Effect of dichloroacetate on gluconeogenesis in vivo in the presence of a fixed gluconeogenic substrate supply to the liver

Michael P. Diamond, Philip E. Williams, William W. Lacy, Alan D. Cherrington

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Administration of dichloroacetate (DCA) to conscious 48 h fasted dogs causes a reduction in the conversion of circulating alanine and lactate to glucose coincident with both a reduction in the load of alanine and lactate delivered to the liver and a decrease in the plasma insulin-glucagon ( I G) molar ratio. To determine whether DCA inhibits gluconeogenesis independent of its effect on alanine and lactate levels, the drug was infused concurrently with alanine and lactate in order to fix the load of these gluconeogenic precursors reaching the liver. When the circulating levels of alanine and lactate were fixed, DCA increased the net hepatic uptake of alanine markedly (98 ± 26%) but increased lactate uptake only slightly (8 ± 7%). However, the fraction of these gluconeogenic precursors which were converted to 14C-glucose decreased. Since the net effect of these changes was to increase the overall conversion of alanine and lactate to glucose, it is evident that the increase in precursor uptake overrode the inhibition of the gluconeogenic process per se. This increase in hepatic precursor uptake may have been due to DCA stimulation of pyruvate dehydrogenase activity or the observed decline in the I G molar ratio. The observed increase in overall glucose production (33 ± 10%) was probably attributable to the increase in gluconeogenesis as well as an increase in glycogenolysis since 48 h fasted dogs still have some hepatic glycogen (15 mg/gm). By overcoming the peripheral effects of DCA on gluconeogenic precursor supply it becomes evident that DCA has: (1) a direct inhibitory action on intrahepatic gluconeogenesis, and (2) an effect on the pancreas which by virtue of a change in the I G molar ratio may offset the direct intrahepatic effect of the drug.

Original languageEnglish (US)
Pages (from-to)880-885
Number of pages6
JournalMetabolism
Volume30
Issue number9
DOIs
StatePublished - Sep 1981
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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