Synergistic inhibition of hepatic glycogenolysis in the presence of insulin and a cAMP antagonist.
The effects of insulin on the ability of the specific intracellular cAMP-dependent protein kinase antagonist, the Rp diastereomer of adenosine cyclic 3',5'-phosphorothioate, to inhibit glycogenolysis induced by the Sp diastereomer was studied in hepatocytes isolated from fed rats. Addition of the cAMP agonist, (Sp)-cAMPS, to hepatocytes resulted in a concentration-dependent increase in glycogenolytic glucose production concomitant with the cAMP-dependent activation of phosphorylase and inhibition of glycogen synthase. Activity curves were shifted to the right in the presence of the cAMP antagonist, (Rp)-cAMPS. Preincubation of the hepatocytes with a maximally effective concentration of insulin did not affect the concentration of (Sp)-cAMPS required for half-maximal activation of phosphorylase but did result in a 10-fold shift in the concentration of (Sp)-cAMPS required for half-maximal inactivation of glycogen synthase. Preincubation of hepatocytes with a combination of the cAMP antagonist, (Rp)-cAMPS, and insulin resulted in synergistic inhibition of (Sp)-cAMPS-induced phosphorylase activation, glycogen synthase inactivation, and glycogenolytic glucose production. Since neither phosphorothioate diastereomer was hydrolyzed significantly during the course of the experiments, the synergistic effects of insulin are postulated to be working through a mechanism subsequent to the phosphodiesterase activation step.
D000818:Animals; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006006:Glycogen Synthase / Q000037:antagonists & inhibitors; D007328:Insulin / Q000494:pharmacology*; D008112:Liver Glycogen / Q000378:metabolism*; D008297:Male; D006005:Phosphorylases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors
D007328:Insulin; D008112:Liver Glycogen; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; D000242:Cyclic AMP; D006005:Phosphorylases; D006006:Glycogen Synthase