Superior potency of infused IGF-I analogues which bind poorly to IGF-binding proteins is maintained when administered by injection

The relative potency of IGF-I and the analogue LR(3)IGF-I to either promote growth or reverse catabolism in rats when administered by injection rather than by continuous infusion has been examined. LR(3)IGF-I has very low affinity for the IGF-binding proteins in the rat and hence is cleared from the circulation more quickly than is IGF-I. Experiments were performed in normal growing rats (150 g body weight) and in rats made catabolic by dexamethasone infusion (20 mu g/day). IGFs or vehicle were delivered subcutaneously for 7 days either by continuous infusion via osmotic pumps or by injection once or twice daily at 320 and 400 mu g/day in normal and catabolic rats respectively. As expected, continuous infusion of IGFs showed greater efficacy than either of the injection modes especially in its anti-catabolic actions. When infused continuously LR(3)IGF-I was generally 1.5- to 2-fold more potent than IGF-I for changes in body weight gain, visceral organ weights and feed use efficiency. Notably, LR(3)IGF-I remained more potent than IGF-I in several of these effects even when the peptides were given by once-daily injection. In addition, N-tau-methylhistidine excretion by dexamethasone-treated rats was reduced to a threefold greater extent by injected LR(3)IGF-I than by injected IGF-I. Notwithstanding these effects, LR(3)IGF-I was barely equipotent with IGF-I for reversal of carcass muscle loss in dexamethasone-treated rats. Despite its more rapid clearance from the circulation, injected LR(3)IGF-I retains superior potency to injected IGF-I for several actions, albeit the potency is much reduced compared with continuous infusion. Thus our data indicate that use of IGF analogues which have low affinity for binding proteins may have advantages in potency and/or tissue specificity where IGFs are necessarily administered by injection.