Insulin decreases phosphoenolpyruvate carboxykinase (GTP) mRNA activity by a receptor-mediated process.
The mRNA that codes for phosphoenolpyruvate carboxykinase accounts for approximately 0.2% of the protein synthesized in H4IIEC3 hepatoma cells maintained for 24 h in serum-free medium containing N6,O2'-dibutyryl cAMP and theophylline. This value decreases to 0.04% within 3 h after the addition of insulin. Maximal effects are produced by 10(-10) M insulin, and half-maximal deinduction of both the relative rate of synthesis of P-enolpyruvate carboxykinase and mRNA coding for P-enolpyruvate carboxykinase activity occurs at approximately 2 X 10(-12) M insulin. Porcine proinsulin is 4% as potent as porcine insulin since half-maximal deinduction of mRNA coding for P-enolpyruvate carboxykinase occurs at 5 X 10(-11) M. The concentration of proinsulin required to inhibit 125I-insulin binding by 50% is 2 X 10(-7) M, as compared to 6 X 10(-9) M for insulin; thus, the decreased sensitivity of this deinduction to proinsulin parallels the decreased binding affinity H4IIEC3 cells have for proinsulin as compared to insulin. These data indicate that insulin regulates P-enolpyruvate carboxykinase synthesis through a receptor-mediated process, that the effect occurs when less than 2% of the insulin receptors are occupied, and that this effect is exerted prior to the level of mRNA translation.
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D008114:Liver Neoplasms, Experimental / Q000201:enzymology*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D011972:Receptor, Insulin / Q000502:physiology*; D013806:Theophylline / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*
D007328:Insulin; D012333:RNA, Messenger; D003994:Bucladesine; D013806:Theophylline; D011972:Receptor, Insulin; D010729:Phosphoenolpyruvate Carboxykinase (GTP)