Differential long-term effects of insulin-like growth factor-I (IGF-I) growth hormone (GH), and IGF-I plus GH on body growth and IGF binding proteins in hypophysectomized rats.

The long-term effects of recombinant human insulin-like growth factor-I (rhIGF-I) and GH (rhGH) on body growth and the IGF-I/IGF binding protein (IGFBP)/acid-labile subunit (ALS) axis were investigated in hypophysectomized (hypox) rats given excipient, rhIGF-I (2 mg/kg.day s.c., minipumps), rhGH (2 mg/kg.day, s.c., daily injections), or rhIGF-I plus rhGH for 28 days. The relative growth-promoting activity of the treatments was rhGH plus rhIGF-I more than rhGH more than rhIGF-I. Weight gain induced by rhIGF-I progressively declined after 4 days, compared with a more maintained effect of rhGH. At day 28, growth responses did not correlate with serum IGF-I levels [rhGH plus rhIGF-I (492 +/- 140) > rhIGF-I (322 +/- 75) > rhGH (85 +/- 26) > control (39 +/- 7 ng/ml)]. Serum ALS concentrations in hypox rats were remarkably low (0.42 +/- 0.04 micrograms/ml) but were restored toward normal by rhGH (12.55 +/- 4.78) or rhGH plus rhIGF-I (12.85 +/- 6.64) but not by rhIGF-I alone (0.85 +/- 0.25). Antibodies against rhGH were present at day 28, with titer being negatively related to weight gain, IGF-I, and ALS levels. All treatments increased serum IGFBP-3. The molecular size distribution of IGFBP-3 in rhGH-treated rats was similar to that of normal rats (IGFBP-3 in the 150K mol wt range), due to rhGH increasing serum ALS, but was altered by rhIGF-I (IGFBP-3 in the 200-300K and 44K mol wt range). In a GH-deficient animal, restoring the IGF/IGFBP-3/ALS axis towards normal is associated with greater growth promotion.

[1]  W. Daughaday.  A Personal History of the Origin of the Somatomedin Hypothesis and Recent Challenges to Its Validity , 2015, Perspectives in biology and medicine.

[2]  D. Clemmons,et al.  Insulin-like growth factors and their binding proteins: biological actions. , 1995, Endocrine reviews.

[3]  M. Rechler,et al.  A major portion of the 150-kilodalton insulin-like growth factor-binding protein (IGFBP) complex in adult rat serum contains unoccupied, proteolytically nicked IGFBP-3 that binds IGF-II preferentially. , 1995, Endocrinology.

[4]  A. Sommer,et al.  Biochemical analysis of prostate specific antigen-proteolyzed insulin-like growth factor binding protein-3. , 1994, Growth regulation.

[5]  R. Baxter,et al.  Regulation of the acid-labile subunit of the insulin-like growth factor complex in cultured rat hepatocytes. , 1994, Endocrinology.

[6]  R. Clark,et al.  Enhanced body growth in uremic rats treated with IGF-I and growth hormone in combination. , 1994, Kidney international.

[7]  R. Baxter.  Insulin-like growth factor binding proteins in the human circulation: a review. , 1994, Hormone research.

[8]  R. Baxter,et al.  Cellular localization and regulation of gene expression for components of the insulin-like growth factor ternary binding protein complex. , 1994, Endocrinology.

[9]  L. Phillips,et al.  Coculture of primary rat hepatocytes and nonparenchymal cells permits expression of insulin-like growth factor binding protein-3 in vitro. , 1994, Endocrinology.

[10]  R. Baxter,et al.  Purification and characterization of the acid-labile subunit of rat serum insulin-like growth factor binding protein complex. , 1994, Endocrinology.

[11]  R. Baxter,et al.  Bioavailability of insulin-like growth factors (IGFs) in rats determined by the molecular distribution of human IGF-binding protein-3. , 1993, Endocrinology.

[12]  K. Alberti,et al.  A low dose euglycemic infusion of recombinant human insulin-like growth factor I rapidly suppresses fasting-enhanced pulsatile growth hormone secretion in humans. , 1993, The Journal of clinical investigation.

[13]  G. Cooney,et al.  Effect of human insulin-like growth factor-binding protein-1 on the half-life and action of administered insulin-like growth factor-I in rats. , 1993, The Journal of endocrinology.

[14]  R. Baxter,et al.  Enhancement of the anabolic effects of growth hormone and insulin-like growth factor I by use of both agents simultaneously. , 1993, The Journal of clinical investigation.

[15]  D. Clemmons,et al.  Determination of the pharmacokinetic profiles of insulin-like growth factor binding proteins-1 and -2 in rats. , 1992, Endocrinology.

[16]  A. Hoffman,et al.  Effects of recombinant human insulin-like growth factor-I (rhIGF-I) on total and free IGF-I concentrations, IGF-binding proteins, and glycemic response in humans. , 1992, The Journal of clinical endocrinology and metabolism.

[17]  F. Talamantes,et al.  Characterization of insulin-like growth factor binding proteins (IGFBPs) during gestation in mice: effects of hypophysectomy and an IGFBP-specific serum protease activity. , 1990, Endocrinology.

[18]  R. Baxter,et al.  Circulating levels and molecular distribution of the acid-labile (alpha) subunit of the high molecular weight insulin-like growth factor-binding protein complex. , 1990, The Journal of clinical endocrinology and metabolism.

[19]  D. Clemmons,et al.  Insulin-like growth factor-I (IGF-I) infusion into hypophysectomized or protein-deprived rats induces specific IGF-binding proteins in serum. , 1989, Endocrinology.

[20]  E. Froesch,et al.  Insulin-like growth factors I and II in healthy man. Estimations of half-lives and production rates. , 1989, Acta endocrinologica.

[21]  E. Froesch,et al.  Recombinant human insulin-like growth factor I induces its own specific carrier protein in hypophysectomized and diabetic rats. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[22]  A. Parlow,et al.  Highly improved precision of the hypophysectomized female rat body weight gain bioassay for growth hormone by increased frequency of injections, avoidance of antibody formation, and other simple modifications. , 1987, Endocrinology.

[23]  R. Baxter,et al.  Radioimmunoassay of growth hormone-dependent insulinlike growth factor binding protein in human plasma. , 1986, The Journal of clinical investigation.

[24]  M. Binoux,et al.  Analysis of serum insulin-like growth factor binding proteins using western blotting: use of the method for titration of the binding proteins and competitive binding studies. , 1986, Analytical biochemistry.

[25]  A. Herington,et al.  Tissue distribution and regulation of insulin-like growth factor (IGF)-binding protein-3 messenger ribonucleic acid (mRNA) in the rat: comparison with IGF-I mRNA expression. , 1992, Endocrinology.

[26]  Janet L. Martin,et al.  High Molecular Weight Insulin-like Growth Factor Binding Protein Complex , 1989 .

[27]  R. Clark,et al.  Recombinant human insulin-like growth factor: testing the somatomedin hypothesis in hypophysectomized rats. , 1987, The Journal of endocrinology.