Growth Hormone Induces Resistance to the Mitogenic Action of Insulin Through Local IGF-I: Studies in Normal and Pygmy T-Cell Lines

Growth hormone (GH) and insulin have both mitogenic and metabolic actions. The growth-promoting effects of GH in vivo are thought to be mediated by insulin-like growth factor-I (IGF-I), whereas the metabolic effects of GH are thought to be either direct or mediated by factors other than IGF-I. In previous studies using HTLV-II-transformed T-lymphoblast cell lines established from normal individuals, we have shown that GH preincubation induces resistance to the growth-promoting (mitogenic) action of insulin. In this study, using T-cell lines from 3 American control subjects, 1 African control subject, and 1 African Pygmy (the latter previously shown to be resistant to the growth-promoting actions of both IGF-I and GH), we examined the role of local IGF-I in the mediation of GH-induced resistance to the mitogenic action of insulin. In these studies, we quantified the stimulation of T-cell colony formation in response to insulin in the presence and absence of either GH or IGF-I. We found that 1) GH or IGF-I preincubation of normal T-cell lines completely blunts mitogenic responsiveness to subsequent stimulation with insulin (all P < 0.001 versus either no GH or no IGF-I); 2) pretreatment with a monoclonal antibody against the IGF-I receptor blocks both GH- and IGF-I-induced resistance to the mitogenic action of insulin in normal T-cell lines (both P = NS versus insulin alone); and 3) neither GH nor IGF-I preincubation induces resistance to the growth-promoting action of insulin in the Pygmy T-cell line (P = 0.37 and P = 0.74, respectively, versus insulin alone). We conclude from these data that 1) GH-induced resistance to the mitogenic action of insulin is mediated by local IGF-I, and 2) the Pygmy T-cell line does not develop insulin resistance in response to GH or IGF-I treatment because of a primary variation in IGF-I receptor function.