Plasma clearance and tissue distribution of labelled insulin-like growth factor-I (IGF-I) and an analogue LR3IGF-I in pregnant rats

1993 ◽  
Vol 138 (2) ◽  
pp. 327-336 ◽  
Author(s):  
S. E. P. Bastian ◽  
P. E. Walton ◽  
J. C. Wallace ◽  
F. J. Ballard
Keyword(s):  
Growth Factor ◽  
Tissue Distribution ◽  
Rat Plasma ◽  
Pharmacokinetic Parameters ◽  
Metabolic Clearance ◽  
Insulin Like Growth Factor ◽  
Pregnant Rats ◽  
Pregnant Rat ◽  
Fetal Plasma ◽  
Igf I

ABSTRACT To determine whether the changes in insulin-like growth factor-binding proteins (IGFBPs) and IGF-I levels during pregnancy in rats affect the clearance of IGFs from the circulation, we have measured pharmacokinetic parameters and the tissue distribution of radiolabelled IGF-I and LR3IGF-I, a potent analogue which has a markedly reduced affinity of binding to the IGFBPs. Intravenous boluses of radiolabelled growth factors were administered to catheterized virgin and age-matched pregnant rats on day 18 of gestation when plasma IGFBPs, in particular IGFBP-3, are dramatically reduced. IGF-I was cleared more rapidly from plasma in pregnant rats compared with the virgins; metabolic clearance rate (MCR) = 2·88±0·12 (s.e.m.) and 0·90±0·05 ml/min per kg respectively. Although LR3IGF-I was cleared more rapidly than IGF-I from plasma, similar clearance rates for the analogue were obtained in both pregnant and virgin animals, MCR = 9·19±0·15 and 9·84±0·28 ml/min per kg respectively. In virgin rat plasma, labelled IGF-I was mainly associated with the 150 kDa complex, whereas in pregnant rat plasma IGF-I was predominantly associated with lower Mr IGFBPs (approximately 30–50 kDa). The majority of LR3IGF-I was detected as free peptide. A larger proportion of the tracer was detected as small Mr breakdown products in plasma from rats under conditions of reduced binding to IGFBPs, e.g. during pregnancy or when LR3IGF-I was the labelled tracer, suggesting greater rates of IGF degradation. More LR3IGF-I tracer was detected in kidneys, ovaries and adrenals of virgin rats and in the ovaries and adrenals of pregnant rats, compared with IGF-I tracer. IGF-I radioactivity was greater than LR3IGF-I in caecum, brain, liver and heart in virgin rats and in kidneys, caecum, brain, liver, heart, placenta, fetus and fetal plasma of the pregnant rats. These results show that the reduction in IGFBP during pregnancy dramatically increased the clearance of IGF-I from the circulation towards that obtained with LR3IGF-I. The observation that less LR3IGF-I was detected in placenta, fetus and fetal plasma compared with IGF-I raises the possibility that the ability to bind IGFBPs during pregnancy may enhance IGF uptake by the conceptus. Journal of Endocrinology (1993) 138, 327–336

Metabolic clearance of insulin-like growth factor-II in sheep

1989 ◽  
Vol 123 (3) ◽  
pp. 461-468 ◽  
Author(s):  
S. C. Hodgkinson ◽  
S. R. Davis ◽  
L. G. Moore ◽  
H. V. Henderson ◽  
P. D. Gluckman
Keyword(s):  
Molecular Weight ◽  
Growth Factor ◽  
Binding Proteins ◽  
Binding Protein ◽  
Total Radioactivity ◽  
Size Exclusion ◽  
Metabolic Clearance ◽  
Insulin Like Growth Factor ◽  
Factor Ii ◽  
Igf I

ABSTRACT The metabolic clearance of ovine insulin-like growth factor-II (IGF-II) was examined in sheep using 131I-labelled IGF-II. Following i.v. administration the tracer was distributed in a volume similar to that of the vascular space (58-5 ±3.3 ml/kg; mean ± s.e.m., n = 5) and demonstrated a triphasic pattern of clearance. Size-exclusion chromatography of a plasma sample collected 1 min after injection revealed peaks of radioactivity corresponding to hormone complexed to binding proteins of 150 and 40–50 kDa (relative abundance 21 and 65% respectively), a high molecular weight binding protein (>200 kDa; 5%) and 'free' tracer (9%). Chromatography of sequential plasma samples revealed different patterns of clearance for these constituents. Half-lives of 131I-labelled IGF-II complexed to the 150 and 40–50 kDa binding proteins, as calculated from rate constants for their decay, were 351 ± 30 and 9.6 ± min respectively (n = 5). These differ markedly from estimates for the clearance of IGF-I (545 ± 25 min, n = 8, and 34 ± 2.3 min, n = 6) associated with carrier proteins of the same apparent molecular weights. This was reflected in calculated metabolic clearance rates for IGF-I (3.9 ± 0.5 ml/min) and IGF-II (7.8 ±1.0 ml/min). Chromatography also revealed that free IGF-II was reduced to negligible levels by 12 min. In contrast, radioactivity eluting in the position expected for the > 200 kDa binding protein was cleared from the circulation very slowly. However, the small proportion of total radioactivity eluting in these molecular weight regions precluded calculation of decay constants for these species. Tracer degradation was monitored throughout the clearance study and estimated to be <20% at 800 min following i.v. administration. Less than 20% of tracer was cleared into urine over the 24 h of sampling, concurrent with a >90% fall in plasma radioactivity. Tracer in urine was completely degraded. Journal of Endocrinology (1989) 123, 461–468

Characterization of insulin-like growth factor-binding protein in ovine amniotic fluid

1990 ◽  
Vol 127 (2) ◽  
pp. 325-333 ◽  
Author(s):  
J.-F. Wang ◽  
L. J. Fraher ◽  
D. J. Hill
Keyword(s):  
Growth Factor ◽  
Amniotic Fluid ◽  
Binding Protein ◽  
Binding Activity ◽  
Scatchard Analysis ◽  
Insulin Like Growth Factor ◽  
Fetal Plasma ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein

ABSTRACT We have characterized an insulin-like growth factor (IGF)-binding protein present in ovine amniotic fluid. Using an activated charcoal-binding assay, whole amniotic fluid specifically bound approximately 20–30% of 125I-labelled human (h) IGF-II added, while the binding of 125I-labelled hIGF-I was minimal. Radioimmunoassay for IGF-I or -II in ovine biological fluids showed that values in amniotic fluid were 9- to 13-fold less than in fetal plasma, while gel filtration of amniotic fluid on Sephadex G-50 eluted with 1 mol acetic acid/l revealed no additional binding activity which had been complexed to IGFs at neutral pH. Together, these observations suggest that the binding activity in amniotic fluid is largely unsaturated. Competition studies for the displacement of 125I-labelled IGF-II binding to amniotic fluid by increasing amounts of unlabelled IGF-I or -II, using the charcoal assay, showed that IGF-II was 30-fold more potent than IGF-I. Scatchard analysis revealed a single class of binding site for IGF-II, with a binding affinity of 0·68 ±0·18 litres/nmol (mean ± s.d., n = 3). Ligand blot analysis of amniotic fluid by separation on 8% SDS-PAGE, transfer to nitrocellulose membranes, incubation with 125I-labelled IGF-II and autoradiography revealed a single band of IGF-binding protein with approximate molecular size of 38 kDa. Additional IGF-binding species of 20, 28, 48 and > 180 kDa were present in ovine fetal plasma. Separation of amniotic fluid on Concanavalin A–Sepharose revealed that it had little carbohydrate content. These results show that ovine amniotic fluid contains an unsaturated, non-glycosylated IGF-binding protein with high affinity for IGF-II. These characteristics differ from those of the IGF-binding proteins purified from human amniotic fluid. Journal of Endocrinology (1990) 127, 325–333

Insulin-like growth factor-I (IGF-I) and IGF-binding proteins both decline in the rat during late pregnancy

1990 ◽  
Vol 127 (3) ◽  
pp. 383-390 ◽  
Author(s):  
S. E. Gargosky ◽  
P. E. Walton ◽  
P. C. Owens ◽  
J. C. Wallace ◽  
F. J. Ballard
Keyword(s):  
Growth Factor ◽  
Binding Proteins ◽  
Late Pregnancy ◽  
Insulin Like Growth Factor ◽  
Igf Binding Proteins ◽  
Pregnant Rats ◽  
Factor I ◽  
Igf I ◽  
Igf Binding ◽  
Igfbp 3

ABSTRACT Insulin-like growth factor-I (IGF-I), IGF-II and IGF-binding proteins (IGFBP) were examined in rat serum during pregnancy and lactation. IGF-I concentrations determined after acid column chromatography of serum were low during the last third of pregnancy. IGF-II was undetectable in pregnant and non-pregnant rats. IGF-binding protein (IGFBP) concentrations, measured as high molecular mass activity in the IGF-I RIA and the IGF-II RRA of acid column fractions, paralleled the changes observed with IGF-I. Western ligand blot analysis of serum from non-pregnant rats revealed a 40–50 kDa IGFBP aligning with IGFBP-3, a smaller 28–30 kDa doublet and 24 kDa IGFBP. Serum from rats in late pregnancy lacked IGFBP-3, whereas the smaller IGFBP persisted during late pregnancy. IGFBP-3 reappeared in postpartum animals. The fall in serum IGF-I is consistent with a maternal catabolic state during late pregnancy which may maximize substrate availability for the developing fetus. Journal of Endocrinology (1990) 127, 383–390

Administration of insulin-like growth factor-I, but not growth hormone, increases maternal weight gain in late pregnancy without affecting fetal or placental growth

1991 ◽  
Vol 130 (3) ◽  
pp. 395-400 ◽  
Author(s):  
S. E. Gargosky ◽  
J. A. Owens ◽  
P. E. Walton ◽  
P. C. Owens ◽  
J. C. Wallace ◽  
...  
Keyword(s):  
Weight Gain ◽  
Growth Factor ◽  
Late Pregnancy ◽  
Placental Weight ◽  
Insulin Like Growth Factor ◽  
Maternal Weight Gain ◽  
Maternal Weight ◽  
Pregnant Rats ◽  
Factor I ◽  
Igf I

ABSTRACT During late pregnancy in the rat, circulating levels of insulin-like growth factor-I (IGF-I) and some IGF-binding proteins (IGFBP) decline. The aim of the present study was to determine the relationship of GH to circulating IGF and IGFBP in the late-pregnant rat and to examine the effects on maternal, fetal and placental growth of preventing the decline in serum IGF and IGFBP concentrations. During the first 9 days of pregnancy, IGF-I concentrations increased from 340 to 500 μg/l. Recombinant human (rh) GH at 2·4 mg/kg per day and rhIGF-I at 1·4 mg/kg per day were infused into pregnant rats via osmotic mini pumps during the second half of pregnancy. After pump implantation on day 11 of pregnancy, only IGF-I infusion significantly increased circulating IGF-I. A maximum IGF-I concentration of 907 μg/l was measured on day 14 during treatment with IGF-I, after which the serum concentration decreased to 510 μg/l by day 20 of pregnancy. The serum IGFBPs were examined using a Western ligand blot technique. Infusion of neither GH nor IGF-I returned the IGFBPs to non-pregnant levels. Administration of IGF-I slightly increased IGFBP-3 and a smaller 32 kDa IGFBP at days 17 and 20 of pregnancy. Neither fetal nor placental weight was significantly different between treatment groups. However, administration of IGF-I significantly increased maternal weight gain during the 10-day treatment period. Thus, pregnant rats infused with IGF-I gained 99±4 g (mean ± s.e.m., n = 10) compared with rats treated with GH or vehicle which gained 72±4 g (n = 9) and 77±4 g (n = 10) respectively. The increase in maternal weight after administration of IGF-I was not due to increased litter size, fetal or placental weight. The increased maternal weight gain after IGF administration, without affecting fetal and placental weights, suggests a modification in the mode of maternal nutrient repartitioning during late pregnancy. Journal of Endocrinology (1991) 130, 395–400

Fetal plasma insulin-like growth factor-binding protein-3 concentrations are elevated following bilateral nephrectomy in fetal sheep

1995 ◽  
Vol 7 (3) ◽  
pp. 345
Author(s):  
C Beanland ◽  
C Browne ◽  
R Young ◽  
J Owens ◽  
P Walton ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Insulin Like Growth Factor ◽  
Bilateral Nephrectomy ◽  
Fetal Sheep ◽  
Factor Binding ◽  
Fetal Plasma ◽  
Igf I ◽  
Igf Binding ◽  
Igfbp 3

Insulin-like growth factors mediate many of the effects of growth hormone and are important in the regulation of growth, especially in the fetus where growth is less dependent on circulating growth hormone. In the ovine fetus, insulin-like growth factor-I (IGF-I) is bound mainly to the low molecular weight insulin-like growth factor-binding proteins (IGFBP), IGFBP-1 and IGFBP-2, with little binding to IGFBP-3 until near term at 147 days gestation. To determine if there was any difference in plasma IGF-I and IGFBP-3 concentrations in growth-retarded fetal sheep with altered renal status, concentrations were measured by specific radioimmunoassay from bilaterally nephrectomized fetal sheep between Days 113 and 135 gestation. Plasma IGFBP-3 concentrations were significantly (P < 0.001) increased in bilaterally nephrectomized fetuses (4.19 +/- 0.19 micrograms mL-1, n = 7) compared with control fetuses (2.33 +/- 0.10 micrograms mL-1, n = 7). There was no change in plasma IGFBP-3 concentration with gestational age in either experimental group. Maternal plasma IGFBP-3 concentrations did not differ between the bilateral nephrectomy group (3.11 +/- 0.09 micrograms mL-1, n = 7) and the control group (3.25 +/- 0.11 micrograms mL-1, n = 7) and showed no change within groups over the experimental period. Total plasma IGF-I concentrations in bilaterally nephrectomized fetuses and ewes were similar to those in control fetuses and ewes. The results indicate that the profile of IGF binding in fetal plasma is altered in the anephric fetal sheep. In nephrectomized fetal sheep, increased IGFBP-3 concentrations, and therefore increased IGF-binding capacity in fetal plasma, may have contributed to a decrease in free IGF in plasma and decreased IGF-I bioactivity. This would provide a possible mechanism for the growth retardation reported in bilaterally nephrectomized fetal sheep.

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