Inhibition of lactate glucogneogenesis in rat kidney by dichloroacetate

Abstract

Sodium dichloroacetate (1 mM) inhibited glucose production from L-lactate in kidney cortex slices from fed, starved or alloxan-diabetic rats. In general gluconeogenesis from other substrates was not inhibited. Sodium dichloroacetate inhibited glucose production from L-lactate but not from pyruvate in perfused isolated kidneys from normal or alloxan-diabetic rats. Sodium dichloroacetate is an inhibitor of the pyruvate dehydrogenase kinase reaction and it effected conversion of pyruvate dehydrogenase into its active (dephosphorylated) form in kidney in vivo. Pyruvate dehydrogenase was mainly in the active form in kidneys perfused or incubated with L-lactate and the inhibitory effect of dichloroacetate on glucose production was not dependent on activation of pyruvate dehydrogenase. Balance data from kidney slices showed that dichloroacetate inhibits lactate uptake, glucose and pyruvate production from lactate, but not oxidation of lactate. The mechanism of this effect of dichloroacetate on glucose production from lactate has not been fully defined, but evidence suggests that it may involve a fall in tissue pyruvate concentration and inhibition of pyruvate carboxylation.