Differential responses of IGF-I molecular complexes to military operational field training

2003 ◽  
Vol 95 (3) ◽  
pp. 1083-1089 ◽  
Author(s):  
Bradley C. Nindl ◽  
John W. Castellani ◽  
Andrew J. Young ◽  
John F. Patton ◽  
M. Javad Khosravi ◽  
...  
Keyword(s):  
Nutritional Status ◽  
Relative Proportion ◽  
Molecular Complexes ◽  
Energy Deficit ◽  
Short Term ◽  
Igf Binding Proteins ◽  
Igf I ◽  
Before And After ◽  
Term Energy ◽  
Igfbp 3

Insulin-like growth factor (IGF) I and IGF binding proteins (IGFBPs) modulate metabolic activity and tissue repair and are influenced by nutritional status. IGF-I circulates in free, ternary [IGF-I + IGFBP-3 + acid labile subunit (ALS)], and binary (IGF-I + IGFBP) molecular complexes, and the relative proportions regulate IGF-I extravascular shifting and bioavailability. This study examined the hypothesis that sustained physical activity and sleep deprivation superimposed on a short-term energy deficit would alter the IGFBP concentrations and alter the proportions of IGF-I circulating in ternary vs. binary molecular complexes. Components of the IGF-I system (total and free IGF-I; IGFBP-1, -3, and ALS; nonternary IGF-I and IGFBP-3), biomarkers of metabolic and nutritional status (transferrin, ferritin, prealbumin, glucose, free fatty acids, glycerol, β-hydroxybutyrate), and body composition were measured in 12 men (22 ± 3 yr, 87 ± 8 kg, 183 ± 7 cm, 20 ± 5% body fat) on days 1, 3, and 4 during a control and experimental (Exp) period. During Exp, subjects performed prolonged work (energy expenditure of ∼4,500 kcal/day) with caloric (1,600 kcal/day) and sleep (6.2 h total) restriction. IGF-I and IGFBP-3 were measured by immunoassay before and after immunoaffinity depletion of ALS-based complexes (i.e., ternary complex removal). Exp produced losses in body mass (-3.0%), lowered total IGF-I (-24%), free IGF-I (-42%), IGFBP-3 (-6%), nonternary IGF-I (-27%), and IGFBP-3 (-16%), and increased IGFBP-1 (256%). No Exp effects were observed for ALS. No changes were observed in the proportion of IGF-I circulating in free (∼1.2%), ternary (∼87.4%), or nonternary (∼11.4%) molecular complexes. During Exp, glucose concentrations were lower on day 3, but days 1 and 4 were statistically similar. In conclusion, during a short-term energy deficit in young, healthy men, 1) IGF-I system components differentially respond (both in direction and magnitude) to a given metabolic perturbation and 2) the relative proportion of IGF-I sequestered in ternary vs. nonternary molecular complexes appears to be well maintained.

Ontogenic and nutritional changes in circulating insulin-like growth factor (IGF)-I, IGF-II and IGF-binding proteins in growing ewe and ram lambs

1997 ◽  
Vol 155 (1) ◽  
pp. 47-54 ◽  
Author(s):  
KL Gatford ◽  
KJ Quinn ◽  
PE Walton ◽  
PA Grant ◽  
BJ Hosking ◽  
...  
Keyword(s):  
Sex Differences ◽  
Feed Intake ◽  
Plasma Concentrations ◽  
Endocrine System ◽  
Igf Binding Proteins ◽  
Igf I ◽  
Before And After ◽  
Igf Binding ◽  
Igf Binding Protein ◽  
Igfbp 3

The ontogeny of the IGF endocrine system was investigated in 15 young lambs before and after weaning at 62 days of age. Before weaning, plasma IGF-I concentrations were higher in rams than ewes, and plasma concentrations of IGF-II and IGF-binding protein-3 (IGFBP-3) also tended to be higher in rams than in ewes. Feed intake of ewes and rams was restricted after weaning to remove sex differences in feed intake. Plasma concentrations of IGF-I and IGFBP-3 did not differ between rams and ewes at 100 days of age, but plasma IGF-II was higher in rams than in ewes at this time. Since circulating concentrations of GH were higher in rams than in ewes at 100 days of age, this implies that the restricted feed intake blocked the IGF-I and IGFBP-3 responses to GH. We conclude that sex differences in circulating IGF-I and IGFBP-3 concentrations in the growing lamb alter with age, and are not present when nutrition is restricted.

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.

The effect of epidermal growth factor on circulating levels of IGF and IGF-binding proteins in adult Goettingen minipigs

1996 ◽  
Vol 151 (3) ◽  
pp. 401-407 ◽  
Author(s):  
L Vinter-Jensen ◽  
C Orloff Juhl ◽  
J Frystyk ◽  
E Z Dajani ◽  
N Oksbjerg ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Binding Proteins ◽  
Igf Binding Proteins ◽  
Igf I ◽  
Before And After ◽  
Igf Binding ◽  
Epidermal Growth ◽  
Circulating Levels ◽  
Igfbp 3

Abstract It has recently been demonstrated that epidermal growth factor (EGF) administration to neonatal rodents causes growth retardation with concomitant reductions in circulation levels of IGF-I. We describe the effects of systemic EGF administration for 4 weeks on circulating levels of IGF-I and IGF-binding proteins (IGFBPs) and on thyroid hormones (tri-iodothyronine, T3; thyroxine, T4) in sexually mature pigs. Goettingen minipigs of either sex were treated with placebo (n=5) or EGF (30 μg/kg per day, n=6) s.c. for 4 weeks (in relation to an oesophageal sclerotherapy regimen). Blood samples were taken under anaesthesia before and after 1, 2, 3 and 4 weeks of treatment. Circulating levels of IGF-I, insulin, glucose, T3 and T4 were analysed every week and IGFBPs every second week. IGF-I was not reduced significantly after 1 week but significantly reduced after 2 and 3 weeks of EGF treatment. A similar decline was observed for the major IGFBP, IGFBP-3, which was reduced after 2 and 4 weeks. IGFBP-1, IGFBP-2 and IGFBP-4 increased throughout the treatment period (all significantly at week 4). EGF treatment induced increased circulating T3 after 2, 3 and 4 weeks of EGF treatment. In conclusion, we report that EGF treatment for 4 weeks in Goettingen minipigs reduces circulating IGF-I and IGFBP-3, increases circulating IGFBP-1, IGFBP-2 and IGFBP-4, and induces a slight hyperthyroidism as judged from increased circulating levels of T3. Journal of Endocrinology (1996) 151, 401–407

scholarly journals Leptin Does Not Mediate Short-Term Fasting-Induced Changes in Growth Hormone Pulsatility but Increases IGF-I in Leptin Deficiency States

2008 ◽  
Vol 93 (7) ◽  
pp. 2819-2827 ◽  
Author(s):  
Jean L. Chan ◽  
Catherine J. Williams ◽  
Patricia Raciti ◽  
Jennifer Blakeman ◽  
Theodore Kelesidis ◽  
...  
Keyword(s):  
Binding Protein ◽  
Major Effect ◽  
Normal Weight ◽  
Energy Deficit ◽  
Short Term ◽  
Hypothalamic Amenorrhea ◽  
Igf System ◽  
Leptin Deficiency ◽  
Igf I ◽  
Igfbp 3

Abstract Context: States of acute and chronic energy deficit are characterized by increased GH secretion and decreased IGF-I levels. Objective: The objective of the study was to determine whether changes in levels of leptin, a key mediator of the adaptation to starvation, regulate the GH-IGF system during energy deficit. Design, Setting, Patients, and Intervention: We studied 14 healthy normal-weight men and women during three conditions: baseline fed and 72-h fasting (to induce hypoleptinemia) with administration of placebo or recombinant methionyl human leptin (r-metHuLeptin) (to reverse the fasting associated hypoleptinemia). We also studied eight normal-weight women with exercise-induced chronic energy deficit and hypothalamic amenorrhea at baseline and during 2–3 months of r-metHuLeptin treatment. Main Outcome Measures: GH pulsatility, IGF levels, IGF and GH binding protein (GHBP) levels were measured. Results: During short-term energy deficit, measures of GH pulsatility and disorderliness and levels of IGF binding protein (IGFBP)-1 increased, whereas leptin, insulin, IGF-I (total and free), IGFBP-4, IGFBP-6, and GHBP decreased; r-metHuLeptin administration blunted the starvation-associated decrease of IGF-I. In chronic energy deficit, total and free IGF-I, IGFBP-6, and GHBP levels were lower, compared with euleptinemic controls; r-metHuLeptin administration had no major effect on GH pulsatility after 2 wk but increased total IGF-I levels and tended to increase free IGF-I and IGFBP-3 after 1 month. Conclusions: The GH/IGF system changes associated with energy deficit are largely independent of leptin deficiency. During acute energy deficit, r-metHuLeptin administration in replacement doses blunts the starvation-induced decrease of IGF-I, but during chronic energy deficit, r-metHuLeptin administration increases IGF-I and tends to increase free IGF-I and IGFBP-3.

scholarly journals IGFs and IGF-binding proteins in short children with steroid-dependent nephrotic syndrome on chronic glucocorticoids: changes with 1 year exogenous GH

2001 ◽  
pp. 237-243 ◽  
Author(s):  
X Zhou ◽  
KY Loke ◽  
CC Pillai ◽  
HK How ◽  
HK Yap ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Growth Retardation ◽  
Bone Age ◽  
Gh Treatment ◽  
Igf Binding Proteins ◽  
Steroid Dependent ◽  
Igf I ◽  
Igf Binding ◽  
Pre Treatment ◽  
Igfbp 3

OBJECTIVE: Children with steroid-dependent nephrotic syndrome (SDNS), despite being in remission on glucocorticoids, continue to have growth retardation and short stature. The mechanism is uncertain as both chronic glucocorticosteroids and the nephrotic syndrome may independently affect growth. We investigated the changes in the IGFs and IGF-binding proteins (IGFBPs) in a group of short SDNS children, and studied the changes prospectively with 1 year's treatment with GH. DESIGN AND METHODS: Total and 'free' IGF-I, IGFBP-3 and acid-labile subunit (ALS) were studied in eight SDNS boys (mean age=12.6 years; mean bone age=9.1 years) on long term oral prednisolone (mean dose 0.46 mg/kg per day) before, during, and after, 1 year's treatment with GH (mean dose 0.32 mg/kg per week). Pretreatment comparisons were made with two control groups, one matched for bone age (CBA; mean bone age=9.2 years), and another for chronological age (CCA; mean chronological age=13 years). Subsequently, three monthly measurements of serum and urine IGFBPs were carried out in the GH-treated SDNS patients using Western ligand blot and Western immunoblot. RESULTS: Pre-treatment serum total IGF-I levels and the IGF-I/IGFBP-3 ratio were elevated significantly in SDNS compared with CBA, and were similar to CCA. Serum free IGF-I levels were elevated significantly compared with both control groups, but serum IGFBP-3 did not differ significantly. Urinary IGFBP-2, IGFBP-3 and ALS were detectable in the SDNS children only. With GH treatment, IGF-I and IGFBP-3, but not IGF-II, increased significantly compared with pre-treatment values, and returned to baseline after cessation of GH treatment. Urinary IGFBPs did not change significantly with GH treatment. CONCLUSIONS: There is persistent urinary loss of IGFBP-2, IGFBP-3 and ALS in children with SDNS in remission with growth retardation. However, the significant elevation in serum IGF-I suggests that glucocorticoid-induced resistance to IGF is the main factor responsible for the persistent growth retardation in these children. Exogenous GH was able to overcome this resistance by further increasing serum IGF-I.

Measurement of Human Igf-II Using Sephacryl Extraction: A Rapid and Reliable Assay Method

1996 ◽  
Vol 33 (3) ◽  
pp. 201-208 ◽  
Author(s):  
Barbara H Mason ◽  
Michele A Tatnell ◽  
Ian M Holdaway
Keyword(s):  
Growth Factor ◽  
Binding Proteins ◽  
Complete Removal ◽  
Assay Method ◽  
Insulin Like Growth Factor ◽  
Serum Concentrations ◽  
Igf Binding Proteins ◽  
Factor Ii ◽  
Igf I ◽  
Igfbp 3

Measurement of insulin-like growth factor II (IGF-II) in human serum is complicated by the presence of IGF binding proteins and usually involves cumbersome extraction procedures followed by radioimmunoassay. We have utilized an extraction process developed for measuring insulin-like growth factor II in ovine serum using Sephacryl HR100, and have applied this to the extraction of human samples followed by radioimmunoassay for human IGF-II. The assay yielded 98% recovery of unlabelled IGF-II, parallelism between dilutions of eluate and the standard curve, complete removal of binding proteins and near-complete removal of IGF-I, and intra- and interassay coefficients of variation of 5% and 9%, respectively. The normal range for serum IGF-II in women was 490–1056 μg/L, and IGF-II levels were positively correlated with serum concentrations of insulin-like growth factor binding protein-3 (IGFBP-3) but not with IGF-I levels. Mean serum concentrations of IGF-II were reduced below normal in a number of hypopituitary patients and children with short stature and IGF-II concentrations in these subjects correlated positively with IGF-I and IGFBP-3. In acromegalic patients IGF-II levels were usually normal and were negatively correlated with IGF-I concentrations. From our experience with the above results the present assay appears particularly suitable for clinical measurements and research projects where high sample throughput is required.

Circulating insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs) and tissue mRNA levels of IGFBP-2 and IGFBP-4 in the ovine fetus

1995 ◽  
Vol 145 (3) ◽  
pp. 545-557 ◽  
Author(s):  
J M Carr ◽  
J A Owens ◽  
P A Grant ◽  
P E Walton ◽  
P C Owens ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Mrna Level ◽  
Common Factor ◽  
Late Gestation ◽  
Mrna Levels ◽  
Igf Binding Proteins ◽  
Fetal Sheep ◽  
Igf I ◽  
Igf Binding ◽  
Igfbp 3

Abstract The IGF-binding proteins (IGFBPs) are a family of at least six structurally related proteins, which bind the IGFs and modulate their actions, including the regulation of preand postnatal growth. In this study we have examined the relationship between circulating and tissue mRNA levels of IGFBPs and related this to circulating IGFs in the fetal sheep over the gestational period when rapid growth and development occurs. Circulating IGFBP-2, as measured by Western ligand blot (WLB), increases between early and mid gestation, remains high, then declines throughout late gestation (P=0·0002). Circulating IGFBP-3 increases throughout gestation, as measured by WLB or RIA (P=0·04 and P=0·0001 respectively), as does circulating IGFBP-4 (P=0·004). These ontogenic changes in circulating IGFBPs-2 and -4 are paralleled by changes in liver mRNA for these proteins and, for IGFBP-2, by those in kidney IGFBP-2 mRNA also. This suggests that liver and kidney may be the primary contributors to circulating IGFBP-2 and the liver to circulating IGFBP-4. IGFBP-2 mRNA is present in the heart and lung in early gestation but barely detectable in these tissues after approximately 60 days gestation. IGFBP-4 mRNA is also present in the heart in early but not late gestation, but is abundant in the lung throughout gestation. These results demonstrate tissue specific and developmental regulation of IGFBPs-2 and -4 at the mRNA level. To assess any role the circulating IGFs may play in mediating these changes in IGFBPs, or vice versa, both plasma IGF-I and IGF-II were measured by RIA. Circulating IGF-I increases as gestation progresses (P=0·0001), while circulating IGF-II increases between early and mid gestation, remains high (P=0·01), then declines. Circulating IGF-I is positively correlated with fetal weight (r=0·66, P=0·03), circulating IGFBP-3 (r=0·54, P=0·01) and IGFBP-4 (r=0·52, P=0·01). Circulating IGF-II positively correlates with circulating IGFBP-2 (r=0·48, P=0·02) throughout gestation and at 1 day postnatally. These relationships are consistent with circulating IGF-I influencing IGFBPs-3 and -4, and similarly, IGF-II determining IGFBP-2, or vice versa. Alternatively, these correlations may reflect coordinate regulation of IGF and IGFBP by a common factor. Journal of Endocrinology (1995) 145, 545–557

scholarly journals Insulin-like Growth Factor II Signaling in Neoplastic Proliferation Is Blocked by Transgenic Expression of the Metalloproteinase Inhibitor Timp-1

1999 ◽  
Vol 146 (4) ◽  
pp. 881-892 ◽  
Author(s):  
David C. Martin ◽  
John L. Fowlkes ◽  
Bojana Babic ◽  
Rama Khokha
Keyword(s):  
Growth Factor ◽  
T Antigen ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Early Event ◽  
Mrna Levels ◽  
Insulin Like Growth Factor ◽  
Igf Binding Proteins ◽  
Protein Levels ◽  
Igf I ◽  
Igfbp 3

Insulin-like growth factor (IGF) II is overexpressed in many human cancers and is reactivated by, and crucial for viral oncogene (SV40 T antigen, [TAg])–induced tumorigenesis in several tumor models. Using a double transgenic murine hepatic tumor model, we demonstrate that tissue inhibitor of metalloproteinase 1 (TIMP-1) blocks liver hyperplasia during tumor development, despite TAg-mediated reactivation of IGF-II. Because the activity of IGFs is controlled by IGF-binding proteins (IGFBPs), we investigated whether TIMP-1 overexpression altered the IGFBP status in the transgenic liver. Ligand blotting showed that IGFBP-3 protein levels were increased in TIMP-1–overexpressing double transgenic littermates, whereas IGFBP-3 mRNA levels were not different, suggesting that TIMP-1 affects IGFBP-3 at a posttranscriptional level. IGFBP-3 proteolysis assays demonstrated that IGFBP-3 degradation was lower in TIMP-1–overexpressing livers, and zymography showed that matrix metalloproteinases (MMPs) were present in the liver homogenates and were capable of degrading IGFBP-3. As a consequence of reduced IGFBP-3 proteolysis and elevated IGFBP-3 protein levels, dissociable IGF-II levels were significantly lower in TIMP-1–overexpressing animals. This decrease in bioavailable IGF-II ultimately resulted in diminished IGF-I receptor signaling in vivo as evidenced by diminished receptor kinase activity and decreased tyrosine phosphorylation of the IGF-I receptor downstream effectors, insulin receptor substrate 1 (IRS-1), extracellular signal regulatory kinase (Erk)-1, and Erk-2. Together, these results provide evidence that TIMP-1 inhibits liver hyperplasia, an early event in TAg-mediated tumorigenesis, by reducing the activity of the tumor-inducing mitogen, IGF-II. These data implicate the control of MMP-mediated degradation of IGFBPs as a novel therapy for controlling IGF bioavailability in cancer.

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