Journal of Clinical Endocrinology & Metabolism, Vol 80, 3520-3527, Copyright © 1995 by Endocrine Society

ARTICLES

Hormonal regulation of circulating insulin-like growth factor-binding protein-1 phosphorylation status

M Westwood, JM Gibson, AC Williams, PE Clayton, O Hamberg, A Flyvbjerg and A White
Department of Medicine, University of Manchester, United Kingdom.

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.

This article has been cited by other articles:

				K. R. Short, J. Nygren, M. L. Bigelow, and K. S. Nair Effect of Short-Term Prednisone Use on Blood Flow, Muscle Protein Metabolism, and Function J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6198 - 6207. [Abstract] [Full Text] [PDF]

				A. H. Heald, K.W. Siddals, W. Fraser, W. Taylor, K. Kaushal, J. Morris, R. J. Young, A. White, and J. M. Gibson Low Circulating Levels of Insulin-Like Growth Factor Binding Protein-1 (IGFBP-1) Are Closely Associated With the Presence of Macrovascular Disease and Hypertension in Type 2 Diabetes Diabetes, August 1, 2002; 51(8): 2629 - 2636. [Abstract] [Full Text] [PDF]

				J. Frystyk, K. Hojlund, K. N. Rasmussen, S. P. Jorgensen, M. Wildner-Christensen, and H. Orskov Development and Clinical Evaluation of a Novel Immunoassay for the Binary Complex of IGF-I and IGF-Binding Protein-1 in Human Serum J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 260 - 266. [Abstract] [Full Text] [PDF]

				C. H. Gravholt, J. Frystyk, A. Flyvbjerg, H. Orskov, and J. S. Christiansen Reduced free IGF-I and increased IGFBP-3 proteolysis in Turner syndrome: modulation by female sex steroids Am J Physiol Endocrinol Metab, February 1, 2001; 280(2): E308 - E314. [Abstract] [Full Text] [PDF]

				K. Sakai, A. J. D'Ercole, L. J. Murphy, and D. R. Clemmons Physiological Differences in Insulin-Like Growth Factor Binding Protein-1 (IGFBP-1) Phosphorylation in IGFBP-1 Transgenic Mice Diabetes, January 1, 2001; 50(1): 32 - 38. [Abstract] [Full Text]

				R. C. Baxter Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities Am J Physiol Endocrinol Metab, June 1, 2000; 278(6): E967 - E976. [Abstract] [Full Text] [PDF]

				D. Fowler, G. Albaiges, C. Lees, J. Jones, K. Nicolaides, and J. Miell The role of insulin-like growth factor binding protein-1 phosphoisoforms in pregnancies with impaired placental function identified by Doppler ultrasound Hum. Reprod., November 1, 1999; 14(11): 2881 - 2885. [Abstract] [Full Text] [PDF]

				J. Frystyk, H. Gronbak, C. Skjarbak, A. Flyvbjerg, H. Orskov, and R. C. Baxter Developmental Changes in Serum Levels of Free and Total Insulin-Like Growth Factor I (IGF-I), IGF-Binding Protein-1 and -3, and the Acid-Labile Subunit in Rats Endocrinology, October 1, 1998; 139(10): 4286 - 4292. [Abstract] [Full Text] [PDF]

				E. Fernqvist-Forbes, A. Hilding, K. Ekberg, and K. Brismar Influence of Circulating Epinephrine and Norepinephrine on Insulin-Like Growth Factor Binding Protein-1 in Humans J. Clin. Endocrinol. Metab., August 1, 1997; 82(8): 2677 - 2680. [Abstract] [Full Text] [PDF]

				B. L. G. Nyomba, L. Berard, and L. J. Murphy Free Insulin-Like Growth Factor I (IGF-I) in Healthy Subjects: Relationship with IGF-Binding Proteins and Insulin Sensitivity J. Clin. Endocrinol. Metab., July 1, 1997; 82(7): 2177 - 2181. [Abstract] [Full Text] [PDF]

				N. A. Martina, E. Kim, U. Chitkara, N. C. Wathen, T. Chard, and L. C. Giudice Gestational Age-Dependent Expression of Insulin-Like Growth Factor-Binding Protein-1 (IGFBP-1) Phosphoisoforms in Human Extraembryonic Cavities, Maternal Serum, and Decidua Suggests Decidua as the Primary Source of IGFBP-1 in these Fluids during Early Pregnancy J. Clin. Endocrinol. Metab., June 1, 1997; 82(6): 1894 - 1898. [Abstract] [Full Text] [PDF]

				D. L. Mortensen, W. B. Won, J. Siu, D. Reifsnyder, M. Gironella, T. Etcheverry, and R. G. Clark Insulin-Like Growth Factor Binding Protein-1 Induces Insulin Release in the Rat Endocrinology, May 1, 1997; 138(5): 2073 - 2080. [Abstract] [Full Text] [PDF]

				M. Westwood, J M. Gibson, and A. White Purification and Characterization of the Insulin-Like Growth Factor-Binding Protein-1 Phosphoform Found in Normal Plasma Endocrinology, March 1, 1997; 138(3): 1130 - 1136. [Abstract] [Full Text] [PDF]

				M. J. Khosravi, A. Diamandi, and J. Mistry Immunoassay of insulin-like growth factor binding protein-1 Clin. Chem., March 1, 1997; 43(3): 523 - 532. [Abstract] [Full Text] [PDF]