lactate gluconeogenesis nor the depression of PEP level, but further elevated malate and aspartate accumulation. Exogenous butyrate had the same effect as glucagon on these parameters. Butylmalonate (BM), an inhibitor of mitochondrial malate transport, inhibited lactate and propionate gluconeogenesis to similar extents. The addition of 10(-9) M glucagon had no effect on BM inhibition of lactate gluconeogenesis, but almost completely reversed BM inhibition of propionate gluconeogenesis. These results suggest that glucagon may act on at least two sites, resulting in elevated hepatic gluconeogenesis. First, it may stimulate dicarboxylic acid synthesis (malate and oxaloacetate, specifically) through activation of pyruvate carboxylation. Secondly, it may stimulate synthesis of other dicarboxylic acids (fumarate, for example) by activating certain steps of the tricarboxylic acid cycle. The stimulatory effect of glucagon on gluconeogenesis in the perfused rat liver is well documented (1, 2). Exton et al., who earlier located the site of stimulation between pyruvate and PEP synthesis (3), proposed that glucagon stimulated PEP synthesis in the perfused rat liver (4), while reports from Williamson et al. (5) suggested the pyruvate-carboxylase reaction as the site of glucagon action. Stimulation at sites above PEP formation and of portions of the tricarboxylic acid cycle (4) by glucagon have also been suggested (6). In the present experiments, we have used substrates entering at different parts of the gluconeogenic pathway, and specific inhibitors to further resolve the action of glucagon.
D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000187:drug effects*; D007773:Lactates / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D010728:Phosphoenolpyruvate / Q000378:metabolism; D011422:Propionates / Q000378:metabolism*; D011805:Quinolinic Acids / Q000494:pharmacology; D051381:Rats
D002087:Butyrates; D007773:Lactates; D011422:Propionates; D011805:Quinolinic Acids; D010728:Phosphoenolpyruvate; D005934:Glucagon