EFFECTS OF INTERACTIONS BETWEEN IGFBPS AND IGFS ON THE PLASMA-CLEARANCE AND INVIVO BIOLOGICAL-ACTIVITIES OF IGFS AND IGF ANALOGS

The relative activities in vivo of IGFs that differ in their associati on affinities towards IGF binding proteins (IGFBPs) have been examined in a series of comparisons between IGF-I and LR3IGF-I. IGF-I has appr oximately 1000 fold higher affinity than LR3IGF-I towards IGFBP-3, IGF BP4, total rat plasma IGFBPs and L6 myoblast BP. In cultured L6 myobla sts the reduced association with IGFBPs gives LR3IGF-I a 5-10 fold gre ater biological potency. Chronic administration of the peptides over 1 4 days to normal female rats produces marked increases in body weight, nitrogen retention and food conversion efficiency as well as retentio n 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 reflectin g the in vitro difference. In a second series of experiments in which the clearance rates of the two peptides were compared, LR3IGF-I was sh own to be removed from the plasma much more rapidly than was IGF-I, a difference reflecting the poor association of LR3IGF-I with plasma IGF BPs. The crucial relevance of binding protein association in explainin g the difference was confirmed in pregnant rats where IGFBP levels are markedly reduced. In this condition only the clearance of IGF-I was a ffected to produce a clearance rate almost as rapid as that found with LR3IGF-I. These experiments demonstrate that an IGF variant which ass ociates poorly with IGFBPs is removed more rapidly from the blood and is more potent than IGF-I.