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

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.

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Zinc partitions IGFs from soluble IGF binding proteins (IGFBP)-5, but not soluble IGFBP-4, to myoblast IGF type 1 receptors

Journal of Endocrinology ◽

10.1677/joe.0.1800227 ◽

2004 ◽

Vol 180 (2) ◽

pp. 227-246 ◽

Cited By ~ 7

Author(s):

RH McCusker ◽

J Novakofski

Keyword(s):

Cell Surface ◽

Binding Sites ◽

Affinity Binding ◽

Igf Binding Proteins ◽

Igf I ◽

Igf Binding ◽

Igf Receptor ◽

Igf Binding Protein

Zinc (Zn(2+)), a multifunctional micronutrient, was recently shown to lower the affinity of cell-associated insulin-like growth factor (IGF) binding protein (IGFBP)-3 and IGFBP-5 for both IGF-I and IGF-II, but to increase the affinity of the cell surface type 1 IGF receptor (IGF-1R) for the same two ligands. However, there is a need for data concerning the effects of Zn(2+) on soluble IGFBPs and the type 2 IGF receptor (IGF-2R). In the current work, we demonstrate that Zn(2+) affects the affinity of IGFBP-5 secreted by myoblasts but not IGFBP-4. Zn(2+), at physiological levels, depressed binding of both IGF-I and IGF-II to IGFBP-5, affecting (125)I-IGF-I more than (125)I-IGF-II. Both (125)I-IGF-I and (125)I-IGF-II bound to high and low affinity sites on IGFBP-5. Zn(2+) converted the high affinity binding sites of IGFBP-5 into low affinity binding sites. An IGF-I analog, (125)I-R(3)-IGF-I, did not bind to the soluble murine IGFBP-5. Zn(2+) also decreased the affinity of the IGF-2R on L6 myoblasts. In contrast, Zn(2+) increased IGF-I, IGF-II and R(3)-IGF-I binding to the IGF-1R by increasing ligand binding affinity on both P(2)A(2a)-LISN and L6 myoblasts. Soluble IGFBP-5 and IGFBP-4 depressed the binding of (125)I-IGF-I and (125)I-IGF-II to the IGF-1R, but did not affect binding of (125)I-R(3)-IGF-I. By depressing the association of the IGFs with soluble IGFBP-5, Zn(2+) partitioned (125)I-IGF-I and (125)I-IGF-II from soluble IGFBP-5 onto cell surface IGF-1Rs. This effect is not seen when soluble L6-derived IGFBP-4 is present in extracellular fluids. We introduce a novel mechanism by which the trace micronutrient Zn(2+) may alter IGF distribution, i.e. Zn(2+) acts to increase IGF-1R binding at the expense of IGF binding to soluble IGFBP-5 and the IGF-2R.

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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

Journal of Endocrinology ◽

10.1677/joe.0.1460247 ◽

1995 ◽

Vol 146 (2) ◽

pp. 247-253 ◽

Cited By ~ 19

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

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IGF-I stimulates chemotaxis of human neuroblasts. Involvement of type 1 IGF receptor, IGF binding proteins, phosphatidylinositol-3 kinase pathway and plasmin system

Journal of Endocrinology ◽

10.1677/joe.0.1650123 ◽

2000 ◽

Vol 165 (1) ◽

pp. 123-131 ◽

Cited By ~ 36

Author(s):

A Puglianiello ◽

D Germani ◽

P Rossi ◽

S Cianfarani

Keyword(s):

Cell Migration ◽

Cell Motility ◽

Igf Binding Proteins ◽

Neuroblast Migration ◽

Igf I ◽

Igf Binding ◽

Igf Receptor ◽

Kinase Pathway

SH-SY5Y human neuroblastoma cells express IGF receptors, IGFs and IGF binding proteins (IGFBPs), and provide a model for studying the role of the IGF system in human neuronal development. We investigated the effect of IGF-I and des(1-3)IGF-I on the motility of SH-SY5Y cells by a cell migration assay based on the assessment of the number of cells which migrated across 8 microm pore size membranes and around an agarose drop. IGF-I and des(1-3)IGF-I stimulated neuroblast chemotaxis in a dose-dependent manner. Treatment of cells with these agents for 24 h resulted in a significant increase (IGF-I by 70% and des(1-3)IGF-I by 90%; P<0. 0001) in cell motility relative to control conditions. Addition of monoclonal antibody against type 1 IGF receptor (alpha-IR3), significantly (P<0.05) reduced the cell motility induced by IGF-I (by 30%) and des(1-3)IGF-I (by 70%). Wortmannin, a specific inhibitor of phosphatidylinositol (PI)-3 kinase intracellular signalling, also reduced the IGF-stimulated cell migration (by over 40%, P<0.01), indicating a key role of the PI-3 kinase pathway in mediating the IGF effect on neuroblast migration. Finally, cell treatment with plasminogen (PLG) markedly enhanced neuroblast migration (by over 200%, P<0.01), whereas incubation with the PLG inhibitor 4-(2-aminoethyl)-benzenesulphonyl fluoride reduced cell motility (by 80%, P<0.01), thus suggesting an involvement of PLG-dependent IGFBP proteolysis in the regulation of neuroblast motility. In conclusion, IGF-I is a potent stimulator of neuroblast migration through the activation of type 1 IGF receptor and the PI-3 kinase intracellular pathway. IGFBPs and the plasmin system seem to play a role in cell motility, although the nature and the extent of their involvement has yet to be elucidated.

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

Journal of Molecular Endocrinology ◽

10.1530/jme-18-0016 ◽

2018 ◽

Vol 61 (1) ◽

pp. T139-T169 ◽

Cited By ~ 28

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.

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Growth Hormone-Binding Proteins, IGF-I and IGF-Binding Proteins in Children and Adolescents with Type 1 Diabetes mellitus

Hormone Research ◽

10.1159/000185444 ◽

1997 ◽

Vol 47 (3) ◽

pp. 110-115 ◽

Cited By ~ 14

Author(s):

G. Radetti ◽

C. Paganini ◽

F. Ántoniazzi ◽

B. Pasquino ◽

R. Valentini ◽

...

Keyword(s):

Diabetes Mellitus ◽

Growth Hormone ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Binding Proteins ◽

Hormone Binding ◽

Igf Binding Proteins ◽

Igf I ◽

Igf Binding

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Role of insulin-like growth factor-I (IGF-I) receptor, IGF-I, and IGF binding protein-2 in human colorectal cancers

Growth Hormone & IGF Research ◽

10.1016/s1096-6374(98)80300-6 ◽

1998 ◽

Vol 8 (6) ◽

pp. 473-479 ◽

Cited By ~ 29

Author(s):

L. Mishra ◽

B. Bass ◽

B.S. Ooi ◽

A. Sidawy ◽

L. Korman ◽

...

Keyword(s):

Growth Factor ◽

Binding Protein ◽

Colorectal Cancers ◽

Insulin Like Growth Factor ◽

Factor I ◽

Igf I ◽

Igf Binding ◽

Growth Factor I ◽

Igf Binding Protein

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The role of IGF binding protein-3 as a parameter of activity in acromegalic patients

Acta Endocrinologica ◽

10.1530/eje.0.1410145 ◽

1999 ◽

pp. 145-148 ◽

Cited By ~ 6

Author(s):

I Halperin ◽

R Casamitjana ◽

L Flores ◽

M Fernandez-Balsells ◽

E Vilardell

Keyword(s):

Binding Protein ◽

Serum Levels ◽

Glucose Load ◽

Gh Secretion ◽

Igf I ◽

Igf Binding ◽

Igf Binding Protein ◽

Normal Standard ◽

Igfbp 3

OBJECTIVE: The production of insulin-like growth factor binding protein-3 (IGFBP-3), the main IGF-I binding protein, is regulated by GH, and its serum levels are increased in acromegaly. We investigated its potential value as a parameter of acromegaly activity or remission in comparison with IGF-I, taking GH suppression below 2 microg/l after glucose load as the normal standard. METHODS: Data from 40 acromegalic patients (12 males and 28 females, aged 28 to 79 years) were obtained retrospectively from stored samples. From these, 145 pairs of IGF-I/IGFBP-3 values were collected; in 67 of them, simultaneous measurement of GH after glucose loading allowed their classification as active or inactive acromegaly. Relationships between IGF-I, IGFBP-3 and GH after glucose load were assessed, as well as differences between IGF-I and IGFBP-3 levels in active and inactive acromegaly. RESULTS: Significant positive correlation between IGF-I and IGFBP-3 in 145 samples was observed (r=0.49, P<0. 0001). As for the 67 samples in which activity or remission could be defined in terms of GH after glucose load, 50 were active and 17 inactive. Both IGF-I and IGFBP-3 significantly correlated with minimum GH (r=0.53, P<0.0001 and r=0.41, P<0.001 respectively). For both parameters, significant differences of means between active and inactive cases were observed (623+/-296 vs 300+/-108 ng/ml, P<0.0001 for IGF-I, and 4.1+/-1.3 vs 3.2+/-0.9 microg/ml, P<0.006 for IGFBP-3). Yet, when comparing in individual cases their classification as active or inactive with the finding of normal or increased IGF-I and IGFBP-3, among active cases 16% appeared as normal according to IGF-I, and 50% appeared as normal in terms of IGFBP-3. Among inactive cases, 23.5% appeared as active according to IGF-I, while 17.5% appeared as active in terms of IGFBP-3. CONCLUSION: Even though IGFBP-3 reflects GH secretion, it offers no advantage over IGF-I in the assessment of acromegaly, and it may underestimate disease activity in acromegalic patients.

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