Metabolic effects of dichloroacetate in diabetic dogs

Abstract

In fasted, diabetic dogs treated with dichloroacetate (DCA) (300 mg X kg-1 X h-1 iv), we determined the relative contributions by skeletal muscle and gut to the supply of precursors used for hepatic gluconeogenesis. The total production of lactate and alanine by skeletal muscle and gut decreased from 2,370 to 1,160 mumol X kg-1 X h-1 during treatment with DCA. Hepatic uptake of these substrates decreased from 1,040 to 435 mumol X kg-1 X h-1, and blood glucose decreased from 370 +/- 18 to 279 +/- 22 mg/dl (P less than 0.001). DCA treatment decreased the skeletal muscle production of both lactate and alanine to 40% of control, whereas gut production was decreased to only 72% of control levels. Hepatic uptake of the two substrates decreased in proportion to the change in blood levels because fractional hepatic extraction was unaltered. The effects of DCA on the interorgan metabolism of plasma amino acids showed that diminished availability of alanine for hepatic gluconeogenesis was compensated in part by increased release of other gluconeogenic amino acids from muscle and gut. Gut uptake of glutamine appeared unchanged, but most of its metabolic end products were released in greater amounts by DCA treatment, suggesting enhanced glutamine degradation. These results in fasted, diabetic dogs indicate that 1) DCA treatment lowers blood glucose in part by limitation of gluconeogenic substrate supply from skeletal muscle and gut, and 2) DCA has complex and diverse effects on the interorgan metabolism of plasma amino acids.