Insulin-like growth factors-I and -II and their binding proteins during postnatal development of dwarf Snell mice before and during growth hormone and thyroxine therapy

1994 ◽  
Vol 143 (1) ◽  
pp. 191-198 ◽  
Author(s):  
S C van Buul-Offers ◽  
R J Bloemen ◽  
M G Reijnen-Gresnigt ◽  
H A van Leiden ◽  
C M Hoogerbrugge ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factors ◽  
Size Distribution ◽  
Culture Media ◽  
Gel Chromatography ◽  
Gh Treatment ◽  
Igf I ◽  
Dwarf Mice ◽  
Igfbp 3 ◽  
Insulin Like Growth Factors

Abstract The ontogeny of serum insulin-like growth factors (IGFs)-I and -II and their binding proteins (IGFBPs) was studied in normal and dwarf Snell mice. IGF-I concentrations in serum of normal mice increased between 4 and 8 weeks of age; dwarf mice had very low serum IGF-I levels. In both normals and dwarfs, serum IGF-II levels were highest soon after birth and dropped steadily thereafter. Western ligand blots of serum IGFBPs with 125I-IGF-II as tracer revealed the expected bands 41·5, 38·5, 30–32 and 24 kDa. In normal mice the IGFBP-3 doublet was already detectable at 2 weeks of age, and its intensity increased with age. In dwarf mice the IGFBP-3 doublet was hardly detectable. The changes of IGFs and their IGFBPs were studied in sera of dwarf mice after treatment with growth hormone (GH) and/or thyroxine (T4) for 4 weeks. In spite of a comparable growth response obtained using these hormones, serum IGF-I was increased only by GH treatment; a small but significant decrease of serum IGF-II was obtained following GH or T4 treatment. An increase of the IGFBP-3 doublet was only obtained with GH; T4 and GH+T4 had no effect. The rise of IGFBP-3 after GH treatment was accompanied by the formation of the IGFBP 150 kDa complex, as measured by neutral gel chromatography. The size distribution of 125 I-IGF-II was restored to normal, while with 125I-IGF-I only a small peak at 150 kDa was observed. Elution profiles of sera after treatment with T4 or GH+T4 were identical to those of dwarf controls. The presence of the IGFBPs was investigated in media conditioned by liver and lung explants of normal and dwarf animals. In culture media of liver explants from normal mice, bands at 30–32 and 24 kDa predominated; the intensity of the IGFBP-3 doublet was relatively low. In dwarfs the 30–32 kDa predominated. In culture media of the lung from normal mice the IGFBP-3 doublet and the 24 kDa band were clearly visible; in dwarf mice IGFBPs could not be detected. We were unable to identify the 150 kDa IGFBP-complex in this medium using the size distribution of 125I-IGFs on neutral gel chromatography after incubation with the conditioned media. This was in contrast to data obtained with normal serum. Our data suggest that serum IGFBP-3 and IGF-I are regulated by GH and not by T4. In dwarf Snell mice, serum IGF-II is down regulated by GH as well as T4. The 150 kDa IGFBP complex is absent in dwarfs and, when induced by GH, seems to have a high affinity for IGF-II. Journal of Endocrinology (1994) 143, 191–198

Serum concentrations of insulin-like growth factors (IGFs), IGF binding proteins 1 and 3 and growth hormone binding protein in obese women and the effects of growth hormone administration: a double-blind, placebo-controlled study

1995 ◽  
Vol 133 (1) ◽  
pp. 65-70 ◽  
Author(s):  
Jens OL Jørgensen ◽  
Sten B Pedersen ◽  
Jens Børglum ◽  
Jan Frystyk ◽  
Ken KY Ho ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factors ◽  
Binding Proteins ◽  
Controlled Study ◽  
Obese Women ◽  
Gh Treatment ◽  
Double Blind ◽  
Igf I ◽  
Igfbp 3 ◽  
Insulin Like Growth Factors

Jørgensen JOL, Pedersen SB, Borglum J, Frystyk J, Ho KKY, Christiansen JS, Ørskov H, Blum WF, Richelsen B. Serum concentrations of insulin-like growth factors (IGFs), IGF binding proteins 1 and 3 and growth hormone binding protein in obese women and the effects of growth hormone administration: a double-blind, placebo-controlled study. Eur J Endocrinol 1995;133:65–70. ISSN 0804–4643 Obesity is associated with suppressed growth hormone (GH) concentrations but relatively little is known about insulin-like growth factors(IGFs) and binding proteins for GH and IGFs (GHBP and IGFBPs) and the modulatory effect of GH administration. In a double-blind, crossover design we studied the impact of 5 weeks of placebo or GH administration (0.03 mg·kg−1 body wt·day−1) in nine obese women (mean± sem; age 30.4 ± 2.4 years; body mass index 37.0 ± 2.8kg/m2) on IGF-I, IGF-II, IGFBP-1 and -3 and GHBP. Serum IGF-I (μg/l) levels were subnormal and increased significantly following GH (117 ± 16 (placebo) vs 434 ± 33 (GH) vs 198 ± 15 (control (p < 0.01)). By contrast, serum IGF-II (μg/l) levels were in the normal range and remained unchanged (608 ± 20 (placebo) vs 647 ± 40 (GH) (NS)). Serum IGFBP-3 was in the normal range and increased significantly during GH treatment, although relatively less than IGF-I, such that the molar ratio between IGF-I and IGFBP-3 increased with GH treatment, whereas the ratio between IGF-I + IGF-II and IGFBP-3 remained unchanged. Serum IGFBP-1 was low in the placebo situation but became further and almost completely suppressed during GH treatment. During a 2-h hyperinsulinemic, euglycemic glucose clamp, IGFBP-1 decreased in the placebo study and remained suppressed during GH. Serum GHBP (nmol/l) levels were elevated substantially compared to non-obese controls (p < 0.001) and did not change during GH treatment (2.37 ± 0.36 (placebo) vs 2.21 ± 0.25 (GH) vs 0.80 ± 0.19 (control)). In conclusion. obese subjects have low total IGF-I levels but may exhibit relatively increased free IGF-I levels due to the suppression of IGFBP-1. This presumed elevation in free IGF-1 in obesity may explain the normal levels of IGFBP-3 and IGF-II, which contrasts with classic GH deficiency. Furthermore, obese subjects are responsive to exogenous GH in terms of total IGF-I generation and normalization of the ratio between IGF-I and IGFBP-3. Finally, obesity is associated with marked elevations in GHBP levels that were unaffected by 5 weeks of GH administration. Jens OL Jørgensen, Medical Department M, Aarhus Kommunehospital, DK-8000 C, Aarhus, Denmark

Insulin-like growth factors and their binding proteins in plasma and milk after growth hormone-stimulated galactopoiesis in normally lactating women

1993 ◽  
Vol 129 (5) ◽  
pp. 427-435 ◽  
Author(s):  
Bernhard H Breier ◽  
Stella R Milsom ◽  
Werner F Blum ◽  
Jürg Schwander ◽  
Brian W Gallaher ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factors ◽  
Plasma Levels ◽  
Binding Proteins ◽  
Recombinant Human Growth Hormone ◽  
Lactating Women ◽  
Igf I ◽  
Milk Volume ◽  
Igfbp 3 ◽  
Insulin Like Growth Factors

We performed a double-blind randomized placebo-controlled trial of recombinant human growth hormone (hGH) in normally lactating women (N = 8 per group) to investgate the endocrine mode of action of the galactopoietic effect of this hormone. Insulin-like growth factors I (IGF-I) and II (IGF-II) and their binding proteins (IGFBP-1, IGFBP-2 and IGFBP-3) were measured by radioimmunoassay in plasma and milk samples collected throughout the study. All assays were validated for human plasma and milk. Human GH treatment (0.1 IU·kg−1 body wt·day−1 for 7 days) increased plasma concentrations of IGF-I from 22.1±1.3 nmol/l (mean±sem) to 59.7±2.5 nmol/l (p<0.01). At the end of the study the increase in plasma IGF-I correlated significantly with the increase in milk volume (r=0.67, p<0.005, N=16). The IGF-I levels were considerably lower in milk, with 0.14±0.03 nmol/l before and 0.31±0.04 nmol/l after hGH treatment. The increase in milk IGF-I levels (134.0±14.5%) with hGH treatment was significant (p<0.01) and plasma and milk IGF-I concentrations correlated significantly when considering all samples of the study (r=0.45, p<0.001, N= 56). The concentrations of IGF-II were not changed significantly with hGH treatment in plasma (52.5±2.5 nmol/l before and 42.6±3.9 nmol/l after treatment) or milk (2.1±0.29 nmol/l before and 2.3±0.49 nmol/l after hGH treatment). The IGFBP-1 levels were not changed with hGH treatment in plasma (approximately 1.3 nmol/l) or milk (approximately 0.2 nmol/l). Although IGFBP-2 concentrations in plasma were reduced significantly (p<0.05) after hGH treatment (11.1±1.5 before and 8.4±0.9 nmol/l after hGH treatment), milk IGFBP-2 levels did not respond to hGH treatment. Milk levels were markedly higher (sevenfold) in comparison to plasma levels. Plasma IGFBP-3 showed a delayed and smaller rise with hGH treatment in comparison to the rise observed in IGF-I. However, at the end of the study the response (38.6±4.9%) to hGH was significant (p<0.01) and a significant correlation was observed also between the increase in IGFBP-3 and the increase in milk volume (r=0.55, p =0.03, N=16). Plasma IGF-I and IGFBP-3 concentrations correlated significantly when considering all samples of the study (r=0.61, p<0.001, N=63). Milk IGFBP-3 levels were approximately 100-fold lower in comparison to plasma levels and did not correlate with any other measurements. Our data show that hGH-stimulated galactopoiesis in normally lactating women is mediated by significant elevations of plasma and milk IGF-I and plasma IGFBP-3. While IGF-I may be a principal mediator of the galactopoietic effect of hGH, we cannot simply attribute the action of hGH solely to a systemic rise in IGF-I. The increase in plasma IGFBP-3 with hGH treatment suggests that IGFBP-3 could facilitate the delivery of IGF-I to the mammary gland. The high concentrations of IGFBP-2 in milk suggest that mammary epithelial IGFBP-2 may direct regional tissue distribution of IGF-I to the site of milk synthesis.

Insulin-like growth factors (IGF) I and II and IGF binding proteins 1, 2 and 3 during low-dose growth hormone (GH) infusion and sequential euglycemic and hypoglycemic glucose clamps: studies in GH-deficient patients

1993 ◽  
Vol 128 (6) ◽  
pp. 513-520 ◽  
Author(s):  
Jens OL Jorgensen ◽  
Werner F Blum ◽  
Nanette Horn ◽  
Niels Møller ◽  
Jens Møller ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factors ◽  
Inverse Correlation ◽  
Short Term ◽  
Igf Binding Proteins ◽  
Igf I ◽  
Igf Binding ◽  
Igfbp 3 ◽  
Strong Inverse Correlation ◽  
Insulin Like Growth Factors

To evaluate the short-term effects of growth hormone (GH), insulin and different levels of glycemia on insulin-like growth factors (IGF) I and II and IGF binding proteins (IGFBP) 1, 2 and 3, we studied six GH-deficient adolescents during a night and the following day in the postabsorptive (basal) state followed by sequential euglycemic (5 mmol/l) and hypoglycemic (3 mmol/l) glucose clamps concomitant with an intravenous infusion (starting at 24.00 h) of GH (35 μg/h) or saline. Current GH therapy was withdrawn 24 h prior to each study. Nocturnal levels of IGF-I, IGF-II, IGFBP-2 and IGFBP-3 remained stable during both studies. Nocturnal serum IGFBP-1 increased and correlated inversely with insulin in both studies. Regression analysis revealed a significant inverse correlation between mean nocturnal IGFBP-2 and IGFBP-3 levels. During the daytime, serum IGF-I declined slowly during saline infusion, whereas serum IGF-II remained stable in both studies. Serum IGFBP-1 displayed a gradual significant decline during the basal state and the euglycemic and hypoglycemic clamps seemed to be unaffected by GH levels. By contrast, serum IGFBP-2 remained stable during the same period in both the GH and the saline study. Serum IGFBP-3 declined insignificantly during the daytime in the saline study. In conclusion: a strong inverse correlation between IGFBP-1 and insulin is confirmed; serum IGFBP-2 exhibits a constant circadian pattern, which seems independent of both ambient glucose and insulin levels and short-term GH deprivation but, on the other hand, shows a strong inverse correlation with IGFBP-3 levels; it is possible that IGFBP-2 levels are regulated by IGFBP-3 or IGFBP-3 binding site availability.

Quantification of urinary insulin-like growth factors (IGFs) and IGF binding protein 3 in healthy volunteers before and after stimulation with recombinant human growth hormone

1995 ◽  
Vol 132 (4) ◽  
pp. 433-437 ◽  
Author(s):  
Burkhard Tönshoff ◽  
Werner F Blum ◽  
Mark Vickers ◽  
Sabine Kurilenko ◽  
Otto Mehls ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factors ◽  
Human Growth Hormone ◽  
Binding Protein ◽  
Recombinant Human Growth Hormone ◽  
Human Growth ◽  
Igf I ◽  
Before And After ◽  
Igfbp 3 ◽  
Insulin Like Growth Factors

Tönshoff B, Blum WF, Vickers M, Kurilenko S, Mehls 0, Ritz E. Quantification of urinary insulin-like growth factors (IGFs) and IGF binding protein 3 in healthy volunteers before and after stimulation with recombinant human growth hormone. Eur J Endocrinol 1995;132:433–7. ISSN 0804–4643 We examined excretion of urinary insulin-like growth factors I and II (IGF-I and IGF-II) and their major binding protein IGFBP-3 in comparison to their respective serum concentration in nine healthy female volunteers (median age 25 years, range 22–27) under baseline conditions and after stimulation with recombinant human growth hormone (rhGH), 4.5 IU twice daily subcutaneously for a period of 3 days. The IGFs were measured in unconcentrated urine by use of recently developed, highly sensitive radioimmunoassays. The IGFBP-3 was measured by a specific radioimmunoassay. The mean (±sd) urinary concentrations of IGF-I (0.08 ± 0.07 μg/l), IGF-II (1.02 ± 0.47 μg/l) and IGFBP-3 (19.1 ± 6.9 μg/l) were two to three orders of magnitude lower than in serum. The ratio of IGF-II over IGF-I concentration in urine (13:1) was five times higher than in serum (2.5:1), and the ratio of IGFBP-3 over the sum of IGF-I and IGF-II in urine (17:1) was four times higher than in serum (4:1). Urinary excretion was 63.3 ± 46.6 ng·m−2 · 24 h−1 for IGF-I, 1002 ± 598 ng·m−2 · 24 h−1 for IGFII and 18039 ± 4983 ng·m−2·24 h−1 for IGFBP-3. Using fast protein liquid exclusion chromatography, only immunoreactive IGFBP-3 components of less than 60 kD were detected in urine, with a major peak at 20kD. Urinary IGFBP-3 excretion correlated with serum IGFBP-3 (r = 0.61, p < 0.01) and the glomerular filtration rate (r = 0.56, p < 0.05) measured by steady-state inulin infusion clearances. Administration of rhGH stimulated significantly (p < 0.005) the serum IGF-I concentration by 50%, but not the urinary IGF-I excretion. In conclusion: the considerably higher ratio of IGF-II to IGF-I in urine compared to serum indicates that urinary IGF excretion does not represent only filtered IGFs, urinary IGF-I is a less sensitive indicator of GH activity than serum IGF-I, and as urinary IGFBP-3 excretion is in proportion to the glomerular filtration rate and serum IGFBP-3, it presumably reflects renal filtration of small immunoreactive IGFBP-3 fragments from the circulation. Burkhard Tönshoff, University Children's Hospital, Im Neuenheimer Feld 150, 69120 Heidelberg, Germany

Serum levels of insulin-like growth factors (IGF-I and IGF-II) and their binding protein (IGFBP-3) are not elevated in pancreatic cancer

1997 ◽  
Vol 22 (2) ◽  
pp. 95-100
Author(s):  
James D. Evans ◽  
Margaret C. Eggo ◽  
Ian A. Donovan ◽  
Simon R. Bramhall ◽  
John P. Neoptolemos
Keyword(s):  
Pancreatic Cancer ◽  
Growth Factors ◽  
Binding Protein ◽  
Serum Levels ◽  
Igf I ◽  
Igfbp 3 ◽  
Insulin Like Growth Factors

Growth hormone and parathyroid hormone stimulate IGFBP-3 in rat osteoblasts

1994 ◽  
Vol 267 (2) ◽  
pp. E226-E233 ◽  
Author(s):  
C. Schmid ◽  
I. Schlapfer ◽  
M. Peter ◽  
M. Boni-Schnetzler ◽  
J. Schwander ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Parathyroid Hormone ◽  
Growth Factor ◽  
Culture Media ◽  
Insulin Like Growth Factor ◽  
Igf I ◽  
Conditioned Cell Culture Medium ◽  
Rat Osteoblasts ◽  
Igfbp 3

Osteoblast-like cells prepared from calvaria of newborn rats produce insulin-like growth factor (IGF) I and several insulin-like growth factor binding proteins (IGFBPs) in vitro. Among the IGFBPs found in conditioned cell culture medium, IGFBP-3 is the most abundant. Intact IGFBP-3, as assessed by 125I-labeled IGF-II ligand blot analysis, is more abundant in culture media of cells exposed to growth hormone (GH) or to parathyroid hormone (PTH), both at 5 x 10(-9) mol/l, for 24 h. At the same time, concentrations of IGF-I are increased in media of cells exposed to PTH but not to GH, compared with hormone-free control cultures. IGFBP-3 mRNA is increased in osteoblasts exposed to PTH or to GH but not in response to 5 x 10(-9) mol/l IGF-I. PTH exerts a rapid (within 2 h) stimulatory effect on IGF-I and IGFBP-3 production, both at the message and peptide levels, whereas GH increases only IGFBP-3, both at the message and peptide levels (after 24 h). We conclude that IGF-I does not mediate increased IGFBP-3 production by rat osteoblasts in response to GH and PTH.

Hemoglobin level is linked to growth hormone-dependent proteins in short children

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 2075-2081 ◽  
Author(s):  
E Vihervuori ◽  
M Virtanen ◽  
H Koistinen ◽  
R Koistinen ◽  
M Seppala ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Skeletal Dysplasia ◽  
Recombinant Human Growth Hormone ◽  
Body Height ◽  
Human Growth ◽  
Gh Treatment ◽  
Blood Hemoglobin ◽  
Igf I ◽  
Igfbp 3

Erythropoiesis was investigated in 32 children wih short stature and in eight children with skeletal dysplasia by studying blood hemoglobin in relation to growth and to serum concentrations of insulin-like growth factor I (IGF-I), IGF binding protein-3 (IGFBP-3), and erythropoietin (EPO) before, during, and after 12 months of recombinant human growth hormone (GH) treatment. Blood hemoglobin concentration was positively correlated with relative body height and with serum IGF-I and IGFBP-3 levels (P = .001 to .02), but not with the concentrations of EPO. The normal age-dependency of hemoglobin was lacking. Hemoglobin levels and their responses to GH treatment were similar in the patients with GH deficiency and those with normal GH secretion. Treatment with GH accelerated growth and elevated the concentrations of hemoglobin, IGF- I, and IGFBP-3. In the eight patients with skeletal dysplasia, body mass increased similarly, but gain in height was less than in the other patients, and the increase in hemoglobin was markedly pronounced. In this group, the correlations between hemoglobin, IGF-I, and IGFBP-3 were extremely close (r = 0.80 to 0.85, P = .031 to .008). These findings are in accord with earlier observations from in vitro and animal studies, and suggest that the GH-IGF axis is involved in the physiologic elevation of hemoglobin levels during childhood.

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