Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
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Evaluation of Serum Insulin-Like Growth Factor(IGF)-I, Insulin-Like Growth Factor Binding Protein(IGFBP)-2 and IGFBP-3 Levels in Healthy Korean Children

정상 어린이에서 혈청 인슐린양 성장인자-I과 인슐린양 성장인자 결합단백-2 및 -3의 농도 분석

  • Yang, Gi Hoon (Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine) ;
  • Jung, Hye Lim (Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine) ;
  • Kim, Deok Soo (Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine) ;
  • Shim, Jae Won (Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine) ;
  • Shim, Jung Yeon (Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine) ;
  • Park, Moon Soo (Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine)
  • 양기훈 (성균관대학교 의과대학 강북삼성병원 소아과) ;
  • 정혜림 (성균관대학교 의과대학 강북삼성병원 소아과) ;
  • 김덕수 (성균관대학교 의과대학 강북삼성병원 소아과) ;
  • 심재원 (성균관대학교 의과대학 강북삼성병원 소아과) ;
  • 심정연 (성균관대학교 의과대학 강북삼성병원 소아과) ;
  • 박문수 (성균관대학교 의과대학 강북삼성병원 소아과)
  • Received : 2004.09.14
  • Accepted : 2004.10.09
  • Published : 2005.03.15
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Abstract

Purpose : We performed this study to evaluate the mean serum levels of insulin-like growth factor (IGF)-I, insulin-like growth factor binding protein(IGFBP)-2 and IGFBP-3 in healthy Korean children according to age and sex. Methods : Ninety two healthy children, consisting of 42 boys and 50 girls, were classified into five groups according to age : neonate; infancy; early childhood; late childhood; and adolescence. We measured serum levels of IGF-I, IGFBP-2 and IGFBP-3 by enzyme-linked immunosorbent assay(ELISA) and analysed the serum levels according to sex and age group. Results : For boys, the mean serum levels of IGF-I(ng/mL) in neonate, infancy, early childhood, late childhood and adolescence were $41.1{\pm}3.6$, $70.9{\pm}33.7$, $103.5{\pm}97.2$, $89.8{\pm}46.5$ and $51.4{\pm}27.8$, respectively. Those of IGFBP-2(ng/mL) were $8.2{\pm}3.4$, $5.8{\pm}0.4$, $9.3{\pm}4.0$, $9.5{\pm}1.1$ and $7.0{\pm}0.5$, respectively. Those of IGFBP-3(ng/mL) were $559.2{\pm}215.2$, $1,333.3{\pm}692.5$, $2,254.6{\pm}1,513.8$, $2,447.1{\pm}1,464.2$, $1,533.6{\pm}807.4$, respectively. For girls, the mean serum levels of IGF-I(ng/mL) according to five age groups were $53.3{\pm}9.5$, $99.3{\pm}45.8$, $69.6{\pm}51.1$, $106.2{\pm}67.0$ and $145.1{\pm}127.8$, respectively. Those of IGFBP-2 (ng/mL) were $9.1{\pm}7.4$, $5.3{\pm}0.9$, $6.9{\pm}2.0$, $10.5{\pm}3.0$ and $7.9{\pm}1.3$, respectively. Those of IGFBP-3(ng/mL) were $858.2{\pm}433.4$, $1,834.8{\pm}851.3$, $1,404.3{\pm}570.2$, $2,203.5{\pm}899.4$ and $2,029.3{\pm}1,316.7$, respectively. There were significant positive correlations observed between IGF-I and IGFBP-3 levels(r=0.589, P=0.000). Conclusion : IGF-I and IGFBP-3 levels increased as children get older. The peak level of IGFBP-3 was observed in late childhood for both boys and girls, suggesting a current trend of children reaching peak growth velocity before adolescence. The IGFBP-2 level was higher in neonates compare to infancy, suggesting that IGFBP-2 is an important substance for fetal growth.

목 적 : 혈청 IGF-I, IGFBP-2, IGFBP-3 농도 및 IGF-I/IGFBP-3 molar ratio는 소아의 성장 발달, 당뇨병, 비만 및 악성종양의 진단, 예후 예측과 치료후 추적에 유용한 지표이지만 성별, 연령별, 인종별 변이가 있다. 저자들은 우리나라 어린이의 성별 및 연령군별 혈청 IGF-I, IGFBP-2, IGFBP-3 농도 및 IGF-I/IGFBP-3 molar ratio의 정상 표준치 확립을 위하여 본 연구를 시행하였다. 방 법 : 총 92명(남자 42명, 여자 50명)의 건강한 어린이를 대상으로 하였고, 신생아군 9명(남자 3명, 여자 6명), 영아군 19명(남자 9명, 여자 10명), 유아군 24명(남자 13명, 여자 11명), 학령군 30명(남자 12명, 여자 18명), 청소년군 10명(남자 5명, 여자 5명)으로 분류 후, ELISA 방법을 이용하여 혈청 IGF-I, IGFBP-2 및 IGFBP-3 농도를 측정하였고, 각 군간의 IGF-I, IGFBP-2, IGFBP-3 및 IGF-I/IGFBP-3 molar ratio를 비교분석하였다. 결 과 : 1) 남자에서는 IGF-I과 IGFBP-3는 출생과 더불어 증가하여 각각 유아군(P<0.05), 학령군(P<0.05)에 최고값에 도달한 후 청소년군으로 갈수록 감소하였다. IGFBP-2와 IGF-I/IGFBP-3 molar ratio는 각각 학령군과 영아군에 최고값을 보이고 감소하였으나 출생시에 비해 통계적으로 유의한 증가를 보이지 않았다. 각 군간의 비교에서 IGFBP-2만이 유의한 차이를 보였다(P<0.05). 2) 여자에서는 IGF-I과 IGFBP-2, IGFBP-3는 출생과 더불어 증가하여 각각 청소년군, 학령군(P<0.05), 학령군(P<0.05)에 최고값에 도달하였으나 IGF-I은 출생시에 비해 통계적으로 유의한 증가를 보이지 않았다. IGF-I/IGFBP-3 molar ratio는 출생시에 최고값을 보였으나 통계적으로 유의한 차이를 보이지 않았다. 각 군간의 비교에서 IGFBP-2 및 IGFBP-3가 유의한 차이를 보였다(P<0.05). 3) 동일연령군별 남녀 비교에서 IGF-I과 IGFBP-2, IGFBP-3 및 IGF-I/IGFBP-3 molar ratio 어느 것도 남녀 간에 통계적으로 유의한 차이를 보이지 않았다. 4) 상관관계 조사시 IGF-I의 농도가 높을수록 IGFBP-3의 농도 역시 의미있게 증가하였고(r=0.504, P=0.000), IGF-I/IGFBP-3 molar ratio와 비만도와의 상관 관계를 조사해 본 결과 통계적으로 의미있는 음의 상관 관계를 보이지 않았다(r=0.051, P=0.629). 또한 비만도와 IGF-I, IGFBP-2 및 IGFBP-3 사이에 통계적으로 유의한 상관 관계는 없었다. 결 론 : IGF-I과 IGFBP-3는 사춘기 진행에 따라 증가하며, 본 연구에서 IGFBP-3가 학령군에서 최고 수준을 보이는 것은 사춘기가 일찍 오는 요즘 어린이들의 성장 추세를 반영하는 것으로 추정되어진다. IGFBP-2는 신생아군에서 가장 높고 영아군에서 감소하는 데 이것은 IGFBP-2가 출생 전 발달 과정에 중요한 물질임을 뒷받침해주는 소견이다. 향후 더 많은 정상아를 대상으로한 연구를 통하여 보다 정확한 우리나라 어린이의 성별 연령군별 정상 표준치 확립이 필요하겠다.

Keywords

References

  1. Bennett A, Wilson DM, Liu F, Nagashima R, Rosenfeld RG, Hintz RL. Levels of insulin-like growth factors I and II in human cord blood. J Clin Endocrinol Metab 1983;57:609-12 https://doi.org/10.1210/jcem-57-3-609
  2. Cohick WS, Clemmons DR. The insulin-like growth factors. Annu Rev Physiol 1993;55:131-53 https://doi.org/10.1146/annurev.ph.55.030193.001023
  3. Furlanetto RW, Cara JF. Somatomedin-C/insulin-like growth factor-I as a modulator of growth during childhood and adolescence. Horm Res 1986;24:177-84 https://doi.org/10.1159/000180557
  4. Lassarre C, Hardouin S, Daffos F, Forestier F, Frankenne F, Binoux M. 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 1991;29:219-25 https://doi.org/10.1203/00006450-199103000-00001
  5. Koc E, Bideci A, Cinaz P, Unlu M, Atalay Y, Turkyilmaz C. Insulin-like growth factor(IGF)-I and IGF-binding protein-3 in relation to hemoglobin concentration in healthy term infants. J Pediatr Endocrinol Metab 1997;10:609-13
  6. Laron Z, Avitzur Y, Klinger B. Carbohydrate metabolism in primary growth hormone resistance(Laron syndrome) before and during insulin-like growth factor-I treatment. Metabolism 1995;44(10 Suppl 4):113S-8S https://doi.org/10.1016/0026-0495(95)90231-7
  7. Martin JL, Willetts KE, Baxter RC. Purification and properties of a novel insulin-like growth factor-II binding protein from transformed human fibroblasts. J Biol Chem 1990;265:4124-30
  8. Hwa V, Oh Y, Rosenfeld RG. The insulin-like growth factor- binding protein(IGFBP) superfamily. Endocr Rev 1999;20:761-87 https://doi.org/10.1210/er.20.6.761
  9. Kim HS, Nagalla SR, Oh Y, Wilson E, Roberts CT Jr, Rosenfeld RG. Identification of a family of low-affinity insulin-like growth factor binding proteins(IGFBPs) : characterization of connective tissue growth factor as a member of the IGFBP superfamily. Proc Natl Acad Sci USA 1997;94:12981-6
  10. Wood TL, Streck RD, Pintar JE. Expression of the IGFBP-2 gene in post-implantation rat embryos. Development 1992;114:59-66
  11. Kim HS, Rosenfeld RG, Oh YM. Biological roles of insulin-like growth factor binding proteins(IGFBPs). Exp Mol Med 1997;29:85-96 https://doi.org/10.1038/emm.1997.13
  12. Thissen JP, Ketelslegers JM, Underwood LE. Nutritional regulation of the insulin-like growth factors. Endocr Rev 1994;15:80-101
  13. Ali O, Cohen P, Lee KW. Epidemiology and biology of insulin-like growth factor binding protein-3(IGFBP-3) as an anti-cancer molecule. Horm Metab Res 2003;35:726-33 https://doi.org/10.1055/s-2004-814146
  14. Oh J, Ramondetta LM, Fritsche HA, Bast RC, Mills GB, Wolf JK. Serum IGF-1, IGFBP-2, and IGFBP-3 in advanced ovarian cancer. Proceedings of the American Association for Cancer Research; 2002 Apr 6-10; San Francisco. Philadelphia : American Association for Cancer Research, 2002
  15. Daughaday WH, Rotwein P. Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr Rev 1989;10:68-91 https://doi.org/10.1210/edrv-10-1-68
  16. Kim SH, Ku SY, Jee BC, Suh CS, Choi YM, Kim JG, et al. Clinical efficacy of serum insulin-like growth factor-I (IGF-I), IGF-II, and IGF binding protein-3(IGFBP-3) in predicting the prognosis of in vitro fertilization and embryo transfer. Korean J Obstet Gynecol 2003;46:802-9
  17. Clayton KL, Holly JM, Carlsson LM, Jones J, Cheetham TD, Taylor AM, et al. Loss of the normal relationships between growth hormone, growth hormone-binding protein and insulin-like growth factor-I in adolescents with insulin-dependent diabetes mellitus. Clin Endocrinol 1994;41:517-24 https://doi.org/10.1111/j.1365-2265.1994.tb02584.x
  18. Tapanainen P, Kaar ML, Leppaluoto J, Huttunen NP, Knip M. Normal stimulated growth hormone secretion but low peripheral levels of insulin-like growth factor I in prepubertal children with insulin-dependent diabetes mellitus. Acta Paediatr 1995;84:646-50 https://doi.org/10.1111/j.1651-2227.1995.tb13718.x
  19. Shin CH, Yang SW. Changes of insulin-like growth factor-I, insulin-like growth factor binding protein-3 and 24-hour urinary growth hormone in prepubertal children with insulin dependent diabetes mellitus. J Korean Diabet Assoc 1999;23:25-35
  20. Amiel SA, Sherwin RS, Hintz RL, Gertner JM, Press CM, Tamborlane WV. Effect of diabetes and its control on insulin-like growth factors in the young subject with type I diabetes. Diabetes 1984;33:1175-9 https://doi.org/10.2337/diabetes.33.12.1175
  21. Gerich JE. Rationale for inhibition of growth hormone secretion in the management of the diabetic patient. Scand J Gastroenterol Suppl 1986;119:154-7
  22. Press M, Tamborlane WV, Sherwin RS. Importance of raised growth hormone levels in mediating the metabolic derangements of diabetes. N Engl J Med 1984;310:810-5 https://doi.org/10.1056/NEJM198403293101302
  23. Bloch CA, Clemons P, Sperling MA. Puberty decreases insulin sensitivity. J Pediatr 1987;110:481-7 https://doi.org/10.1016/S0022-3476(87)80522-X
  24. Ehrlich RM. Diabetes mellitus in childhood. Pediatr Clin North Am 1974;21:871-84
  25. Kelley KM, Oh Y, Gargosky SE, Gucev Z, Matsumoto T, Hwa V, et al. Insulin-like growth factor-binding proteins (IGFBPs) and their regulatory dynamics. Int J Biochem Cell Biol 1996;28:619-37 https://doi.org/10.1016/1357-2725(96)00005-2
  26. Guler HP, Zapf J, Schmid C, Froesch ER. Insulin-like growth factors I and II in healthy man. Estimations of half-lives and production rates. Acta Endocrinol 1989;121:753-8
  27. Valentinis B, Bhala A, DeAngelis T, Baserga R, Cohen P. The human insulin-like growth factor(IGF) binding protein-3 inhibits the growth of fibroblasts with a targeted disruption of the IGF-I receptor gene. Mol Endocrinol 1995;9:361-7 https://doi.org/10.1210/me.9.3.361
  28. Juul A, Bang P, Hertel NT, Main K, Dalgaard P, Jorgensen K, et al. Serum insulin-like growth factor-I in 1030 healthy children, adolescents, and adults : relation to age, sex, stage of puberty, testicular size, and body mass index. J Clin Endocrinol Metab 1994;78:744-52 https://doi.org/10.1210/jc.78.3.744
  29. Lofqvist C, Andersson E, Gelander L, Rosberg S, Blum WF, Albertsson-Wikland K. Reference values for IGF-I throughout childhood and adolescence : a model that accounts simultaneously for the effect of gender, age, and puberty. J Clin Endocrinol Metab 2001;86:5870-6 https://doi.org/10.1210/jc.86.12.5870
  30. Brabant G, von zur Muhlen A, Wuster C, Ranke MB, Kratzsch J, Kiess W, et al. Serum insulin-like growth factor I reference values for an automated chemiluminescence immunoassay system : results from a multicenter study. Horm Res 2003;60:53-60 https://doi.org/10.1159/000071871
  31. Bang P, Westgren M, Schwander J, Blum WF, Rosenfeld RG, Stangenberg M. Ontogeny of insulin-like growth factor-binding protein-1, -2, and -3 : quantitative measurements by radioimmunoassay in human fetal serum. Pediatr Res 1994;36:528-36 https://doi.org/10.1203/00006450-199410000-00020
  32. Barrios V, Buno M, Pozo J, Munoz MT, Argente J. Insulin-like growth factor-binding protein-2 levels in pediatric patients with growth hormone deficiency, eating disorders and acute lymphoblastic leukemia. Horm Res 2000;53:221-7 https://doi.org/10.1159/000023571
  33. Batch JA, Baxter RC, Werther G. Abnormal regulation of insulin-like growth factor binding proteins in adolescents with insulin-dependent diabetes. J Clin Endocrinol Metab 1991;73:964-8 https://doi.org/10.1210/jcem-73-5-964
  34. Juul A, Dalgaard P, Blum WF, Bang P, Hall K, Michaelsen KF, et al. Serum levels of insulin-like growth factor(IGF)-binding protein-3(IGFBP-3) in healthy infants, children, and adolescents : the relation to IGF-I, IGF-II, IGFBP-1, IGFBP-2, age, sex, body mass index, and pubertal maturation. J Clin Endocrinol Metab 1995;80:2534-42 https://doi.org/10.1210/jc.80.8.2534
  35. Blum WF, Albertsson-Wikland K, Rosberg S, Ranke MB. Serum levels of insulin-like growth factor I(IGF-I) and IGF binding protein 3 reflect spontaneous growth hormone secretion. J Clin Endocrinol Metab 1993;76:1610-6 https://doi.org/10.1210/jc.76.6.1610
  36. Gomez JM, Maravall FJ, Gomez N, Navarro MA, Casamitjana R, Soler J. The IGF-I system component concentrations that decrease with aging are lower in obesity in relationship to body mass index and body fat. Growth Horm IGF Res 2004;14:91-6. https://doi.org/10.1016/j.ghir.2003.11.004
  37. Hoybye C, Hilding A, Jacobsson H, Thoren M. Growth hormone treatment improves body composition in adults with Prader-Willi syndrome. Clin Endocrinol 2003;58:653-61 https://doi.org/10.1046/j.1365-2265.2003.01769.x
  38. Gapstur SM, Gann PH, Kopp P, Colangelo LA, Longcope C, Liu K. Serum IGF-I and IGFBP-3 concentrations in young men : cross-sectional and longitudinal associations with age, BMI, waist circumference, physical activity and race. Proceedings of the American Association for Cancer Research; 2002 Apr 6-10; San Francisco. Philadelphia : American Association for Cancer Research, 2002