Effects of recombinant human insulin-like growth factor-I (rhIGF-I) on total and free IGF-I concentrations, IGF-binding proteins, and glycemic response in humans

To examine the effects of repeated administration of recombinant human insulin-like growth factor–I (rhIGF–I) on IGF–I levels, free IGF–I pharmacokinetics, glycemic response, and IGF–binding proteins (IGFBP), we administered rhIGF–I (0.03 mg/kg iv bolus) to 12 healthy males each morning for 5 consecutive days. Serum was collected over 24 h on days 1 and 5 for measurement of total and free IGF–I, glucose, insulin, and IGFBP. Total IGF–I was measured by RIA after acid/ethanol extraction. Free IGF–I was separated from binding protein–complexed IGF–I using size exclusion high performance liquid chromatography before measurement by RIA. IGFBP were quantitated by optical densitometry of Western ligand blots. Total IGF–I increased significantly from 0–24 h after administration on day 1 (mean ± SD, μgrams/L: 120 ± 44 to 166 ± 51, P = 0.0002) but did not increase significantly from 24 h on day 1 to 0 h on day 5 (166 ± 51 to 178 ± 62) or from 0–24 h on day 5 (178 ± 62 to 209 ± 89). The area under the total IGF–I concentration curve was greater on day 5 than day 1 (311 ± 99 min.g/L vs. 249 ± 77, P = 0.0001). There were no significant differences in free IGF–I concentration or pharmacokinetic parameters or in the degree or timing of hypoglycemia between days 1 and 5. Plasma insulin levels decreased significantly following rhIGF–I administration (day 1 baseline: 53 ± 11 pmol/L, nadir: 18 ± 6 pmol/L at 30 min, P = 0.003); day 5 baseline: 47 ± 15 pmol/L, nadir: 16 ± 8 pmol/L at 30 min, P = 0.0003. Western ligand blotting revealed the transient appearance of a 30–kilodalton band which migrates in a manner similar to IGFBP–1. This band was undetectable at baseline, peaked between 150 and 210 min after rhIGF–I administration, and diminished by 480–600 min. The response was similar on days 1 and 5. There were no substantial changes in the serum levels of any other IGFBP. In summary, repeated iv bolus administration of rhIGF–I increased the level of total circulating IGF–I without changing free IGF–I disposition or glycemic response. A 30–kilodalton IGFBP band, most likely IGFBP–1, appeared transiently following rhIGF–I administration, probably as a result of suppression of insulin levels. IGFBP–2, –3, and –4 were unaffected.