scholarly journals Stimulation of the 150-Kilodalton Insulin-Like Growth Factor-Binding Protein-3 Ternary Complex by Continuous and Pulsatile Patterns of Growth Hormone (GH) Administration in GH-Deficient Patients1

2000 ◽  
Vol 85 (11) ◽  
pp. 4310-4314 ◽  
Author(s):  
Torben Laursen ◽  
Allan Flyvbjerg ◽  
Jens O. L. Jørgensen ◽  
Robert C. Baxter ◽  
Jens S. Christiansen

In the circulation insulin-like growth factor I (IGF-I), IGF-binding protein 3 (IGFBP-3), and the acid-labile subunit (ALS) form a 150-kDa ternary complex that is of importance for the regulation of IGF-I bioactivity. GH administration is known to increase each of the single components of the ternary complex, and in GH-deficient rats formation of the 150-kDa complex is induced more by continuous than by pulsatile GH patterns. The aim of the present studies was to study the effects of the GH administration pattern on the formation of the 150-kDa ternary complex in humans. A fixed total GH dose (2 IU/m2·24 h) was administered iv randomly as 1) continuous infusion or 2) eight bolus injections to five GH-deficient patients over a period of 24 h. GH administration significantly increased serum IGF-I and IGFBP-3 levels and the IGF-I/IGFBP-3 ratio. IGF-I levels increased most pronouncedly after continuous administration (P < 0.01). Serum ALS levels increased significantly (both P < 0.005) from 94 ± 21 to 180 ± 29 (infusion) and from 85 ± 17 to 155 ± 17 nmol/L (pulses). Employment of neutral size exclusion chromatography enabled separation of IGFBP-3 in ternary complex and noncomplex-bound fractions. IGFBP-3 in the ternary complex increased significantly after GH administration[ by 44% (P = 0.048) during infusion and by 62% (P = 0.004) during bolus]. The noncomplex-associated IGFBP-3 fraction, however, did not increase significantly after GH administration (P = NS). Finally, formation of the ternary complex was unaffected by the pattern of GH delivery. In conclusion, short-term GH administration increased all components of the 150-kDa ternary complex. Higher levels of IGF-I after constant GH exposure could indicate an increased bound fraction. However, the GH pattern did not influence the induction of the ternary complex itself. Continuous and intermittent GH patterns may be clinically equally effective during long-term GH therapy, as judged by levels of the components of the ternary complex.

1993 ◽  
Vol 294 (3) ◽  
pp. 847-852 ◽  
Author(s):  
R C Baxter ◽  
A M Suikkari ◽  
J L Martin

During pregnancy, insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) undergoes proteolysis, rendering it undetectable by radioligand binding techniques. This study examines the physical and functional defect in pregnancy IGFBP-3. Ternary complex formation has been measured by the binding of the acid-labile subunit of the circulating IGFBP-3 complex, which also requires IGF-I or IGF-II binding. IGF-depleted pregnancy IGFBP-3, prepared by size-exclusion chromatography at low pH, could not form a ternary complex in the presence of [Tyr60]IGF-I or of an IGF-I analogue extensively altered in the A-domain, whereas analogues altered in the C- or D-domains complexed as well as native IGF-I. After purification by immunoaffinity chromatography, non-pregnancy and pregnancy IGFBP-3 formed ternary complexes with IGF-I equally well, although the pregnancy-proteolysed protein appeared degraded to approximately 30 kDa. On analysis by affinity labelling, cross-linked ternary complexes containing non-pregnancy or pregnancy IGFBP-3 were predominantly 135-140 kDa, with an additional complex of 110-115 kDa in the pregnancy preparation. After reverse-phase h.p.l.c., affinity-isolated pregnancy IGFBP-3 was inactive, whereas the protein from non-pregnancy serum retained activity. Thus pregnancy-proteolysed IGFBP-3 is altered in its specificity for IGF analogues, and is more labile than non-pregnancy IGFBP-3, but shows little impairment in normal IGF binding or ternary complex formation.


2006 ◽  
Vol 16 (2) ◽  
pp. 86-92 ◽  
Author(s):  
Tiffany G. Harris ◽  
Howard D. Strickler ◽  
Herbert Yu ◽  
Michael N. Pollak ◽  
E. Scott Monrad ◽  
...  

2007 ◽  
Vol 92 (9) ◽  
pp. 3660-3666 ◽  
Author(s):  
Iona Cheng ◽  
Katherine DeLellis Henderson ◽  
Christopher A. Haiman ◽  
Laurence N. Kolonel ◽  
Brian E. Henderson ◽  
...  

2001 ◽  
Vol 169 (1) ◽  
pp. 123-133 ◽  
Author(s):  
M Galanis ◽  
SM Firth ◽  
J Bond ◽  
A Nathanielsz ◽  
AA Kortt ◽  
...  

Insulin-like growth factor-binding protein-3 (IGFBP-3) is a member of a family of structurally conserved proteins (IGFBP-1 to -6) which act as carriers and regulators of the mitogenic peptide hormones IGF-I and IGF-II. Members of the IGFBP family share conserved cysteine-rich amino- and carboxyl-terminal regions. The amino-terminal domain of these proteins is recognised to contain an IGF-binding determinant, but evidence to support a binding site in the carboxyl-terminal region of the protein is less rigorous. To further investigate this, we have synthesised both the amino-terminal (residues 1-88; N-88) and carboxyl-terminal (residues 165-264; C-165) domains of human IGFBP-3 in bacteria, as fusion proteins with a carboxyl-terminal FLAG peptide. Although only C-165 showed binding to IGF-I and -II by solution-binding assays, both N-88 and C-165 demonstrated binding to IGF-I and -II by biosensor analysis albeit with reduced affinities compared with full-length IGFBP-3. Only the carboxyl-terminal fragment (C-165) was able to form hetero-trimeric complexes with IGF-I and the acid-labile subunit (ALS). We conclude that the carboxyl-terminal domain of IGFBP-3 contains an IGF-binding determinant and can form ternary complexes with ALS.


Author(s):  
Martin W. Elmlinger ◽  
Werner Kühnel ◽  
Matthias M. Weber ◽  
Michael B. Ranke

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


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