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, micrograms/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.
Lieberman
S A
SA
Medical Service, Palo Alto Veterans Affairs Medical Center, California 94304.
Bukar
J
J
Chen
S A
SA
Celniker
A C
AC
Compton
P G
PG
Cook
J
J
Albu
J
J
Perlman
A J
AJ
Hoffman
A R
AR
D000328:Adult; D001786:Blood Glucose / Q000032:analysis*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000097:blood / Q000187:drug effects*; D006801:Humans; D007003:Hypoglycemia / Q000097:blood; D007328:Insulin / Q000097:blood; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I / Q000032:analysis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D011994:Recombinant Proteins / Q000494:pharmacology; D013002:Somatomedins / Q000187:drug effects
D001786:Blood Glucose; D002352:Carrier Proteins; D007328:Insulin; D018969:Insulin-Like Growth Factor Binding Proteins; D011994:Recombinant Proteins; D013002:Somatomedins; D007334:Insulin-Like Growth Factor I