Synergistic inhibition of glucagon-induced effects on hepatic glucose metabolism in the presence of insulin and a cAMP antagonist.
Inhibition of hepatic glycogenolysis by an intracellular inhibitor of cAMP-dependent protein kinase in glucagon-stimulated hepatocytes was potentiated by insulin. When hepatocytes isolated from fed rats were treated with 0.3 nM glucagon, which activates glycogen breakdown half-maximally, the Rp diastereomer of adenosine cyclic 3',5'-phosphorothioate [Rp-cAMPS), a cAMP antagonist, inhibited glucose production half-maximally at 3 microM. A 10-fold lower concentration of antagonist was required to half-maximally inhibit glucose production in the presence of 10 nM insulin, which alone produced only 15% inhibition. Under the same experimental conditions, the maximal effect of (Rp)-cAMPS was also potentiated. In addition, the increase in the concentration of glucagon required for half-maximal activation of phosphorylase activity and inactivation of glycogen synthase activity in the presence of minimally effective concentrations of insulin and (Rp)-cAMPS were clearly synergistic. It is postulated that the synergism observed is a consequence of action at several enzymatic sites leading to, and including, alteration of the phosphorylation state of the two rate-limiting enzymes in glycogen metabolism.
D000818:Animals; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004357:Drug Synergism; D005934:Glucagon / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D006006:Glycogen Synthase / Q000032:analysis; D007328:Insulin / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D006005:Phosphorylases / Q000032:analysis; D051381:Rats; D013873:Thionucleotides / Q000494:pharmacology*
D007328:Insulin; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; D005934:Glucagon; D000242:Cyclic AMP; D006005:Phosphorylases; D006006:Glycogen Synthase; D005947:Glucose