THE INSULIN-LIKE GROWTH-FACTOR (IGF)-BINDING PROTEINS AND IGF BIOACTIVITY IN LARON-TYPE DWARFISM

Laron-type dwarfism (LTD) is caused by a varible defect in the GH receptor gene and is, therefore, an ideal model to study the physiology of the insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) in the complete absence of GH action. In this study we examined the overnight variation of the IGFs, IGFBPs, and IGF bioactivity in two prepubertal subjects with LTD. Subject 1 was a 14-yr-old female, 103 cm tall (-8.3 SD), and subject 2 was a 11.5-yr-old male, 103.6 cm tall (-5.9 SD). Both had serum IGF-I levels below 0.07 U/mL and low constant serum IGF-II levels overnight (185 +/- 10 and 232 +/- 8-mu-g/L), despite high serum GH levels [mean GH, 65 (32.5-mu-g/L) and 53 mU/L (26.5-mu-g/L)]. Serum IGFBP-1 levels increased overnight (from 24 and 22-mu-g/L at 2000 h to 83 and 110-mu-g/L at 0800 h) as serum insulin levels fell [from 19 (136 pmol/L) and 17 mU/L (122 pmol/L) at 2000 h to < 2 (< 14 pmol/L) and 5 mU/L (36 pmol/L) at 0800 h] in subjects 1 and 2, respectively. Serum IGFBP-2 levels remained constant overnight, as assessed on Western Ligand blotting and, despite the changes in IGFBP-1, remained the most prominent IGFBP throughout. On size separation, most of the IGF-II (> 60%) eluted with IGFBP-2 and the other low mol wt IGFBPs. Serum IGFBP-3 levels were reduced, IGFBP-3 was not major IGF carrier in LTD serum, in contrast to normal serum. An IGFBP-3-specific protease that was heat sensitive and cation dependent was identified as the cause of an apparent overnight rise of serum IGFBP-3 levels. No IGFBP-3 variation and no proteolytic activity was seen in normal serum or rapidly separated LTD plasma. Serum IGF bioactivity, measured in a porcine cartilage bioassay, was 0.18 and 0.55 U/mL in subjects 1 and 2; differences in bioactivity between subjects did not relate to serum IGF-II levels, but, rather, to differences in IGFBP-3 levels. Serum IGF bioactivity was not constant overnight and varied in a similar fashion in both subjects 1 and 2, with reduction in bioactivity between 0600-0800 h by 55% and 32%, suggesting the presence of inhibitory factors in the LTD serum; this decrease coincided with the rise in serum IGFBP-1 levels. In LTD, the regulation of IGFBP-1 remains insulin dependent, but in contrast to normal subjects, IGFBP-2 is the dominant binding protein, and IGFBP-3 binds very little of the circulating IGF-II. The finding of an IGFBP-3-specific protease in LTD, but not in normal subjects, requires further study, as this suggests an in vivo mechanism which may enhance IGF release to the tissues in situations of low serum IGF levels. Variation in serum IGF bioactivity appeared to be due largely to variations in the IGFBPs, rather than IGF-II, suggesting that the IGFBPs play an important role in IGF physiology in the GH-resistant syndrome of LTD.