Abstract
Thirty-seven children with intrauterine growth retardation (IUGR) were enrolled in a 3-mo longitudinal study. Weight, length, and knee-heel length(by knemometry) were measured at birth and at 7, 14, 30, 60, and 90 d. GH, IGF-I, IGF binding protein (BP)-3, IGFBP-1, and C-peptide were measured at birth and at 2 mo. IGFBP-3 Western immunoblotting and proteolytic activity assay were also performed. Twenty-five newborns with birth weight appropriate for gestational age were chosen as controls. At birth IUGR newborns showed levels of GH and IGFBP-1 significantly higher, and IGF-I, IGFBP-3, and C-peptide significantly lower than control subjects. At 2 mo GH and IGFBP-1 levels decreased, whereas IGF-I, IGFBP-3, and C-peptide rose, attaining the concentrations found in control subjects at birth. Baseline peptide levels as well as their 2-mo variations did not correlate with the gain in weight, supine length, and knee-heel length recorded at 3 mo. Fourteen of nineteen IUGR cord blood samples showed the presence of the intact ∼42-39-kD IGFBP-3 doublet and the major ∼29-kD fragment. At 2 mo the IGFBP-3 band pattern was characterized by the predominance of a ∼18-kD fragment in 6 of 19 tested IUGR infants. The incubation of 2-mo IUGR samples with normal adult serum induced the appearance of the ∼18-kD band, which was not modified by the addition of EDTA. These results suggest that: 1) the IGF-related growth-promoting mechanism is impaired in IUGR children at birth but is fully restored at 2 mo; 2) the cord blood levels of GH, IGF-I, IGFBP-3, IGFBP-1, and C-peptide are not predictive of the weight and length gain during the first 3 mo of life; 3) IUGR children have at least two different IGFBP-3 proteases, one cation-dependent protease that is present at birth and able to yield the major ∼29-kD IGFBP-3 fragment and a second one, with a different activation timing, which exhibits cation independence and induces the formation of a ∼18-kD IGFBP-3 form.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- IUGR:
-
intrauterine growth retardation
- IGFBP:
-
IGF binding protein
- P.I.:
-
ponderal index
- CV:
-
coefficient of variation
References
Fitzhardinge PM, Steven EM 1972 The small-for-date infant. I. Later growth patterns. Pediatrics 49: 671–681.
Karlberg J, Albertsson-Wikland K 1995 Growth in full-term small-for-gestational-age infants: from birth to final height. Pediatr Res 38: 733–739.
Barker DJP, Winter PD, Osmond C, Margetts B 1989 Weight in infancy and death from ischaemic heart disease. Lancet 2271: 577–580.
Barker DJP, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS 1993 Fetal nutrition and cardiovascular disease in adult life. Lancet 341: 938–941.
Gluckman PD 1995 The endocrine regulation of fetal growth in late gestation: the role of insulin-like growth factors. J Clin Endocrinol Metab 80: 1047–1050.
Cianfarani S, Holly JMP 1989 Somatomedin-binding proteins: what role do they play in the growth process?. Eur J Pediatr 149: 76–79.
Shimasaki S, Ling N 1991 Identification and molecular characterization of insulin-like growth factor binding proteins (IGFBP-1, -2,-3, -4, -5, and -6). Prog Growth Factor Res 3: 243–266.
Wilson DM, Bennet A, Adamson GD, Nagashima IW, Liu F, deNatale ML, Hintz RL, Rosenfeld RG 1982 SM in pregnancy: a cross sectional study of IGF-I and II and SM peptide content in normal human pregnancies. J Clin Endocrinol Metab 55: 858–865.
Bennet A, Wilson DM, Liu F, Nagashima R, Rosenfeld RG, Hintz RL 1983 Levels of insulin-like growth factors I and II in human cord blood. J Clin Endocrinol Metab 57: 609–612.
Gluckman PD, Johnson-Barrett JJ, Butler JH, Edgar BW, Gunn TR 1983 Studies of insulin-like growth factor-I and -II by specific radioligand assays in umbilical cord blood. Clin Endocrinol 19: 405–413.
Ashton IK, Zapf J, Einschenk I, MacKenzie IZ 1985 Insulin-like growth factor (IGF) I and II in human foetal plasma and relationship to gestational age and foetal size during mid-pregnancy. Acta Endocrinol 10: 558–563.
Lassarre C, Hardouin S, Daffos F, Forestier F, Frankenne F, Binoux M 1991 Serum insulin-like growth factors and insulin-like growth factor binding proteins in the human fetus. Relationships with growth in normal subjects and in subjects with intrauterine growth retardation. Pediatr Res 29: 219–225.
Verhaeghe J, Van Bree R, Van Herck E, Laureys J, Bouillon R, Van Assche A 1993 C-peptide, insulin-like growth factors I and II and insulin-like growth factor binding protein-1 in umbilical cord serum: correlations with birth weight. Am J Obstet Gynaecol 169: 89–97.
Reece EA, Wiznitzer A, Le E, Homko CJ, Behrman H, Spencer EM 1994 The relation between human fetal growth and fetal blood levels of insulin-like growth factors I and II, their binding proteins, and receptors. Obstet Gynecol 84: 88–95.
Crawford AF, Halls FA, Farkas A, Chard T 1995 Elevated levels of insulin-like growth factor binding protein-1 in fetal distress. Br J Obstet Gynaecol 102: 538–540.
Wang HS, Lim J, English J, Irvine L, Chard T 1991 The concentration of insulin-like growth factor-I and insulin-like growth factor-binding protein-1 in human umbilical cord serum at delivery: relation to fetal weight. J Endocrinol 129: 459–464.
Giudice LC, de Zegher F, Gargosky SE, Dsupin BA, De Las Fuentes L, Crystal RA, Hintz RL, Rosenfeld RG 1995 Insulin-like growth factors and their binding proteins in the term and preterm human fetus and neonate with normal and extremes of intrauterine growth. J Clin Endocrinol Metab 80: 1548–1555.
Hills FA, English J, Chard T 1996 Circulating levels of IGF-I and IGF-binding protein-1 throughout pregnancy: relation to birth weight and maternal weight. J Endocrinol 148: 303–309.
Liu J-P, Baker J, Perkins AS, Robertson EJ, Efstratiadis A 1993 Mice carrying null mutations of the genes encoding insulin-like growth factor-I (Igf-1) and type-1 IGF receptor (Igf1r). Cell 75: 59–72.
Baker J, Liu J-P, Robertson EJ, Efstratiadis A 1993 Role of insulin-like growth factors in embryonic and postnatal growth. Cell 75: 73–82.
Woods KA, Camacho-Hubner C, Savage MO, Clark AJL 1996 Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med 335: 1363–1367.
Rajkumar K, Barron D, Lewitt MS, Murphy LJ 1995 Growth retardation and hyperglycemia in insulin-like growth factor binding protein-1 transgenic mice. Endocrinology 136: 4029–4034.
Langford KS, Nicolaides KH, Jones J, Abbas A, McGregor AM, Miell JP 1995 Serum insulin-like growth factor binding protein-3(IGFBP-3) levels and IGFBP-3 protease activity in normal, abnormal, and multiple human pregnancy. J Clin Endocrinol Metab 80: 21–27.
Lubchenco LO, Hansman C, Dressler M, Boyd R 1963 Intrauterine growth as estimated from liveborn birth weight data at 24 to 42 wk of gestation. Pediatrics 32: 793–800.
Lubchenko LO, Hansman C, Boyd E 1966 Intrauterine growth in length and head circumference as estimated from live births at gestational ages from 26 to 42 wk. Pediatrics 37: 403–408.
Guo S, Roche Af, Fomon SJ, Nelson SE, Chumlea WC, Rogers RR, Baumgartner RN, Ziegler EE, Siervogel RM 1991 Reference data on gains in weight and length during the first two years of life. J Pediatr 119: 355–362.
Michaelsen KF, Skov L, Badsberg JH, Jorgensen M 1991 Short-term measurement of linear growth in preterm infants: validation of a hand-held knemometer. Pediatr Res 30: 464–468.
Gargosky SE, Pham HM, Wilson KF, Liu F, Giudice LC, Rosenfeld RG 1992 Measurement and characterization of insulin-like growth factor binding protein-3 in human biological fluids: discrepancies between radioimmunoassay and ligand blotting. Endocrinology 131: 3051–3060.
Consensus Statement 1994 Valid measurement of total IGF concentrations in biological fluids. Recommendations from the 3rd International Symposium on Insulin-Like Growth Factors. J Endocrinol 143: C1 C2
Holly JMP, Biddlecombe RA, Dunger DB, Edge JA, Amiel SA, Howell R, Chard T, Rees LH, Wass JAH 1988 Circadian variation of GH(mcg/L)-independent IGF-binding protein in diabetes mellitus and its relationship to insulin. A new role for insulin?. Clin Endocrinol 29: 667–675.
Liu X-J, Malkowski M, Guo Y, Erickson GF, Shimasaki S, Ling N 1993 Development of specific antibodies to rat insulin-like growth factor-binding proteins (IGFBP-2 to -6): analysis of IGFBP production by rat granulosa cells. Endocrinology 132: 1186–1183.
Bernardini S, Spadoni GL, Povoa G, Boscherini B, Hall K 1992 Plasma levels of insulin-like growth factor binding protein-1, and growth hormone binding protein activity from birth to the third month of life. Acta Endocrinol 127: 313–318.
Leger J, Noel M, Limal JM, Czernichow P 1996 Growth factors and intrauterine growth retardation. II. Serum growth hormone, insulin-like growth factor-I, and IGF-binding protein-3 levels in children with intrauterine growth retardation compared with normal control subjects: prospective study from birth to two years of age. Pediatr Res 40: 101–107.
Rajaram S, Carlson SE, Koo WWK, Rangachari A, Kelly DP 1995 Insulin-like growth factor (IGF)-I and IGF-binding protein 3 during the first year in term and preterm infants. Pediatr Res 37: 581–585.
Cornblath M, Parker ML, Reisner SH, Forbes AE, Daughaday WH 1965 Secretion and metabolism of growth hormone in premature and full term infants. J Clin Endocrinol Metab 25: 209–218.
Unterman TG, Simmons RA, Glick RP, Ogata ES 1993 Circulating levels of insulin, insulin-like growth factor-I (IGF-I), IGF-II, IGF-binding proteins in the small for gestational age fetal rat. Endocrinology 132: 327–336.
Bang P, Westgren M, Schwander J, Blum WF, Rosenfeld RG, Stangenberg M 1994 Ontogeny of insulin-like growth factor-binding protein-1, -2, and-3: quantitative measurements by radioimmunoassay in human fetal serum. Pediatr Res 36: 528–536.
Lindgren BF, Isaksson M, Stern I, Hall K 1993 Insulin-like growth factor binding protein-1 from Hep G2 cells is potently inhibited by the truncated IGF-I analogue des-(1-3)IGF-I. Acta Endocrinol 128: 81–87.
Zapf J, Hauri C, Waldvogel M, Futo E, Hasler H, Binz K, Guler HP, Schmid C, Froesch ER 1989 Recombinant human insulin-like growth factor I induces its own specific carrier protein in hypophysectomized and diabetic rats. Proc Natl Acad Sci USA 86: 3813–3817.
Hardouin S, Gourmelen M, Noguiez P, Seurin D, Roghani M, Le Bouc Y, Povoa G, Merimee TJ, Hossenlopp P, Binoux M 1989 Molecular forms of serum insulin-like growth factor (IGF) binding proteins in man: relationships with growth hormone and IGFs and physiological significance. J Clin Endocrinol Metab 69: 1291–1301.
Conover CA 1990 Regulation of insulin-like growth factor (IGF) binding protein synthesis by insulin and IGF-I in cultured bovine fibroblasts. Endocrinology 126: 3139–3145.
Bale LK, Conover CA 1992 Regulation of insulin-like growth factor binding protein-3 messenger ribonucleic acid expression by insulin-like growth factor I. Endocrinology 131: 608–614.
Neely EK, Rosenfeld RG 1992 Insulin-like growth factors (IGFs) reduce IGF-binding protein-4 (IGFBP-4) concentration and stimulate IGFBP-3 independently of IGF receptors in human fibroblasts and epidermal cells. Endocrinology 130: 985–993.
Baxter RC, Martin JL 1989 Structure of the Mr 140,000 growth hormone-dependent insulin-like growth factor binding protein complex: determination by reconstitution and affinity-labeling. Proc Natl Acad Sci USA 86: 6898–6902.
Guler H-P, Zapf J, Schmid C, Froesch J 1989 Insulin-like growth factor I and II in healthy man. Estimations of half lives and production rates. Acta Endocrinol 121: 753–758.
Hossenlopp P, Sergovia B, Lassarre C, Roghani M, Bredon M, Binoux M 1990 Evidence of enzymatic degradation of insulin-like growth factor binding proteins (IGFBPs) in the 150 K complex during pregnancy. J Clin Endocrinol Metab 71: 797–805.
Giudice LC, Farrell EM, Pham H, Lamson G, Rosenfeld RG 1990 Insulin-like growth factor binding proteins (IGFBPs) in maternal serum throughout gestation and in puerperium: effects of pregnancy-associated serum protease activity. J Clin Endocrinol Metab 71: 806–816.
Davenport ML, Clemmons DR, Miles MV, Camacho-Hubner C, D'Ercole AJ, Underwood LE 1990 Regulation of serum insulin-like growth factor-I (IGF-I) and IGF binding proteins during rat pregnancy. Endocrinology 127: 1278–1286.
Fielder PJ, Thordarson G, Talamantes F, Rosenfeld RG 1990 Characterization of insulin-like growth factor binding proteins (IGFBPs) during gestation in mice: effects of hypophysectomy and an IGFBP-specific serum protease activity. J Clin Endocrinol Metab 127: 2270–2280.
Bang P, Brismar K, Rosenfeld RG 1994 Increased proteolysis of insulin-like growth factor binding protein (IGFBP)-3 in NIDDM serum, with elevation of a 29 kDa glycosylated IGFBP-3 fragment contained in the ternary complex. J Clin Endocrinol Metab 78: 1119–1127.
Bang P, Stangenberg M, Westgren M, Rosenfeld RG 1994 Decreased ternary complex formation and predominance of a 29 kDs IGFBP-3 fragment in human fetal serum. Growth Regul 4: 68–76.
Spagnoli A, Gargosky SE, Spadoni GL, McGillivray M, Oh Y, Boscherini B, Rosenfeld RG 1995 Characterization of a low molecular mass form of insulin-like growth factor binding protein-3 (17.7 kilodaltons) in urine and serum from healthy children and growth hormone (GH)-deficient patients: relationship with GH therapy. J Clin Endocrinol Metab 80: 3668–3676.
Lassarre C, Lalou C, Perin L, Binoux M 1994 Protease-induced alteration of insulin-like growth factor binding protein-3 as detected by radioimmunoassay. Agreement with ligand blotting data. Growth Regul 4: 48–55.
Bereket A, Lang CH, Fan J, Frost RA, Wilson TA 1995 Insulin-like growth factor binding protein (IGFBP)-3 proteolysis in children with insulin-dependent diabetes mellitus: a possible role for insulin in the regulation of IGFBP-3 protease activity. J Clin Endocrinol Metab 80: 2282–2288.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Cianfarani, S., Germani, D., Rossi, P. et al. Intrauterine Growth Retardation: Evidence for the Activation of the Insulin-Like Growth Factor (IGF)-Related Growth-Promoting Machinery and the Presence of a Cation-Independent IGF Binding Protein-3 Proteolytic Activity by Two Months of Life. Pediatr Res 44, 374–380 (1998). https://doi.org/10.1203/00006450-199809000-00018
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/00006450-199809000-00018
This article is cited by
-
The role and regulation of IGFBP-1 phosphorylation in fetal growth restriction
Journal of Cell Communication and Signaling (2015)
-
Catch up growth in low birth weight infants: Striking a healthy balance
Reviews in Endocrine and Metabolic Disorders (2012)
-
Growth and body composition in very young SGA children
Pediatric Nephrology (2010)