Continuous s.c. infusion rather than twice-daily injections of IGF-I more effectively increases serum IGF binding protein-3 in female monkeys.

OBJECTIVE: In order to better understand how the IGF-I axis is affected by exogenous IGF-I, this study compared the effects of a constant s.c. infusion of IGF-I with that of twice-daily injections of IGF-I in young adult female rhesus monkeys. Clinical studies suggest that circulating concentrations of insulin-like growth factor binding protein-3 (IGFBP-3) are decreased or unaffected by IGF-I administration, whereas acute increases in IGF-I may increase serum IGFBP-1. However, studies in monkeys indicate that acute or continuous infusion of IGF-I effectively increases serum IGFBP-3. DESIGN AND METHODS: Female monkeys were studied for 5 days with no IGF-I supplementation (baseline) and for 5 days of IGF-I treatment by either constant infusion (120 microg/kg per day s.c., n = 5) or twice-daily injections of IGF-I (60 microg/kg per injection s.c., n = 5). Serum samples were collected daily at 0800 h and at 0800, 0900, 1100, 1500, and 2000 h on days 1 and 4 for each condition. Samples were assayed for IGF-I, IGFBPs-1 and -3, insulin, and glucose. RESULTS: Serum IGF-I was consistently increased above baseline within 24 h of the initiation of constant infusion, but was delayed until the second day of treatment in the injection group. Serum IGFBP-3 followed the pattern of IGF-I, with concentrations increased by day 1 during constant infusion and by day 2 during intermittent injections. Although both treatments effectively increased serum IGFBP-3, the increase was greater during constant infusion (31% above baseline) compared with injection (17%). Immunoblotting revealed that the constant infusion of IGF-I resulted in quantitatively more lower-molecular-mass fragments of IGFBP-3 than were observed during baseline or intermittent injections. Size-exclusion chromatography and ultrafiltration indicated that most IGFBP-3 was found in the ternary complex, with a greater percentage found in the ternary complex during baseline (90%) than during constant infusion (86%) or intermittent injections of IGF-I (87%). In contrast, serum concentrations of IGFBP-1 were increased on day 1 of both treatments, but declined towards baseline values as treatment progressed. Serum concentrations of insulin and glucose were unaffected by either mode of IGF-I treatment. Serum concentrations of IGF-I and IGFBP-3 were increased within 3h of the injection, before declining towards the pre-injection level. In contrast, the daily pattern of serum hormone concentrations was similar between the baseline condition and during constant infusion of IGF-I. Although higher during the treatment phase, serum IGF-I and IGFBP-3 concentrations decreased significantly from 0800 h until the afternoon meal, reaching a nadir in the evening before increasing again the next morning. Serum insulin decreased also after the morning meal and increased significantly immediately after the afternoon meal. Although serum IGFBP-1 also decreased initially after the morning meal, concentrations reached a peak before the afternoon meal as serum insulin reached its nadir. CONCLUSION: The results of the present analysis indicate that the constant infusion of IGF-I more effectively sustains serum concentrations of IGF-I and IGFBP-3 than do twice-daily injections. Although the percentage of IGF-I and IGFBP-3 in the ternary complex was similar during both treatments, the constant infusion regimen produced lower-molecular-mass fragments of IGFBP-3. In addition, serum IGF-I and IGFBP-3 appeared to be regulated diurnally, even during IGF-I infusion, whereas IGFBP-1 and insulin were affected by the timing of food intake. Taken together, these data suggest that, in the monkey, IGFBP-3 is regulated by factors in addition to GH, and that IGF-I can affect its own bioavailability by increasing circulating concentrations of IGFBP-3.

IGF-I but not the IGF-I variant long R(3)IGF-I increases serum IGFBP-3 in adolescent monkeys.

Previous work in rhesus monkeys has shown that both acute or chronic subcutaneous (s.c.) administration of insulin-like growth factor (IGF)-I elevates serum concentrations of IGF binding protein (IGFBP)-3. In order to determine whether an analog of IGF-I, which has a reduced affinity for the IGFBPs, has similar effects, a series of studies using adolescent female rhesus monkeys were conducted. In the first study, an s.c. injection of IGF-I (110 mg/kg;n = 6) significantly elevated serum IGFBP-3 concentrations through 7 h following treatment. In contrast, serum IGFBP-3 decreased throughout the day following an injection of Long R(3)IGF-I (110 mg/kg, s.c., n = 5). However, this decrease was not due to the analog treatment as serum IGFBP-3 also declined in a similar fashion in untreated females (n = 5) sampled on the same schedule. Serum GH levels were acutely suppressed by both IGFs but were not altered in untreated females. In the second study, serum IGFBP-3 were compared between untreated control females (n = 6) and females treated continuously by s.c. infusion with either Long R(3)IGF-I (120 mg/kg/day, s.c.;n = 5) or IGF-I (120 mg/kg/day, s.c.;n = 5) or IGF-I s.c.;n = 4). Serum IGFBP-3 was consistently elevated by IGF-I infusion, whereas levels in analog-treated monkeys were similar to those in control females. Although acute or chronic administration of Long R(3)IGF-I did not elevate serum IGFBP-3, chronic administration of the analog did not block the acute facilitating effects of IGF-I on serum IGFBP-3. The increase in serum IGFBP-3 following an acute injection of IGF-I (110 mg/kg, s.c.) was not significantly different between untreated females and females receiving a constant s.c. infusion of Long R(3)IGF-I. These data indicate either acutely or chronically administered IGF-I but not its analog Long R(3)IGF-I can elevate serum concentrations of IGFBP-3. Although the analog fails to increase serum IGFBP-3, it does not block the facilitating effects of IGF-I on concentrations of this IGFBP. Taken together, these data suggest that the increase in serum IGFBP-3 by exogenous IGF-I may not be a receptor mediated event but may be the result of IGF-I binding to IGFBP-3 and forming the binary and ternary complex, slowing IGFBP-3 degradation.