Dichloroacetate lowers blood glucose and diminishes blood levels of lactate, pyruvate, and alanine in both starvation and diabetes. To determine the role of skeletal muscle in these changes, studies were carried out in intact rats, with the isolated perfused rat hindquarter and soleus muscle preparation. In hindquarters from fed, starved, and diabetic rats, dichloroacetate alone or in the presence of insulin did not augment glucose uptake. On the other hand, it dramatically curtailed the release of the gluconeogenic precursors lactate, pyruvate, and alanine. Dichloroacetate increased markedly the generation of 14CO2 from lactate-1-14C in starved and diabetic rats, suggesting activation of pyruvate dehydrogenase. The increment in lactate oxidation was stoichiometri-cally equivalent to the decrease in lactate plus alanine release. Glycolysis, as determined from the sum of lactate and alanine release plus lactate oxidation in the hindquarter and from the formation of 3H2O from 3-3H-glucose by the incubated soleus muscle, was not altered by dichloroacetate. Dichloroacetate curtailed the release of most amino acids in the perfused hindquarter of fed rats. In starved and diabetic rats, it caused an increase in the release of valine, leucine, and isoleucine, suggesting inhibition of their metabolism. As judged from lactate-pyruvate and 3-hydroxybutyrate-acetoacetate ratios and changes in tissue α-glycerol-phosphate, perfusion with dichloroacetate caused the cytosol of the muscle cell to become more reduced and the mitochondria more oxidized. Similar changes occurred when it was administered to intact animals. These findings suggest that the hypoglycemic effect of dichloroacetate is, at least in part, due to a decrease in the release of gluconeogenic precursors from skeletal muscle secondary to activation of pyruvate dehydrogenase.

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