Hormonal regulation of circulating insulin-like growth factor-binding protein-1 phosphorylation status.
Insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) normally circulates as a single, highly phosphorylated species. However, IGFBP-1 phosphorylation status can be altered, such as in pregnancy where non- and lesser phosphorylated isoforms are also present. We have examined how hormonal regulators of circulating IGFBP-1 influence its phosphorylation status and, hence, its ability to modulate IGF activity. In response to insulin-induced hypoglycemia (0.2 U/kg, iv), an increase in the highly phosphorylated isoform was observed after 5 h [16 (range, 11.5-35.5) to 77 (range, 63-250) microgram/L; 4.8-fold increase; P = 0.009], but no non- or lesser phosphorylated variants could be detected. Glucagon (1 mg, sc), increased IGFBP-1 from 27 (range, 13-36.5) to 112 (range, 100.5-129) micrograms/L (4.1-fold increase; P = 0.009) after 90 min despite preceding insulin concentrations of more than 500 pmol/L, but again the IGFBP-1 remained in the highly phosphorylated form. Regulation of IGFBP-1 phosphorylation by sex steroids was studied by comparing women receiving a combined oral contraceptive with women on no medication. Although plasma IGFBP-1 levels were significantly elevated in the treatment group [120 (range, 97.5-237.5) vs. 52 (range, 38-70) micrograms/L; P < 0.004], there was no difference in the form of IGFBP-1 present. The acute effect of somatostatin (500 micrograms/h) on IGFBP-1 phosphorylation status was also studied. Somatostatin only increased the phosphoform characteristic of normal subjects; the appearance of non- or lesser phosphorylated variants was not induced. The effect of rhIGF-I (80 or 120 micrograms, sc) on plasma IGFBP-1 was studied in three subjects with Laron's syndrome. A transient increase in the highly phosphorylated isoform of IGFBP-1 was noted; there was no rise in the non- and lesser phosphorylated isoforms also found in the plasma of Laron's syndrome subjects. These data suggest that only the highly phosphorylated species of IGFBP-1 is under hormonal control; regulation of the non- and lesser phosphorylated variants remains to be determined.
Department of Medicine, University of Manchester, United Kingdom.
M
M
Westwood
J M
JM
Gibson
A C
AC
Williams
P E
PE
Clayton
O
O
Hamberg
A
A
Flyvbjerg
A
A
White
D000328:Adult; D002648:Child; D003276:Contraceptives, Oral / Q000494:pharmacology; D004392:Dwarfism / Q000097:blood; D005260:Female; D005934:Glucagon / Q000494:pharmacology; D006728:Hormones / Q000502:physiology*; D006801:Humans; D007003:Hypoglycemia / Q000097:blood / Q000139:chemically induced; D007328:Insulin / Q000097:blood; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008297:Male; D010766:Phosphorylation; D011247:Pregnancy; D011994:Recombinant Proteins; D013004:Somatostatin / Q000494:pharmacology; D013997:Time Factors
D003276:Contraceptives, Oral; D006728:Hormones; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D011994:Recombinant Proteins; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; D005934:Glucagon