Insulin-like growth factor binding protein-6 (IGFBP-6) is a relatively unknown member of a family of six specific structurally related
IGF binding proteins which are involved in the modulation of the
biological effects of the IGFs. A distinctive property of
IGFBP-6 is its preferential affinity for
IGF-II relative to
IGF-I. In order to obtain more insight into the clinical significance and regulation of circulating levels of
IGFBP-6 we developed a specific radioimmunoassay (RIA) for this
protein.
DESIGN AND PATIENTS: The
IGFBP-6 assay is competitive, utilizing a rabbit polyclonal antibody raised against a synthetic
peptide comprising
amino acids 90-118 of the hIGFBP-6 sequence and an additional
tyrosine residue. It is calibrated against recombinant human (rh)IGFBP-6. The 125I tracer is prepared by iodination of the synthetic
peptide. There is no significant cross-reactivity with other IGFBPs and no interference with the IGFs.
RESULTS: Extensive normative range values for
IGFBP-6 were determined using 847 plasma samples from normal males and females, ranging from 0 to 75 years of age.
IGFBP-6 levels increased gradually (about two-fold) with age. In childhood the plasma levels of
IGFBP-6 in females tended to be slightly higher than those for males. For the adult population the reverse was observed. Overall, the mean +/- SD value for males was higher than that for females (149 +/- 57 vs. 139 +/- 45 micrograms/l, P < 0.004). GH status did not appear to influence
IGFBP-6 level since normal levels were found for both untreated acromegalic patients and GH-deficient subjects. GH treatment of the latter group of patients did not alter
IGFBP-6 in plasma. Pharmacological doses of glucocorticosteroids affected circulating
IGFBP-6 levels only slightly.
IGFBP-6 levels in plasma samples derived both from children with acute lymphoblastic leukaemia and from patients with various types of solid
neoplasms were generally within the normal range. In contrast, plasma samples from four of six patients with non-islet cell tumour induced hypoglycaemia (NICTH) showed elevated concentrations of
IGFBP-6 (SDS > 2.9). An excess of
IGFBP-6 was also found in plasma of both dialysed and non-dialysed prepubertal growth retarded children with
chronic renal failure (CRF) (mean SDS: 23.0 and 9.3, respectively).
IGFBP-6 levels were inversely correlated with glomerular filtration rate. In a group of CRF patients who underwent
renal transplantation circulating
IGFBP-6 levels were markedly lower (mean SDS: 4.6). The presence of
IGFBP-6 could also be demonstrated in several other human
biological fluids. Low amounts were detected in saliva (3-12 micrograms/l) and breast milk (6-45 micrograms/l) while the levels in amniotic fluid and follicular fluid were comparable with those determined in normal plasma. The
IGFBP-6 content of cerebrospinal fluid (CSF) ranged between 25 and 87 micrograms/l, which is rather high in relation to the relatively low concentration of total
protein in this body fluid.
CONCLUSIONS: Measurements of
IGFBP-6 have been shown so far to be of relatively minor clinical relevance. The exceptions are
chronic renal failure patients and subjects with large tumours and non-islet cell tumour induced hypoglycaemia who may exhibit elevated circulating levels of this
IGFBP. The physiological significance of this observation remains to be elucidated. The possibility of quantifying
IGFBP-6 by specific RIA will facilitate further in vitro and in vivo studies of its regulation and function in man.