Insulin-Like Growth Factor Binding Protein (IGFBP)-3-Bound IGF-I and IGFBP-3-Bound IGF-II in Growth Hormone Deficiency

Abstract

In blood, circulating IGFs are bound to six high-affinity IGFBPs, which modulate IGF delivery to target cells. Serum IGFs and IGFBP-3, the main carrier of IGFs, are upregulated by GH. The functional role of serum IGFBP-3-bound IGFs is not well understood, but they constitute the main reservoir of IGFs in the circulation. We have used an equation derived from the law of mass action to estimate serum IGFBP-3-bound IGF-I and IGFBP-3-bound IGF-II, as well as serum free IGF-I and free IGF-II, in 129 control children and adolescents (48 girls and 81 boys) and in 13 patients with GHD. Levels of serum total IGF-I, total IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 were determined experimentally, while those of IGFBP-4, IGFBP-5 and IGFPB-6, as well as the 12 affinity constants of association of the two IGFs with the six IGFBPs, were taken from published values. A correction for in vivo proteolysis of serum IGFBP-3 was also considered. In controls, serum total IGF-I, total IGF-II, IGFBP-3, IGFBP-3-bound IGF-I, IGFBP-3-bound IGF-II and free IGF-I increased linearly with age, from less than 1 to 15 years, in the two sexes. The concentrations of serum free IGF-I and free IGF-II were approximately two orders of magnitude below published values, as well as below the affinity constant of association of IGF-I with the type-1 IGF receptor. Therefore, it is unlikely that these levels can interact with the receptor. In the 13 patients with GHD, mean (± SD) SDS of serum IGFBP-3-bound IGF-I was –2.89 ± 0.97. It was significantly lower than serum total IGF-I, free IGF-I or IGFBP-3 SDSs (–2.35 ± 0.83, –1.12 ± 0.78 and –2.55 ± 1.07, respectively, p = 0.0001). The mean SDS of serum total IGF-II, IGFBP-3-bound IGF-II and free IGF-II were –1.25 ± 0.68, –2.03 ± 0.87 and 0.59 ± 1.10, respectively, in GHD. In control subjects, 89.8 ± 4.47% of serum total IGF-I and 77.3 ± 9.4% of serum total IGF-II were bound to serum IGFBP-3. In patients with GHD, the mean serum IGFBP-3-bound IGF-I and IGFBP-3-bound IGF-II were 8.63 ± 8.53 and 19.1 ± 14.7% below the respective means of control subjects (p < 0.02). In conclusion, in GHD there was a relative change in the distribution of serum IGFs among IGFBPs, due to the combined effects of the decrease in both total IGF-I and IGFBP-3. As a result, serum IGFBP-3-bound IGF-I and IGFBP-3 bound IGF-II, the main reservoirs of serum IGFs, were severely affected. This suggests that the decrease in serum IGFPB-3-bound IGF-I and IGFBP-3-bound IGF-II might have a negative effect for growth promotion and other biological effects of IGF-I and IGF-II. Finally, the estimation of serum IGFBP-3-bound IGF-I, or the percentage of total IGF-I and IGF-II bound to IGFBP-3, might be useful markers in the diagnosis of GHD.

Free Insulin-Like Growth Factor I: Are We Hunting a Ghost?

“…If affinity data from competitive solution affinity assays are used [5], considerably lower free IGF-I concentrations are found, as shown in table 2. Significantly lower calculated serum free IGF-I was also reported by Belgorosky and Rivarola [2] using affinity data from Bach et al [5] and taking all six IGFBPs as well as IGF-II into consideration. It is probable that the presence of excess ALS in serum, which is not taken into consideration here, results in even lower free IGF-I concentrations.…”

“…At equilibrium, the concentration of unbound reactant in a simple reaction between two reactants such as IGF and IGFBP can be calculated from the law of mass action by the equation: Although it may theoretically be possible to calculate the free IGF-I concentration in serum [2], the IGF system is highly complex. It consists of IGF-I and IGF-II, the high-affinity binding proteins-1 to -6, the ALS that forms ternary complexes with IGFs bound by either IGFBP-3 or -5, as well as IGFBP-related proteins with significantly lower affinities.…”

IGF-1 Deficiency Rescue and Intracellular Calcium Blockade Improves Survival and Corresponding Mechanisms in a Mouse Model of Acute Kidney Injury

“…Intramuscular injection of the Lenti-IGF-1 vector rescued the serum IGF-1 deficiency and the elevated serum creatinine (Figure 2). We also evaluated the effects of IGF-1 + IGFBP3 because BP3 is the major IGF binding protein circulating in the blood [30]. However, we observed no superiority using the IGFBP3 in a survival study (data not shown), and therefore, we performed our studies with only in vivo IGF-1 gene therapy.…”

Hydrocortisone Treatment in Girls with Congenital Adrenal Hyperplasia Inhibits Serum Dehydroepiandrosterone Sulfate and Affects the GH-IGF-I System

“…Serum IGF-I was determined by RIA, after acid-ethanol extraction of serum, as previously reported 12 nostic kit (DSL); intra-assay and interassay CVs were 5.3-6.7% and 6.7-8.3%, respectively.…”