Insulin regulation of insulin-like growth factor action in rat hepatoma cells.
We have reported previously that insulin causes a complete but reversible desensitization to insulin action in rat hepatoma HTC cells in tissue culture, and that this insulin resistance is mediated by postbinding mechanisms rather than receptor down-regulation (Heaton, J. H., and Gelehrter, T. D. (1981) J. Biol. Chem. 256, 12257-12262). We report here that insulin causes a similar desensitization to the induction of tyrosine aminotransferase by the insulin-like growth factors IGF-I and IGF-II isolated from human plasma, and by multiplication-stimulating activity, the rat homologue of IGF-II. The results of both competition-binding studies and affinity cross-linking experiments indicate that insulin-like growth factors (IGFs) bind primarily to IGF receptors rather than to insulin receptors. The low concentrations at which these factors induce transaminase is consistent with their acting primarily via IGF receptors. This is confirmed by experiments utilizing anti-insulin receptor antibody which both inhibits 125I-insulin binding and shifts the concentration dependence of insulin induction of tyrosine aminotransferase to the right. This same immunoglobulin does not inhibit 125I-multiplication-stimulating activity binding and only minimally inhibits 125I-IGF-I binding. Anti-insulin receptor antibody also does not significantly shift the concentration dependence for the IGFs, suggesting that IGFs induce transaminase by acting via IGF receptors. Although insulin down regulates insulin receptors, it does not decrease IGF-I or IGF-II binding. We conclude that insulin causes desensitization of HTC cells to IGFs by affecting a postbinding step in IGF action, which may be common to the actions of both insulin and insulin-like growth factors.
D000818:Animals; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology*; D007700:Kinetics; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D013002:Somatomedins / Q000378:metabolism*; D014444:Tyrosine Transaminase / Q000096:biosynthesis
D007328:Insulin; D010455:Peptides; D013002:Somatomedins; D003907:Dexamethasone; D014444:Tyrosine Transaminase; D011972:Receptor, Insulin