Total Alanine-Scanning Mutagenesis of Insulin-like Growth Factor I (IGF-I) Identifies Differential Binding Epitopes for IGFBP-1 and IGFBP-3

Biochemistry ◽  
1999 ◽  
Vol 38 (20) ◽  
pp. 6386-6396 ◽  
Author(s):  
Yves Dubaquié ◽  
Henry B. Lowman
Keyword(s):  
Growth Factor ◽  
Insulin Like Growth Factor ◽  
Alanine Scanning Mutagenesis ◽  
Alanine Scanning ◽  
Factor I ◽  
Igf I ◽  
Differential Binding ◽  
Growth Factor I ◽  
Igfbp 3

Effects of octreotide on insulin-like growth factor I and metabolic indices in growth hormone-treated growth hormone-deficient patients

1993 ◽  
Vol 129 (5) ◽  
pp. 399-408 ◽  
Author(s):  
Torben Laursen ◽  
Jens OL Jorgensen ◽  
Hans Ørskov ◽  
Jens Møller ◽  
Alan G Harris ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Animal Studies ◽  
Area Under The Curve ◽  
Insulin Like Growth Factor ◽  
Gh Secretion ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I ◽  
Igfbp 3

Animal studies have demonstrated that in addition to inhibiting growth hormone (GH) secretion octreotide inhibits in a direct manner hepatic or peripheral insulin-like growth factor I (IGF-I) generation. To test this hypothesis in humans we studied ten GH-deficient patients with frequent blood sampling during 38 h on two occasions. Regular GH therapy was discontinued 72 h prior to each study period. At the start of each study a subcutaneous (sc) injection of GH (3 IU/m2) was given (at 18.00 h). In a single-blinded crossover design, patients received a continuous sc infusion of either octerotide (200 μg/24 h) or placebo (saline). The pharmacokinetics of GH were similar on the two occasions. The area under the curve±sem of serum GH was 142.5±53.6 μg·l−1·h−1 (octreotide) and 144.8±41.8 μg·l−1·h−1 (placebo), (p=0.73); Cmax (μg/l) was 12.5±1.47 (octreotide) and 12.8±1.42 (placebo) (p=0.83), and Tmax (h) was 6.1±0.97 (octreotide) and 5.2±0.65 (placebo) (p=0.49). Growth hormone administration was associated with an increase in serum IGF-I (μg/l), which was identical during the two studies, from 85.3±19.4 to 174.25±30.3 for octreotide and from 97.0±26.4 to 158.8±28.2 for placebo. Mean IGF-I levels (μg/l) were 138.2±25.1 (octreotide) and 134.5±28.6 (placebo) (p=0.78). Similarly, the increase in IGF binding protein 3 (IGFBP-3) levels was identical. Mean IGFBP-3 levels (μg/l) were 2303±323 (octreotide) and 2200±361 (placebo) (p=0.25). Mean insulin levels were significantly lower during octreotide treatment (39.9±17.9 mU/l) than during placebo (59.7±17.8 mU/l) (p<0.05). Mean blood glucose levels were elevated significantly during octreotide infusion (5.98±0.23 mmol/l for octreotide and 5.07±0.16 mmol/l for placebo; p=0.001). Glucagon levels decreased non-significantly (p=0.07) and IGFBP-1 levels tended to increase during infusion of octreotide although not significantly (p=0.41). Levels of the lipid intermediates were identical on the two occasions. Alanine and lactate levels were significantly increased during octreotide infusion. Mean levels of blood alanine (μmol/l) were 470.8±24.2 (octreotide) and 360.1±17.8 (placebo) (p<0.02). Mean levels of blood lactate were 1038±81.0 (octreotide) and 894.4±73.8 (placebo) (p<0.04). We conclude that short-term continuous sc infusion of octreotide has no direct effect on the generation of IGF-I or the pharmacokinetics of exogenous GH in GH-deficient man.

scholarly journals Effects of Recombinant Human Insulin-Like Growth Factor I Administration on Spontaneous and Growth Hormone (GH)-Releasing Hormone-Stimulated GH Secretion in Anorexia Nervosa1

2000 ◽  
Vol 85 (8) ◽  
pp. 2805-2809
Author(s):  
Laura Gianotti ◽  
Angela I. Pincelli ◽  
Massimo Scacchi ◽  
Mimma Rolla ◽  
Deanna Bellitti ◽  
...  
Keyword(s):  
Growth Factor ◽  
Normal Weight ◽  
Insulin Like Growth Factor ◽  
Recombinant Human Insulin ◽  
Releasing Hormone ◽  
Gh Secretion ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I ◽  
Igfbp 3

Exaggerated GH and reduced insulin-like growth factor I (IGF-I) levels are common features in anorexia nervosa (AN). A reduction of the negative IGF-I feedback could account, in part, for GH hypersecretion. To ascertain this, we studied the effects of recombinant human (rh)IGF-I on spontaneous and GH-releasing hormone (GHRH)-stimulated GH secretion in nine women with AN [body mass index, 14.1 ± 0.6 kg/m2] and in weight matched controls (normal weight). Mean basal GH concentrations (mGHc) and GHRH (2.0μ g/kg, iv) stimulation were significantly higher in AN. rhIGF-I administration (20 μg/kg, sc) significantly reduced mGHc in AN (P &lt; 0.01), but not normal weight, and inhibited peak GH response to GHRH in both groups; mGHc and peak GH, however, persisted at a significantly higher level in AN. Insulin, glucose, and IGFBP-1 basal levels were similar in both groups. rhIGF-I inhibited insulin in AN, whereas glucose remained unaffected in both groups. IGFBP-1 increased in both groups (P &lt; 0.05), with significantly higher levels in AN. IGFBP-3 was under basal conditions at a lower level in AN (P &lt; 0.05) and remained unaffected by rhIGF-I. This study demonstrates that a low rhIGF-I dose inhibits, but does not normalize, spontaneous and GHRH-stimulated GH secretion in AN, pointing also to the existence of a defective hypothalamic control of GH release. Moreover, the increased IGFBP-1 levels might curtail the negative IGF-I feedback in AN.

scholarly journals Hyperlipidemia is associated with altered levels of insulin-like growth factor-I

2008 ◽  
pp. 919-925
Author(s):  
J Malík ◽  
T Štulc ◽  
D Wichterle ◽  
V Melenovský ◽  
E Chytilová ◽  
...  
Keyword(s):  
Growth Factor ◽  
Coronary Atherosclerosis ◽  
Molar Ratio ◽  
Insulin Like Growth Factor ◽  
Premature Atherosclerosis ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I ◽  
Mixed Hyperlipidemia ◽  
Igfbp 3

Previous studies revealed altered levels of the circulating insulin-like growth factor-I (IGF-I) and of its binding protein-3 (IGFBP-3) in subjects with coronary atherosclerosis, metabolic syndrome and premature atherosclerosis. Hyperlipidemia is a powerful risk factor of atherosclerosis. We expected IGF-I and IGFBP-3 alterations in subjects with moderate/severe hyperlipidemia but without any clinical manifestation of atherosclerosis. Total IGF-I and IGFBP-3 were assessed in 56 patients with mixed hyperlipidemia (MHL; cholesterol >6.0 mmol/l, triglycerides >2.0 mmol/l), in 33 patients with isolated hypercholesterolemia (IHC; cholesterol >6.0 mmol/l, triglycerides <2.0 mmol/l), and in 29 healthy controls (cholesterol<6.0 mmol/l, triglycerides<2.0 mmol/l). The molar ratio of IGF-I/IGFBP-3 was used as a measure of free IGF-I. IHC subjects differed from controls by lower total IGF-I (164+/-60 vs. 209+/-73 ng/ml, p=0.01) and IGF-I /IGFBP-3 ratio (0.14+/-0.05 vs. 0.17+/-0.04, p=0.04). Compared to controls, MHL subjects had lower total IGF-I (153+/-54 ng/ml, p=0.0002) and IGFBP-3 (2.8+/-0.6 mg/ml, p<0.0001), but higher IGF-I/IGFBP-3 ratio (0.25+/-0.06, p<0.0001). Differences remained significant after the adjustment for clinical and biochemical covariates, except for triglycerides. Patients with both IHC and MHL have lower total IGF-I compared to controls. The mechanism is presumably different in IHC and MHL. Because of prominent reduction of IGFBP-3 in patients with MHL, they have reduced total IGF-I despite the actual elevation IGF-I/IGFBP-3 ratio as a surrogate of free IGF-I.

Comparison of the effectiveness of various procedures for reducing or eliminating insulin-like growth factor-binding protein interference with insulin-like growth factor-I radioimmunoassays on porcine sera

1994 ◽  
Vol 140 (2) ◽  
pp. 229-237 ◽  
Author(s):  
R S Frey ◽  
M R Hathaway ◽  
W R Dayton
Keyword(s):  
Molecular Weight ◽  
Growth Factor ◽  
Binding Proteins ◽  
Insulin Like Growth Factor ◽  
Factor Binding ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I ◽  
Igfbp 3 ◽  
Glycyl Glycine

Abstract We have examined the efficacy of various methods for reducing the interference of insulin-like growth factor-binding proteins (IGFBPs) with insulin-like growth factor-I (IGF-I) radioimmunoassays (RIAs) run on porcine sera. Acid–ethanol (AE) extraction, AE extraction followed by cryoprecipitation, glycyl–glycine (GG) extraction, GG extraction followed by Sephadex G-50 chromatography in 1 mol acetic acid/l (GG/G-50), and Sep-Pak chromatography were analysed. To provide a range of IGF-I and IGFBP levels, sera obtained from control, hypophysectomized, diabetic and somatotrophin-treated pigs were used. Recoveries of IGF-I added to sera prior to treatments other than Sep-Pak chromatography ranged from 85 to 105% and were not significantly different. In contrast, Sep-Pak chromatography gave extremely variable recoveries. 125I-Labelled IGF-I ligand blotting showed that GG extraction followed by acid G-50 chromatography was by far the most effective method of removing or inactivating IGFBPs in porcine sera. Consequently, this procedure was used as a standard against which to compare other extraction procedures. GG extraction alone removed or inactivated low molecular weight binding proteins but appeared to have little effect on IGFBP-3. AE extraction reduced the level of IGFBP-3 but had little effect on lower molecular weight binding proteins. Even though none of the tested procedures completely removed or inactivated the binding proteins, all samples yielded IGF-I displacement curves that were parallel to that obtained for IGF-I standard. Despite yielding parallel displacement curves, sera extracted by various methods gave dramatically different apparent IGF-I levels when subjected to IGF-I RIA. IGF-I RIA of GG extracted sera yielded IGF-I values that were closest to those obtained for identical serum samples subjected to glycyl-glycine extraction followed by G-50 chromatography. For sera from control, hypophysectomized, diabetic and somatotrophin-treated pigs, the relationship of the IGF-I level in GG-extracted sera to that in GG-extracted, acid G-50 chromatographed (GG/G-50) sera was √GG=1·13√GG/G-50−0·23 (r2=0·98). Consequently, GG extraction can be used to remove IGFBP interference with IGF-I RIAs of porcine sera from normal, hypophysectomized, diabetic and somatotrophin-treated animals. Journal of Endocrinology (1994) 140, 229–237

Reference ranges for two automated chemiluminescent assays for serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3)

2004 ◽  
Vol 42 (6) ◽  
Author(s):  
Martin W. Elmlinger ◽  
Werner Kühnel ◽  
Matthias M. Weber ◽  
Michael B. Ranke
Keyword(s):  
Growth Factor ◽  
Binding Protein ◽  
Reference Ranges ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igf I ◽  
Igf Binding ◽  
Growth Factor I ◽  
Igf Binding Protein ◽  
Igfbp 3

AbstractAssays for insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) have become essential tools in the diagnostic work-up of disorders of the somatotropic axis in children and adults. The aim of this study was to evaluate the automated IMMULITE

Pharmacokinetics of insulin-like growth factor I in hypopituitarism: correlation with binding proteins

1999 ◽  
Vol 277 (4) ◽  
pp. E579-E584 ◽  
Author(s):  
Nelly Mauras ◽  
Valerie Quarmby ◽  
Duane C. Bloedow
Keyword(s):  
Growth Factor ◽  
Half Life ◽  
Binding Proteins ◽  
Hormone Deficiency ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Normal Absorption ◽  
Igf I ◽  
Growth Factor I ◽  
Igfbp 3

We investigated the pharmacokinetics of recombinant human insulin-like growth factor I (rhIGF-I) in growth hormone deficiency (GHD). Nine GHD adults [age 25 ± 3 (SE) yr] received rhIGF-I (60 μg/kg sc) twice, 10 h apart, and blood was sampled over 24 h. IGF-I and free IGF-I concentrations increased, whereas IGF binding protein 3 (IGFBP-3) and acid labile subunit (ALS) were unchanged during treatment. There was no correlation between absorption or terminal half-life of IGF-I and IGFBP-3 or ALS, but negative correlations with IGF-I clearance (CL/F) and volume of distribution (V/F). Positive correlations between both IGFBP-3 and ALS and IGF-I maximal concentration (Cmax) and time of Cmax( T max) were observed. Compared with normal individuals studied similarly (using 80 μg/kg), GHD subjects showed a normal absorption half-life, a faster elimination half-life, lower Cmax, yet normal T maxand V/F. In conclusion, GHD is associated with normal absorption and distribution of IGF-I yet faster elimination kinetics. Additionally, IGFBP-3 and ALS concentrations modulate the peak concentrations of IGF-I achieved and correlate reciprocally with its V/F and CL/F, underscoring the critical importance of binding proteins in modulating the bioavailability of IGF-I in vivo in humans.

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