scholarly journals Glycosaminoglycans increase levels of free and bioactive IGF-I in vitro

2006 ◽  
Vol 155 (2) ◽  
pp. 297-305 ◽  
Author(s):  
Anne Vestergård Møller ◽  
Søren Peter Jørgensen ◽  
Jian-Wen Chen ◽  
Anni Larnkjær ◽  
Thomas Ledet ◽  
...  
Keyword(s):  
Dermatan Sulfate ◽  
Post Partum ◽  
Normal Subjects ◽  
Serum Levels ◽  
Dependent Manner ◽  
Igf Binding Proteins ◽  
Igf I ◽  
Igf Binding

Background: It is unclear how IGFs become separated from their IGF-binding proteins (IGFBPs) in vivo. However, the IGFBPs possess binding sites for glycosaminoglycans (GAGs) and interaction with GAGs alters IGFBP ligand affinity. Accordingly, GAGs may control IGF bioavailability. To test this hypothesis, we investigated the effect of GAGs on serum levels of free and bioactive IGF-I, total IGF-I, and IGFBPs in vitro. Methods: Serum was incubated with increasing concentrations of six different GAGs (heparin, tinzaparin (Innohep®), dermatan sulfate, heparan sulfate, non-anticoagulant (nac) heparin, and nac low-molecular weight heparin). To investigate for reversibility, heparin was co-incubated with protamine sulfate (PS). Finally, the effect of heparin was studied in serum from pregnant and post partum women, normal subjects and patients with type 1 diabetes. Results: All GAGs increased free IGF-I in a dose-dependent manner (P < 0.0001), whereas total IGF-I and IGFBP levels remained unchanged. However, the potency of the GAGs differed significantly (P < 0.0001) and did not relate to their anti-coagulating activity. The effect of heparin on free IGF-I was fully reversed by PS. Heparin increased free and bioactive IGF-I in all tested sera (P < 0.0001), but the increase was most pronounced in samples from pregnant women (P < 0.0001). Conclusion: All tested GAGs stimulated the release of free and bioactive IGF-I in several types of serum, most likely by reversible interaction with the IGFBPs. The effect was most pronounced in pregnancy sera, which are characterized by extensive IGFBP-3 proteolysis. Our findings support the view that GAGs localized in the vessel wall and attached to the extracellular matrix control IGF-I tissue accessibility and bioactivity.

scholarly journals Effects of IGF-I bioavailability on bovine preantral follicular development in vitro

Reproduction ◽  
2007 ◽  
Vol 133 (6) ◽  
pp. 1121-1128 ◽  
Author(s):  
Fiona H Thomas ◽  
Bruce K Campbell ◽  
David G Armstrong ◽  
Evelyn E Telfer
Keyword(s):  
Follicular Development ◽  
Follicle Development ◽  
Dependent Manner ◽  
Igf Binding Proteins ◽  
Preantral Follicles ◽  
Follicle Diameter ◽  
Igf I ◽  
Igf Binding ◽  
Development In Vitro

The aim of this study was to determine the effect of regulation of IGF-I bioavailability on preantral follicle development in vitro. Bovine preantral follicles were cultured for 6 days in serum-free medium with increasing doses of Long R3 (LR3) IGF-I (an analog with low affinity for IGF-binding proteins (IGFBPs)), or human recombinant IGF-I (hrIGF-I). Follicle diameter and estradiol production were measured every second day. On day 6, ratios of oocyte/follicle diameter and oocyte morphology were assessed by histological examination, and IGFBP-2 and -3 were detected by immunocytochemistry and in situ hybridization respectively. Both types of IGF-I increased follicle diameter in a dose-dependent manner (P < 0.05) and increased estradiol production over control levels (P < 0.05). However, follicles treated with LR3 IGF-I and the highest concentration of hrIGF-I (1000 ng/ml) had smaller oocyte/follicle ratios, and increased oocyte degeneration, compared with controls or follicles treated with physiological concentrations of hrIGF-I (P < 0.05). IGFBPs were detected in cultured preantral follicles, indicating a requirement for regulation of IGF bioavailability during the early stages of follicular development. Specifically, IGFBP-3 mRNA was found to be expressed in oocytes, and IGFBP-2 immunoreactivity was detected in oocytes and granulosa cells of cultured follicles. In summary, the regulation of IGF-I bioavailability by IGFBPs is necessary for the co-ordination of oocyte and follicle development in vitro.

Differences in the association of insulin-like growth factor-I (IGF-I) and IGF-I variants with rat, sheep, pig, human and chicken plasma-binding proteins

1994 ◽  
Vol 140 (3) ◽  
pp. 475-482 ◽  
Author(s):  
A P D Lord ◽  
S E P Bastian ◽  
L C Read ◽  
P E Walton ◽  
F J Ballard
Keyword(s):  
Binding Proteins ◽  
Rat Plasma ◽  
Size Exclusion ◽  
Free Form ◽  
Igf Binding Proteins ◽  
Igf I ◽  
Exclusion Chromatography ◽  
Igf Binding

Abstract Associations between labelled insulin-like growth factors (IGFs) and IGF-binding proteins in plasma have been compared in the rat, sheep, human, pig and chicken. The IGFs tested were recombinant human IGF-I, the truncated variant, des(1–3)IGF-I, and LR3IGF-I, an extended form that had been engineered so as to minimize interactions with IGF-binding proteins. Marked species differences were demonstrated, notably that the IGF-I variants which exhibited extremely weak binding in rat plasma bound significantly in plasma from the other species. This result was shown both by size-exclusion chromatography of labelled IGFs added to plasma, in which the extent of variant IGF-I binding decreased in the order sheep>human>pig=chicken>rat, and by competition for labelled IGF-I binding in vitro, in which the order was pig=chicken>sheep>human>rat. Notwithstanding these differences, the two IGF-I variants showed only slight between-species binding differences when tested with purified rat, sheep and human IGF-binding protein-3. Ligand blotting experiments with plasma from the five species similarly showed a consistent pattern in that IGF-I binding was much greater than des(1–3)IGF-I binding, which in turn was greater than LR3 IGF-I binding. These experiments suggest first that IGF-binding properties measured after the removal of endogenous IGFs do not always reflect the situation with untreated plasma or in vivo, and secondly, the increased potencies of des(1–3)IGF-I and LR3 IGF-I in rat growth studies that have been ascribed to higher concentrations of these peptides in the free form cannot necessarily be extended to other species. Journal of Endocrinology (1994) 140, 475–482

scholarly journals Effects of endotoxin lipopolysaccharide administration on the somatotropic axis

1998 ◽  
Vol 159 (2) ◽  
pp. 239-246 ◽  
Author(s):  
L Soto ◽  
AI Martin ◽  
S Millan ◽  
E Vara ◽  
A Lopez-Calderon
Keyword(s):  
Body Weight ◽  
Body Weight Loss ◽  
Serum Levels ◽  
Dependent Manner ◽  
Igf Binding Proteins ◽  
Somatotropic Axis ◽  
Gh Secretion ◽  
Igf I ◽  
Male Wistar Rats ◽  
Igf Binding

The aim of this work was to study the effect of chronic activation of the immune system on the somatotropic axis. Accordingly, the changes in growth hormone (GH) secretion, circulating insulin-like growth factor-I (IGF-I) and IGF binding proteins (IGFBPs) in response to endotoxin lipopolysaccharide (LPS) administration were examined in adult male Wistar rats. Acute LPS injection (2.5, 25 or 250 microg/kg) increased serum corticosterone in a dose-dependent manner and decreased serum levels of insulin and IGF-I, serum GH concentration declined linearly as the LPS dose increased. Western ligand blot showed an increase in the 33 kDa band (corresponding to IGFBP-1 and IGFBP-2) in the rats that received the highest dose of LPS (250 microg/kg). Chronic LPS administration (250 microg/kg daily for 8 days) significantly decreased body weight, serum levels of IGF-I and pituitary GH content, whereas it increased circulating IGFBP-3 (47 kDa band), IGFBP-1 and IGFBP-2 (33 kDa band) and the 24 kDa band (which possibly corresponds to IGFBP-4). Serum concentration of corticosterone and hypothalamic somatostatin content were also increased by chronic LPS treatment. These data suggest that the decrease in GH and IGF-I secretion and the increase in circulating IGFBPs are important mechanisms in body weight loss during chronic inflammation.

Characterization of serum-derived and recombinant rat IGF-I and their use for measuring true concentrations of IGF-I in rat plasma

1996 ◽  
Vol 149 (3) ◽  
pp. 379-387 ◽  
Author(s):  
Z Upton ◽  
H Webb ◽  
F M Tomas ◽  
F J Ballard ◽  
G L Francis
Keyword(s):  
Rat Plasma ◽  
Reference Standards ◽  
Igf Binding Proteins ◽  
Igf I ◽  
Igf Binding ◽  
Igf Receptor

Abstract While numerous researchers have used rat models to investigate the in vivo actions of IGF-I, interpretation of the results in terms of true concentrations of rat IGF-I (rIGF-I) in plasma has been hampered by the absence of homologous reference standards. In order to overcome this we have produced recombinant rIGF-I (rrIGF-I) from Escherichia coli using procedures similar to those we have previously described for the production of other recombinant IGFs. The rrIGF-I is indistinguishable from serum-derived rIGF-I when characterized in a number of in vitro assays including ability to stimulate protein synthesis and inhibit protein degradation in cultured rat cells, as well as in interactions with the rat type-1 IGF receptor and with rat IGF-binding proteins. Moreover, both the serum-derived and the recombinant rat proteins are similar to recombinant human IGF-I (rhIGF-I) in these assays. However, differences between the human and rat IGFs are apparent when tested in immunoassays using some antibodies raised against rhIGF-I. Furthermore, the differences between rhIGF-I and rrIGF-I are even greater when rhIGF-I is used as the competing radiolabel in these assays, a situation that can lead to a two- to threefold underestimation of the actual concentration of IGF-I in rat plasma. These results indicate that, while immunoassays employing antibodies raised against rhIGF-I and rhIGF-I reference standards reliably indicate trends in IGF-I concentrations in rat plasma, the true amounts of rIGF-I present can only be assured in an assay using homologous tracer and reference peptides. Journal of Endocrinology (1996) 149, 379–387

Circulating forms and biological activity of intact and truncated insulin-like growth factor I in adult and neonatal rats

1990 ◽  
Vol 123 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Katarina Drakenberg ◽  
Claes-Göran Östenson ◽  
Vicki Sara
Keyword(s):  
Biological Activity ◽  
Binding Proteins ◽  
Adult Rats ◽  
Igf Binding Proteins ◽  
Igf I ◽  
Igf Binding ◽  
Old Rats ◽  
In Vivo Administration

Abstract. A variant of IGF-I with a truncated aminoterminal region has been isolated and shown to display increased biological activity in vitro, but weak affinity of binding to the IGF binding proteins compared with intact IGF-I. In the present study, the circulating molecular forms and biological activity of intact and truncated IGF-I were compared after in vivo administration. Adult and 10-day-old rats were given 125I-truncated or 125I-intact IGF-I iv. In both adult and 10-day-old rats 125I-truncated IGF-I showed weaker affinity of binding to the IGF binding proteins and greater degradation than 125I-intact IGF-I. Serum half-life was 2 h for 125I-truncated IGF-I and 3 h for 125I-intact IGF-I in adult rats. The half-life in 10-day-old rats was 20.5 min for 125I-truncated IGF-I and 27 min for 125I-intact IGF-I. The uptake of 125I-truncated IGF-I into the kidney, liver and brain of 10-day-old rats was significantly higher than for 125I-intact IGF-I 15 min after iv administration. The insulin-like effects of the IGF-I peptides were examined in vitro and in vivo. Truncated IGF-I stimulated [3-3H]glucose incorporation into free fatty acids in adipocytes in vitro to a greater extent than did intact IGF-I. In vivo administration of both intact and truncated IGF-I to adult rats significantly decreased serum glucose levels and significantly increased the incorporation of [U-14C]glucose into glycogen. Thus, the present results demonstrated that truncated IGF-I displays reduced binding to the IGF binding proteins in vivo compared with intact IGF-I.

scholarly journals FGF1ΔHBS prevents diabetic cardiomyopathy by maintaining mitochondrial homeostasis and reducing oxidative stress via AMPK/Nur77 suppression

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Dezhong Wang ◽  
Yuan Yin ◽  
Shuyi Wang ◽  
Tianyang Zhao ◽  
Fanghua Gong ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Metabolic Regulation ◽  
Cardiac Injury ◽  
Serum Levels ◽  
Ros Generation ◽  
Dependent Manner ◽  
Cardiac Tissues ◽  
Beneficial Effects

AbstractAs a classically known mitogen, fibroblast growth factor 1 (FGF1) has been found to exert other pleiotropic functions such as metabolic regulation and myocardial protection. Here, we show that serum levels of FGF1 were decreased and positively correlated with fraction shortening in diabetic cardiomyopathy (DCM) patients, indicating that FGF1 is a potential therapeutic target for DCM. We found that treatment with a FGF1 variant (FGF1∆HBS) with reduced proliferative potency prevented diabetes-induced cardiac injury and remodeling and restored cardiac function. RNA-Seq results obtained from the cardiac tissues of db/db mice showed significant increase in the expression levels of anti-oxidative genes and decrease of Nur77 by FGF1∆HBS treatment. Both in vivo and in vitro studies indicate that FGF1∆HBS exerted these beneficial effects by markedly reducing mitochondrial fragmentation, reactive oxygen species (ROS) generation and cytochrome c leakage and enhancing mitochondrial respiration rate and β-oxidation in a 5’ AMP-activated protein kinase (AMPK)/Nur77-dependent manner, all of which were not observed in the AMPK null mice. The favorable metabolic activity and reduced proliferative properties of FGF1∆HBS testify to its promising potential for use in the treatment of DCM and other metabolic disorders.

scholarly journals GH/IGF e neoplasia: o que há de novo nesta associação

2005 ◽  
Vol 49 (5) ◽  
pp. 833-842 ◽  
Author(s):  
Angela M. Spinola e Castro ◽  
Gil Guerra-Júnior
Keyword(s):  
Growth Factors ◽  
Binding Proteins ◽  
De Novo ◽  
Igf Binding Proteins ◽  
Igf I ◽  
Ciclo Celular ◽  
Igf Binding ◽  
Insulin Like Growth Factors

Estudos in vitro e em animais sugerem que os membros do sistema insulin-like growth factors (IGFs), incluindo IGF-I, IGF-II, receptores de IGF-I e IGF-II (IGF-IR e IGF-IIR), e as IGF-binding proteins (IGFBPs) podem ter um importante envolvimento no desenvolvimento e na progressão de neoplasias. Mais especificamente, as IGFs promovem a progressão do ciclo celular e inibem a apoptose tanto por ação direta com outros fatores de crescimento como por ação indireta interagindo com outros sistemas moleculares intracelulares envolvidos na promoção e/ou progressão do câncer. Além disso, inúmeros estudos epidemiológicos têm sugerido que concentrações elevadas das IGFs, independente das alterações nas IGFBPs, podem estar associadas a um aumento no risco de desenvolver determinadas neoplasias. Esta revisão tem como objetivo apresentar o envolvimento do sistema IGF na regulação tumoral, os principais estudos epidemiológicos realizados e o risco de desenvolvimento de neoplasia em pacientes (com ou sem história pessoal de neoplasia prévia) que receberam hormônio de crescimento (rhGH). É importante salientar que o uso clínico de rhGH, nas indicações aprovadas internacionalmente, é seguro e não existem evidências, até o momento, da associação com o desenvolvimento de neoplasias.

Alterations in hepatic production and peripheral clearance of IGF-I after endotoxin

1995 ◽  
Vol 269 (1) ◽  
pp. E33-E42 ◽  
Author(s):  
J. Fan ◽  
D. Char ◽  
A. J. Kolasa ◽  
W. Pan ◽  
S. R. Maitra ◽  
...  
Keyword(s):  
Whole Body ◽  
Pharmacokinetic Analysis ◽  
Igf Binding Proteins ◽  
Sustained Reduction ◽  
Igf I ◽  
Igf Binding ◽  
Peripheral Clearance ◽  
Perfusion Period ◽  
Parenchymal Cells

Lipopolysaccharide (LPS) produces a rapid and sustained reduction in the circulating concentration of insulin-like growth factor I (IGF-I), which may be responsible, in part, for the alterations in protein metabolism observed in these animals. The purpose of the present study was to determine whether this drop was due to a decreased hepatic production of IGF-I and/or an increased clearance of the peptide from the blood. Four hours after intravenous injection of LPS the plasma IGF-I concentration was decreased 50%. IGF-I release by in situ perfused livers from control rats was constant throughout the 60-min perfusion period and averaged 111 +/- 3 ng/min. In contrast, hepatic IGF-I output was decreased 46% by in vivo LPS. In contrast, livers from LPS-injected rats released more IGF binding proteins-1, -2 and -4 than did control livers. Hepatic cell isolation indicated that LPS decreased the IGF-I content in Kupffer and parenchymal cells, but not endothelial cells, by approximately 45%. Pharmacokinetic analysis of blood 125I-IGF-I decay curves indicated that the half-life for whole body clearance of 125I-IGF-I from the circulation was not altered by LPS. However, LPS increased 125I-IGF-I uptake by spleen, liver, lung, and kidney while decreasing uptake by the pancreas and gastrointestinal tract. These results indicate that the LPS-induced decrease in blood IGF-I concentration is primarily due to a reduction in hepatic production, not a change in whole body peptide clearance, and that a decreased production by both parenchymal and Kupffer cells contributes to this alteration.

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