Effects of interactions between IGFBPs and IGFs on the plasma clearance and in vivo biological activities of IGFs and IGF analogs.

The relative activities in vivo of IGFs that differ in their association affinities towards IGF binding proteins (IGFBPs) have been examined in a series of comparisons between IGF-I and LR3IGF-I. IGF-I has approximately 1000 fold higher affinity than LR3IGF-I towards IGFBP-3, IGFBP-4, total rat plasma IGFBPs and L6 myoblast BP. In cultured L6 myoblasts the reduced association with IGFBPs gives LR3IGF-I a 5-10 fold greater biological potency. Chronic administration of the peptides over 14 days to normal female rats produces marked increases in body weight, nitrogen retention and food conversion efficiency as well as retention of the carcass composition and fractional weights of the gut, spleen and thymus that are characteristic of the younger age. In the growth measurements LR3IGF-I is 6 fold more potent than IGF-I, thus reflecting the in vitro difference. In a second series of experiments in which the clearance rates of the two peptides were compared, LR3IGF-I was shown to be removed from the plasma much more rapidly than was IGF-I, a difference reflecting the poor association of LR3IGF-I with plasma IGFBPs. The crucial relevance of binding protein association in explaining the difference was confirmed in pregnant rats where IGFBP levels are markedly reduced. In this condition only the clearance of IGF-I was affected to produce a clearance rate almost as rapid as that found with LR3IGF-I. These experiments demonstrate that an IGF variant which associates poorly with IGFBPs is removed more rapidly from the blood and is more potent than IGF-I.