Synergistic inhibition of hepatic ketogenesis in the presence of insulin and a cAMP antagonist.
The separate or combined effects of insulin and the cAMP antagonist, the Rp-diastereomer of adenosine cyclic 3',5'-phosphorothioate (Rp-cAMPS), were examined on fatty acid-stimulated ketogenesis in hepatocytes from normal fasted rats. Addition of 0.4 mM oleic acid or 0.4 mM octanoic acid resulted in a linear increase in ketone production measured over 60 min. When oleic acid was the substrate, incubation with 1 to 30 microns Rp-cAMPS alone or 0.1 to 10 nM insulin alone caused a variable decrease in the production of ketones which did not exceed an average value of 30% in any one experiment. The simultaneous addition of Rp-cAMPS and insulin resulted in a greater than additive inhibition which reached average values between 47-60% when the theoretical combined inhibitory effect of the insulin alone plus the Rp-cAMPS alone was less than 18%. No significant effects of either insulin or Rp-cAMPS, alone or in combination, were seen when octanoic acid was the substrate. These data imply that Rp-cAMPS can potentiate insulin inhibition of hepatic ketogenesis through inhibition of a cAMP-mediated process.
Olivieri
M C
MC
Sandoz Research Institute, East Hanover, New Jersey 07936.
Botelho
L H
LH
D020155:3-Hydroxybutyric Acid; D000090:Acetoacetates / Q000096:biosynthesis; D000818:Animals; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004357:Drug Synergism; D006885:Hydroxybutyrates / Q000096:biosynthesis; D007328:Insulin / Q000494:pharmacology*; D007659:Ketones / Q000096:biosynthesis*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013873:Thionucleotides / Q000494:pharmacology*
D000090:Acetoacetates; D006885:Hydroxybutyrates; D007328:Insulin; D007659:Ketones; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; C016635:acetoacetic acid; D000242:Cyclic AMP; D020155:3-Hydroxybutyric Acid