scholarly journals 40 YEARS OF IGF1: Role of IGF-binding proteins in regulating IGF responses to changes in metabolism

2018 ◽  
Vol 61 (1) ◽  
pp. T139-T169 ◽  
Author(s):  
David R Clemmons
Keyword(s):  
Binding Protein ◽  
Surface Proteins ◽  
Type I ◽  
Cellular Functions ◽  
Igf Binding Proteins ◽  
Distinct Cell ◽  
Type I Igf Receptor ◽  
Igf Binding ◽  
Igf Binding Protein

The IGF-binding protein family contains six members that share significant structural homology. Their principal function is to regulate the actions of IGF1 and IGF2. These proteins are present in plasma and extracellular fluids and regulate access of both IGF1 and II to the type I IGF receptor. Additionally, they have functions that are independent of their ability to bind IGFs. Each protein is regulated independently of IGF1 and IGF2, and this provides an important mechanism by which other hormones and physiologic variables can regulate IGF actions indirectly. Several members of the family are sensitive to changes in intermediary metabolism. Specifically the presence of obesity/insulin resistance can significantly alter the expression of these proteins. Similarly changes in nutrition or catabolism can alter their synthesis and degradation. Multiple hormones such as glucocorticoids, androgens, estrogen and insulin regulate IGFBP synthesis and bioavailability. In addition to their ability to regulate IGF access to receptors these proteins can bind to distinct cell surface proteins or proteins in extracellular matrix and several cellular functions are influenced by these interactions. IGFBPs can be transported intracellularly and interact with nuclear proteins to alter cellular physiology. In pathophysiologic states, there is significant dysregulation between the changes in IGFBP synthesis and bioavailability and changes in IGF1 and IGF2. These discordant changes can lead to marked alterations in IGF action. Although binding protein physiology and pathophysiology are complex, experimental results have provided an important avenue for understanding how IGF actions are regulated in a variety of physiologic and pathophysiologic conditions.

Immunoreactive and receptor-active insulin-like growth factor-I (IGF-I) and IGF-binding protein in blood plasma from the freshwater fish Macquaria ambigua (golden perch)

1993 ◽  
Vol 136 (2) ◽  
pp. 191-198 ◽  
Author(s):  
T. A. Anderson ◽  
L. R. Bennett ◽  
M. A. Conlon ◽  
P. C. Owens
Keyword(s):  
Binding Protein ◽  
Size Exclusion ◽  
Type I ◽  
Factor I ◽  
Type I Igf Receptor ◽  
Receptor Assay ◽  
Igf I ◽  
Igf Binding ◽  
Igf Receptor ◽  
Igf Binding Protein

ABSTRACT The presence of insulin-like growth factor-I (IGF-I)-related molecules and IGF-binding factors in blood from golden perch, Macquaria ambigua, an Australian native freshwater fish, was investigated. Serum was acidified to dissociate IGF and IGF-binding protein complexes that might be present, and fractionated by size-exclusion high-performance liquid chromatography at pH 2·8. Fractions were neutralized and their activities assessed by (i) an immunoassay for mammalian IGF-I which also detects chicken IGF-I but in which all known forms of IGF-II react very poorly, (ii) a receptor assay for IGF-II in which all known forms of IGF-I react poorly, and (iii) a type-I IGF receptor assay in which mammalian IGF-I and IGF-II polypeptides are almost equivalent. No IGF-II-like activity was detected. Three peaks of IGF-I-like activity were detected by IGF-I immunoassay and type-I IGF receptor assay. The major peak of activity was similar in molecular size to human IGF-binding protein-3, 45–55 kDa ('large IGF'), and a minor peak of activity which was similar in size to mammalian IGFs, 7·5 kDa. A third peak of activity was observed eluting at a time which indicates that it is a smaller molecule than any previously described IGF. The large IGF was temperature-sensitive, but was not a binding protein for 125I-labelled human IGF-I (hIGF-I). This material therefore was able to bind to anti-hIGF-I antibodies and to human type-I IGF receptors, and may represent the fish equivalent of mammalian prepro-IGFs. The two smallest forms of IGF activity identified by IGF-I radioimmunoassay and type-I radioreceptor assay following acidic size-exclusion chromatography were able to stimulate protein synthesis by L-6 myoblasts in culture, although large IGF did not. When fresh (but not frozen and thawed) golden perch serum was incubated with 125I-labelled hIGF-I and then fractionated by size-exclusion liquid chromatography at pH 7·4 through Sephadex G-100, the radioactivity became associated with a complex, intermediate in size between free IGF-I and the major IGF-binding protein in human serum. The association of 125I-labelled hIGF-I with the complex was inhibited by the presence of unlabelled hIGF-I in the incubation. These studies show that receptor-active, immunoreactive and bioactive IGF-I-like activity is present in golden perch serum, and demonstrate the presence of an IGF-I-binding factor in this species. Journal of Endocrinology (1993) 136, 191–198

scholarly journals The Role of IGF-Binding Proteins in Mediating the Effects of Recombinant Human IGF-I on Insulin Requirements in Type 1 Diabetes Mellitus

2001 ◽  
Vol 86 (8) ◽  
pp. 3686-3691 ◽  
Author(s):  
E. C. Crowne ◽  
J. S. Samra ◽  
T. Cheetham ◽  
C. L. Acerini ◽  
A. Watts ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Binding Protein ◽  
Igf Binding Proteins ◽  
Insulin Requirements ◽  
Free Insulin ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein

To determine the role of IGF-binding proteins in mediating the direct effects of recombinant human IGF-I on insulin requirements in type 1(insulin-dependent) diabetes mellitus, overnight changes in IGF-I, IGF-II, and IGF-binding protein-1, -2, and -3, collected under euglycemic conditions, were compared in nine subjects after double blind, randomized, sc administration of recombinant human IGF-I (40μ g/kg) or placebo at 1800 h. On both nights a somatostatin analog infusion (300 ng/kg·h) suppressed endogenous GH production, and three timed discrete GH pulses (total, 0.029 IU/kg·night) ensured identical GH levels. After recombinant human IGF-I administration, IGF-I levels and the IGF-I/IGF-binding protein-3 ratio increased [mean ± sem:IGF-I, 401 ± 22 ng/ml; placebo, 256 ± 20 ng/ml (P = 0.0002); IGF-I, 0.108 ± 0.006; placebo, 0.074 ± 0.004 (P = 0.0003), respectively], and insulin requirements decreased (IGF-I, 0.12 ± 0.03; placebo, 0.23 ± 0.03 U/kg·min; P = 0.008). The normal within-individual inverse relationships between insulin and IGF-binding protein-1 levels were observed (lag time 2 h: r =− 0.34; P < 0.01). Yet despite reduced free insulin levels (8.5 ± 1.5; placebo, 12.2 ± 1.2 mU/liter; P = 0.03), IGF-binding protein-1 levels were reduced after recombinant human IGF-I administration (53.7 ± 6.8; placebo, 82.2 ± 11.8 ng/ml; P = 0.008). The largest reductions in free insulin levels after recombinant human IGF-I and thus putative improvement in insulin sensitivity occurred in subjects with the smallest increase in the plasma IGF-I/IGF-binding protein-3 ratio (r = 0.7; P = 0.03). Taken together, these data are consistent with the hypothesis that transcapillary movement of IGF-I (perhaps mediated by IGF-binding protein-1), out of the circulation facilitates altered insulin sensitivity. These data have important implications for risk-benefit assessment of recombinant human IGF-I therapy in type 1 diabetes mellitus.

scholarly journals Ovarian follicular expression of mRNA encoding the type I IGF receptor and IGF-binding protein-2 in sheep following five days of nutritional supplementation with glucose, glucosamine or lupins

Reproduction ◽  
2004 ◽  
Vol 128 (6) ◽  
pp. 747-756 ◽  
Author(s):  
M Muñoz-Gutiérrez ◽  
D Blache ◽  
G B Martin ◽  
R J Scaramuzzi
Keyword(s):  
Binding Protein ◽  
Control Diet ◽  
Follicular Development ◽  
Type I ◽  
Igf System ◽  
Type I Igf Receptor ◽  
Igf Binding ◽  
Ovarian Folliculogenesis ◽  
Igf Binding Protein

The IGF system is associated with ovarian folliculogenesis. The effect of the IGFs mediated through the type I receptor (IGF-IR) and IGF-binding protein-2 (IGFBP-2), is to regulate the growth and atresia of follicles. To test if the mRNAs for IGF-IR and IGFBP-2 are differentially regulated in the follicle we used nutritional treatments that stimulate folliculogenesis and measured, byin situhybridisation, their mRNAs expression. Groups of five anoestrous Merino ewes were fed wheat straw (control) or the control diet supplemented with lupins (500 g/day). Other ewes were fed the control diet and infused with glucose (50 mmol/h) or with glucosamine (3.5 mmol/h). Intravaginal progestagen sponges were inserted for 12 days, and nutritional treatments were started 5 days before progestagen removal. Follicular development was studied after an artificial follicular phase, simulated by progestagen for 12 days and a regime of GnRH pulses given for 36 h following progestagen withdrawal, when the animals were killed. The ovaries were collected and stored at −80 °C until sectioning at 10 μm. Every 25–28th and 29–32nd section was probed for IGF-IR and IGFBP-2 using35S-labelled oligonucleotide probes. None of the nutritional treatments affected the number or size of follicles positive for IGF-IR, but glucose (P< 0.001) and lupin (P< 0.001) treatments reduced the follicular concentration of mRNA. The nutritional treatments all increased the number of follicles positive for IGFBP-2 (P< 0.05) and reduced their mean diameter (P< 0.05) and with the exception of lupin feeding, the concentration of mRNA (P< 0.05). The results show that all treatments affected the intrafollicular IGF system and suggest that IGF-IR and IGFBP-2 are nutritionally regulated in the follicle. However, the effects of treatments were variable and suggest the existence of multiple regulatory mechanisms that allow for normal variation in composition and balance of the ruminant diet.

Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities

2000 ◽  
Vol 278 (6) ◽  
pp. E967-E976 ◽  
Author(s):  
Robert C. Baxter
Keyword(s):  
Growth Factor ◽  
Binding Proteins ◽  
Specific Cell ◽  
Type I ◽  
Insulin Like Growth Factor ◽  
Serine Kinase ◽  
Homologous Proteins ◽  
Igf Binding Proteins ◽  
Type I Igf Receptor ◽  
Igf Binding

The insulin-like growth factor (IGF)-binding proteins (IGFBPs) are a family of six homologous proteins with high binding affinity for IGF-I and IGF-II. Information from NMR and mutagenesis studies is advancing knowledge of the key residues involved in these interactions. IGF binding may be modulated by IGFBP modifications, such as phosphorylation and proteolysis, and by cell or matrix association of the IGFBPs. All six IGFBPs have been shown to inhibit IGF action, but stimulatory effects have also been established for IGFBP-1, -3, and -5. These generally involve a decrease in IGFBP affinity and may require cell association of the IGFBP, but precise mechanisms are unknown. The same three IGFBPs have well established effects that are independent of type I IGF receptor signaling. IGFBP-1 exerts these effects by signaling through α5β1-integrin, whereas IGFBP-3 and -5 may have specific cell-surface receptors with serine kinase activity. The regulation of cell sensitivity to inhibitory IGFBP signaling may play a role in the growth control of malignant cells.

Long R3 insulin-like growth factor-I (IGF-I) infusion stimulates organ growth but reduces plasma IGF-I, IGF-II and IGF binding protein concentrations in the guinea pig

1995 ◽  
Vol 146 (2) ◽  
pp. 247-253 ◽  
Author(s):  
M A Conlon ◽  
F M Tomas ◽  
P C Owens ◽  
J C Wallace ◽  
G S Howarth ◽  
...  
Keyword(s):  
Body Weight ◽  
Guinea Pig ◽  
Body Weight Gain ◽  
Binding Protein ◽  
Carcass Composition ◽  
Feed Conversion ◽  
Igf Binding Proteins ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein

Abstract We have tested whether an animal with substantial amounts of both IGF-I and IGF-II in circulation, such as the guinea pig, would respond to chronic IGF infusion in the same manner as the adult rat, which has negligible amounts of IGF-II in blood. Female guinea pigs of 350 g body weight were continuously infused for 7 days with recombinant guinea pig IGF-I or -II (120 or 360 μg/day) or long R3 IGF-I (LR3IGF-I) (120 μg/day), an analogue which has much reduced affinities for IGF binding proteins. IGF-I or IGF-II infusion led to substantial increases in plasma IGF-I or IGF-II respectively in comparison with vehicle-infused animals. Nevertheless, body weight gain, feed intake, feed conversion efficiency and carcass composition were not significantly affected by any treatment (significance was deemed to be P<0·05). Amongst the tissues examined only the fractional weight (g/kg body weight) of the adrenals was increased, and that only by the higher dose (360 μg/day) of IGF-I. However, the fractional weight of adrenals, gut, kidneys and spleen were significantly increased by LR3IGF-I, but again overall growth was not stimulated. A possible explanation for the lack of IGF-I effects is that total circulating IGF concentrations were not increased by these treatments. IGF-II significantly raised total IGF concentrations at the higher dose only. Plasma IGF-I was reduced by IGF-II infusion, as was plasma IGF-II by IGF-I infusion. LR3IGF-I treatment lowered both plasma IGF-I and IGF-II concentrations, a response probably related to a reduction in total plasma IGF binding protein (IGFBP), especially IGFBP-3, concentrations. We conclude that although the guinea pig is responsive to IGF treatment, the effects differ markedly from those elicited in rats. Journal of Endocrinology (1995) 146, 247–253

scholarly journals Insulin-Like Growth Factor (IGF) Binding Protein-2, Independently of IGF-1, Induces GLUT-4 Translocation and Glucose Uptake in 3T3-L1 Adipocytes

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Biruhalem Assefa ◽  
Ayman M. Mahmoud ◽  
Andreas F. H. Pfeiffer ◽  
Andreas L. Birkenfeld ◽  
Joachim Spranger ◽  
...  
Keyword(s):  
Growth Factor ◽  
Glucose Uptake ◽  
Binding Protein ◽  
Insulin Like Growth Factor ◽  
Glut 4 ◽  
Igf Binding ◽  
Glut 4 Translocation ◽  
Igf Binding Protein ◽  
The Impact

Insulin-like growth factor binding protein-2 (IGFBP-2) is the predominant IGF binding protein produced during adipogenesis and is known to increase the insulin-stimulated glucose uptake (GU) in myotubes. We investigated the IGFBP-2-induced changes in basal and insulin-stimulated GU in adipocytes and the underlying mechanisms. We further determined the role of insulin and IGF-1 receptors in mediating the IGFBP-2 and the impact of IGFBP-2 on the IGF-1-induced GU. Fully differentiated 3T3-L1 adipocytes were treated with IGFBP-2 in the presence and absence of insulin and IGF-1. Insulin, IGF-1, and IGFBP-2 induced a dose-dependent increase in GU. IGFBP-2 increased the insulin-induced GU after long-term incubation. The IGFBP-2-induced impact on GU was neither affected by insulin or IGF-1 receptor blockage nor by insulin receptor knockdown. IGFBP-2 significantly increased the phosphorylation of PI3K, Akt, AMPK, TBC1D1, and PKCζ/λand induced GLUT-4 translocation. Moreover, inhibition of PI3K and AMPK significantly reduced IGFBP-2-stimulated GU. In conclusion, IGFBP-2 stimulates GU in 3T3-L1 adipocytes through activation of PI3K/Akt, AMPK/TBC1D1, and PI3K/PKCζ/λ/GLUT-4 signaling. The stimulatory effect of IGFBP-2 on GU is independent of its binding to IGF-1 and is possibly not mediated through the insulin or IGF-1 receptor. This study highlights the potential role of IGFBP-2 in glucose metabolism.

scholarly journals Production of recombinant porcine IGF-binding protein-5 and its effect on proliferation of porcine embryonic myoblast cultures in the presence and absence of IGF-I and Long-R3-IGF-I

2005 ◽  
Vol 185 (1) ◽  
pp. 197-206 ◽  
Author(s):  
M S Pampusch ◽  
G Xi ◽  
E Kamanga-Sollo ◽  
K J Loseth ◽  
M R Hathaway ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Affinity Chromatography ◽  
Binding Protein ◽  
Myogenic Cell ◽  
Type I ◽  
Dependent Manner ◽  
Western Blots ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein

IGF-binding protein-5 (IGFBP-5) is produced by porcine embryonic myogenic cell (PEMC) cultures and is secreted into the medium. IGFBP-5 may play some role in myogenesis and/or in changes in myogenic cell proliferation that accompany differentiation. IGFBP-5 reportedly may either suppress or stimulate proliferation or differentiation of cultured cells depending on cell type and culture conditions. Additionally, IGFBP-5 has been shown to possess both IGF-dependent and IGF-independent actions in some cell types. The goal of this study was to produce recombinant porcine IGFBP-5 (rpIGFBP-5) and assess its IGF-I-dependent and IGF-I-independent actions on the proliferation of PEMCs. To accomplish this, we have expressed porcine IGFBP-5 in the baculovirus system, purified and characterized the expressed rpIGFBP-5 and produced an anti-porcine IGFBP-5 antibody that neutralizes the biological activity of porcine IGFBP-5. rpIGFBP-5, purified to 98% homogeneity using nickel affinity chromatography and IGF-I affinity chromatography, suppressed IGF-I-stimulated proliferation of PEMCs in a concentration-dependent manner (P>0.05). rpIGFBP-5 also suppressed Long-R3-IGF-I-stimulated proliferation of PEMCs (P>0.05), even in the presence of significant molar excess of Long-R3-IGF-I compared with rpIGFBP-5, demonstrating the IGF-independent activity that rpIGFBP-5 possesses in PEMCs, since Long-R3-IGF-I is an IGF analog that has very low affinity for the IGFBPs but retains its ability to bind to the type I IGF receptor and thereby can stimulate proliferation. The anti-rpIGFBP-5 IgY produced against rpIGFBP-5 specifically recognized native porcine IGFBP-5 in PEMC media that also contained porcine IGFBP-2, -3, and -4. This antibody is capable of neutralizing the effects of both rpIGFBP-5 and endogenously produced porcine IGFBP-5 on PEMCs as well as detecting IGFBP-5 in Western blots. The production of rpIGFBP-5 and a neutralizing antibody to porcine IGFBP-5 provides a powerful tool to investigate the role of IGFBP-5 in porcine myogenic cell proliferation and differentiation. The data provided here demonstrated that IGFBP-5 has the potential to affect proliferation of PEMCs during critical periods of in vitro muscle cell development and therefore may impact the capacity for ultimate postnatal muscle mass development in vivo.

An acid-stable insulin-like growth factor (IGF)-binding protein from pig serum inhibits binding of IGF-I and IGF-II to vascular endothelial cells

1989 ◽  
Vol 120 (2) ◽  
pp. 231-236 ◽  
Author(s):  
R. Gopinath ◽  
P. E. Walton ◽  
T. D. Etherton
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Binding Protein ◽  
Type I ◽  
Insulin Like Growth Factor ◽  
Igf Receptors ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein ◽  
Acid Stable

ABSTRACT The effects of a porcine insulin-like growth factor (IGF)-binding protein on binding of IGF-I and IGF-II to porcine aortic endothelial cells (PAEC) were determined. Binding of 125I-labelled IGF-I and -II to IGF receptors was inhibited by IGF-binding protein. IGF-binding protein inhibited binding of IGF-I and -II in a dose-dependent manner with half-maximal inhibition occurring at 5·43 and 108 μg/l respectively. A125I-labelled IGF-I–IGF-binding protein complex, formed by incubating 125I-labelled IGF-I with IGF-binding protein overnight at 4 °C, did not effectively bind to endothelial IGF receptors. Addition of IGF-binding protein to PAEC previously incubated with IGF-I caused a marked dissociation of bound IGF-I (47% dissociation within 12 h). These results indicate that the acid-stable IGF-binding protein which appears to be a part of the 150 kDa GH-dependent binding protein, blocks binding of IGF-I and -II by the IGF receptors and appears to exhibit a higher affinity for IGF-I than the endothelial type-I IGF receptor. The ramifications of this latter point with respect to transfer of circulating IGFs (bound to their IGF-binding proteins) across the vascular endothelium are not clear. Journal of Endocrinology (1989) 120, 231–236

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