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IGFs and Binding Proteins in Short Children with Intrauterine Growth Retardation

Department of Pediatrics (W.S.C., P.L.H.), Research Centre for Developmental Medicine and Biology (M.V., B.B.), and the Health Research Council Biostatistics Unit, Department of Community Health (E.M.R.), University of Auckland, Auckland 92019, New Zealand; and Lilly Deutschand GmBH (W.F.B.), Bad Homburg 61350, Germany

Address all correspondence and requests for reprints to: Dr. Wayne Cutfield, Department of Pediatrics, University of Auckland, Private Bag 92019, Auckland, New Zealand. E-mail: waynec{at}ahsl.co.nz

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The aim of this study was to examine the relationship between the IGF-IGF binding protein (IGFBP) axis and insulin secretion in short intrauterine growth retardation (IUGR) children.

Fifteen IUGR and 12 normal short prepubertal subjects had a 90-min frequently sampled iv glucose tolerance test performed to measure plasma glucose, insulin, IGF-I, IGF-II, IGFBP-3, and IGFBP-1. In addition, 29 nonobese prepubertal subjects of normal height had fasting plasma IGF-I and IGFBP-3 levels measured.

In comparison to short normal subjects, IUGR subjects had higher plasma values for IGF-I (42 ± 10 vs. 77 ± 31 µg/liter; P < 0.0001), IGF-II (291 ± 76 vs. 370 ± 66 µg/liter; P < 0.008), IGFBP-3 (1.66 ± 0.28 vs. 2.07 ± 0.48 mg/liter; P < 0.0005), fasting insulin (2 ± 1 vs. 4 ± 2 mU/liter; P < 0.004), and acute insulin response (AIR; 215 ± 36 vs. 504 ± 90 mU/liter; P = 0.008). Nonobese subjects of normal height had higher plasma IGF-I (117 ± 9 µg/liter; P < 0.0001) and IGFBP-3 (2.34 ± 0.12 mg/liter) values than the IUGR group (P < 0.0005). During the frequently sampled iv glucose tolerance test, the magnitude of the AIR in short normal subjects was related to the fall in IGFBP-1 levels (P = 0.03); however, no relationship was seen between AIR and fall in IGFBP-1 in IUGR subjects (P = 0.24).

In conclusion, short IUGR children have higher plasma IGF-I, IGF-II, and IGFBP-3, when compared with normal children matched for height, weight, and pubertal status. We speculate that hyperinsulinism secondary to insulin resistance may have led to these changes to the IGF-IGFBP axis in the IUGR group.

	Introduction

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INTRAUTERINE GROWTH RETARDATION (IUGR) is a common condition in which fetal events have constrained birth size. The childhood endocrine sequela of IUGR that has received greatest attention is short stature with associated regulation of growth (1, 2, 3, 4, 5, 6). Changes to the GH-IGF-IGF binding protein (IGFBP) axis of the growth-retarded fetus and newborn have been explored in some detail (7, 8, 9, 10, 11). IUGR models in rats have shown that during fetal life and at birth, serum insulin and IGF-I levels are considerably reduced and serum IGFBP-1 levels are markedly elevated (7, 8, 9). These observations have been consistently interpreted as indicating that circulating IGFBP-1 may have a role in reducing free IGF-I, limiting fetal growth when fetal nutrition is compromised. IGF-I levels in the IUGR human fetus and newborn are not entirely consistent with these animal studies in that both decreased and elevated IGF-I levels with elevated IGFBP-1 levels have been described (10, 11). Changes in IGF-II and IGFBP-2 are more variable across IUGR studies, with levels of both usually unchanged (7, 8), however small reductions in late gestation have been described (11). Following birth, there is a change from in utero nutritional deprivation to postnatal adequate nutrition for IUGR children. Recently, the effects of IUGR to the IGF-IGFBP axis in short children have begun to be explored. Low spontaneous GH secretion, IGF-I, and IGFBP-3 levels have been described when compared with healthy children of normal size (5, 12, 13, 14).

Over the past 10 yr, Barker and colleagues (15, 16, 17, 18) have broadened the focus of IUGR and poor childhood growth and demonstrated that small birth size is associated with metabolic and cardiovascular diseases in later adult life. The metabolic diseases identified include type 2 diabetes mellitus, hyperlipidemia, and Syndrome X (16, 17). We have previously demonstrated early evidence of these metabolic aberrations in short children born with IUGR (19). These prepubertal children were shown to have reduced insulin sensitivity, a major risk factor for the later development of type 2 diabetes mellitus (20). In addition, impaired insulin-mediated disposal of potassium and magnesium was demonstrated, indicating a more general defect in insulin action (19).

The ramifications of reduced insulin sensitivity in short IUGR children have yet to be fully explored, in particular the impact on the IGF-IGFBP axis has not yet been examined. The purpose of this study was to evaluate insulin secretion and examine its effect on the IGF-IGFBP axis in short IUGR prepubertal children when compared with appropriately matched short normal children.

	Subjects and Methods

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Three groups of children were studied: short IUGR, short normal, and normal statured. The subjects in the short IUGR and the short normal groups were recruited from the Endocrinology Clinics at Starship Children’s Hospital and were being evaluated for short stature. Enrollment criteria for inclusion into the study included: height less than the fifth percentile (21), prepubertal sexual development, normal GH response to clonidine stimulation (defined as a GH level 7 µg/liter), absence of both islet cell antibodies (<10 Juvenile Diabetes Foundation units) and insulin autoantibodies to exclude type 1 prediabetes. IUGR was defined as a birth weight for gestational age less than the 10th percentile for gestational age (22). Subjects were excluded if a chromosomal, intrauterine infection or syndromal cause for IUGR was identified, if a first degree relative had type 2 diabetes mellitus, or if medical therapy was taken that was known to influence insulin sensitivity. Birth weight and height were converted into SD scores to correct for age and sex. The weight for length index (WLI) was used to provide an age- and height-adjusted evaluation of relative obesity (23, 24). Ideal body weight was defined as WLI of 100%, with obesity above 120% and extreme thinness below 80%.

In addition, a normal statured group of prepubertal children of normal height (more than fifth percentile) and weight (more than fifth percentile) were included to compare IGF-I and IGFBP-3 levels to the two short stature study groups. These were normal children recruited from a school study that had attempted to identify children with pre-type 1 diabetes mellitus antibodies. All children in the reference group were negative for islet cell antibodies, insulin autoantibodies, glutamic acid decarboxylase antibodies, and IA2 antibodies. A fasting plasma sample was available from all of the normal statured children.

Study protocol

This study was conducted during a study to evaluate insulin sensitivity in IUGR children (19). Insulin sensitivity was measured by Bergman’s minimal model with data provided from a frequently sampled iv glucose tolerance test that had been modified for use in children and previously detailed (25). Briefly, the iv glucose tolerance test consisted of rapid iv infusions of 25% dextrose (0.3 g/kg) at time zero and tolbutamide at 20 min. Three baseline and 24 postdextrose blood samples were drawn, with the last sample drawn at 90 min. Blood was collected into chilled tubes containing sodium heparin. After completion of the study, the blood samples were centrifuged, and the plasma was separated and frozen for later analysis. Plasma glucose and insulin were measured from all samples, and the values were used for measurement of insulin sensitivity. In addition, further blood was collected for 1) IGFBP-1 at baseline, 19, 40, 60, 80, and 90 min; 2) IGF-I and IGFBP-3 at baseline and 90 min; and 3) IGF-II at baseline and 80 min. Approval for the study was provided by the North Health Ethics Committee, and signed, informed consent was obtained from subjects and their parents.

Assays

Plasma glucose was measured using a Hitachi 911 automated random access analyser (Hitachi Scientific Instruments, Inc., Tokyo, Japan) with an interassay coefficient of variation of 1.2% (26). Insulin was determined by an established double antibody RIA technique with an interassay coefficient of variation of 10.5%. Plasma IGF-I was measured using an established IGFBP-blocked RIA with intra-assay and interassay coefficients of variation of 4.2 and 8.7%, respectively (27, 28). Plasma IGF-II samples were initially treated with acid-ethanol cryoprecipitation to remove IGF-II from binding proteins. Then, IGF-II was measured by RIA using a highly specific polyclonal antibody (29). Residual IGFBPs were blocked by an excess of IGF-I (29). IGFBP-1 was measured using a specific RIA (30). IGFBP-3 was measured by RIA using a specific polyclonal antiserum against authentic IGFBP-3 purified from human Cohn fraction IV, which showed no cross-reactivity with IGFBP-1 or IGFBP-2 up to 1 mg/ml (30). Insulin autoantibodies were measured by a competitive RIA (31), and islet cell antibodies were measured by indirect immunofluorescence (32).

Analysis

The acute insulin response (AIR), which estimates insulin secretory capacity, was measured as the area under the curve from a sum of trapeziums corrected for baseline using the formula:

The second insulin peak in response to iv tolbutamide was calculated as the area under the insulin curve from 20–40 min after dextrose administration, corrected for baseline insulin levels.

Analysis was performed using the statistical package SAS (version 10) for personal computers. Repeated measures analysis was used to investigate the differences in IGF-I, IGF-II, IGFBP-1, and IGFBP-3 between the IUGR and short normal groups over time. Analysis of covariance was used to compare the three groups at baseline. Nonpaired t tests were used to compare analytes between the two study groups. A P value less than 0.05 was defined as significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Twenty-seven subjects fulfilled the enrollment criteria for the two short-statured groups and consisted of 15 IUGR and 12 normal birth weight subjects. The insulin sensitivity indices of these children have been previously described (19). We now report the changes in their IGF-IGFBP axis.

The clinical characteristics were very similar between the groups, as illustrated in Table 1. Such close approximation of characteristics precludes any confounding influence from anthropometric or nutritional status. Importantly, both groups were not only short but also thin, with WLI values at the lower end of the normal range. In excess of 80% of subjects in both groups were Caucasian. Short IUGR subjects were slightly older than the short normal subjects, however no significant differences were noted in any of the clinical parameters assessed between these two groups. There was no difference in age between the normal statured group and either the short IUGR or short normal groups. However, a small difference in age was noted across all three groups when simultaneously compared (P = 0.06). Consequently, age was used as a covariate in all further analyses.

View larger version (19K): [in this window] [in a new window]   Figure 1. Plasma IGFBP-1 levels during a frequently sampled iv glucose tolerance test in short IUGR (open diamond) and short normal (filled square) prepubertal subjects, expressed as mean with SEM. *, P = 0.016.

Further influence of insulin secretory status on the IGF-IGFBP axis can be found when fasting insulin is correlated with IGF-I levels in the short IUGR group (r² = +0.60; P < 0.0001). The range of fasting insulin levels in the short normal group (1–3 mU/liter) was too narrow to correlate with IGF-I values. Interestingly, when the short IUGR and short normal subjects were combined, the regression equation that compared fasting insulin to IGF-I was almost identical to the short IUGR group alone. Conversely, no relationship was observed between fasting insulin and IGFBP-3 values. There was no difference in peak glucose levels achieved during the iv glucose tolerance test between short IUGR and short normal subjects.

Clonidine-stimulated GH levels were no different between the short IUGR and short normal groups as shown in Table 2. Furthermore, there was no relationship between stimulated GH and IGF-I levels for either group or all subjects combined.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We have shown that short IUGR children have higher serum IGF-I, IGF-II, and IGFBP-3 values than short normal children, but lower than normal statured children. Our observations challenge the views that intrauterine growth retardation is associated with low serum IGF-I levels due to either GH resistance or insufficiency and highlight the importance of an appropriately matched control group (12, 13, 14). Other published studies have found either lower or similar IGF-I and IGF-II levels and comparable IGFBP-3 levels in IUGR children when compared with normal children (12, 13, 14). Short IUGR children tend to be thin, whereas normal statured children are not usually thin. Although small, our two short stature study groups were very similar, particularly in regard to height and weight. Other studies have not matched for height and weight when comparing IUGR and normal children (12, 13, 14). Short IUGR children have been compared with short normal children, with considerable differences in body weights of the groups (14). Short IUGR children have also been compared with normal children of normal height and weight (12, 13). Age and height have both been shown to positively influence IGFBP-3 and IGF-I levels in normal healthy and IUGR children (13, 33). In addition, nutritional status (as measured by body mass index) has been shown to positively influence IGFBP-3 levels in normal children (33). Stimulated insulin levels have been shown to be correlated with IGF-I in undernourished children (34). Nutritional status appears to influence IGF-II levels, with the highest values seen in overweight children and the lowest in malnourished children (34). The effect of anthropometric and nutritional statuses on IGFBP-1, IGF-I, and IGF-II highlight the need for matching of these parameters between study groups to allow valid comparison.

We have shown that short IUGR children have elevated fasting insulin levels and are also insulin resistant (19). We hypothesize that in short IUGR children insulin resistance leads to compensatory hyperinsulinemia that in turn increases circulating IGF-I and possibly IGFBP-3 levels. The positive association between fasting insulin and fasting IGF-I levels in the subjects that we studied supports this hypothesis. Insulin has important regulatory effects on the GH/IGF-I axis. This has been best illustrated in malnutrition or poorly controlled type 1 diabetes mellitus, in which low insulin and IGF-I levels are seen despite elevated GH levels (35, 36, 37, 38). Improved insulin therapy of diabetes mellitus leads to a rise in IGF-I and suppression of elevated GH levels (38, 39). Insulin is thought to regulate circulating IGF-I levels by facilitating GH binding to the GH receptor in the liver (40). Furthermore, insulin stimulates IGF-I mRNA production in cultured hepatocytes, presumably by exerting its effect at the transcriptional level as described for other genes regulated by insulin (41, 42). Insulin may increase circulating IGFBP-3 levels by reducing IGFBP-3 degradation. IGFBP-3 is degraded by serine proteases, with increased protease activity and reduced IGFBP-3 levels seen in newly diagnosed, or poorly controlled, type 1 diabetic children (43, 44). Insulin therapy of these children was associated with a reduction in protease activity and an increase in IGFBP-3 levels (43). These observations suggest that insulin plays a role in reducing IGFBP-3 protease activity, which leads to an increase in circulating IGFBP-3 levels.

A fall in IGFBP-1 levels during the iv glucose tolerance test was seen in both study groups. This observation is consistent with the well established effect of insulin, and to a lesser extent glucose, on suppression of IGFBP-1 levels (44). The qualitative difference in AIR between the IUGR and normal subject groups is similar to that seen between prepubertal and pubertal children (25). Although IGFBP-1 levels appear lower in the IUGR study group, significance was only achieved at a single time point during the iv glucose tolerance test. Conversely, markedly lower IGFBP-1 levels have been shown throughout an oral glucose tolerance test in pubertal children when compared with prepubertal children (45). Our observations raise the possibility that there was partial insulin resistance to IGFBP-1 regulation in IUGR subjects. Partial insulin resistance would account for the insulin-induced fall in IGFBP-1 levels, which was inadequate given the greater AIR. The magnitude of the AIR did not affect the change in IGFBP-1 in IUGR subjects, which adds further support to our proposal of partial insulin resistance to IGFBP-1 regulation in IUGR subjects. In normal subjects, the magnitude of the AIR was found to influence the fall in IGFBP-1 levels. Insulin resistance is usually used to refer to impaired insulin action in the regulation of glucose alone; however, insulin has important regulatory effects on a wide range of circulating metabolites that includes amino acids, FFA, cations such as potassium and magnesium, IGF-I, and IGFBPs. We have already demonstrated insulin resistance to glucose, potassium, and magnesium in IUGR children. Therefore, it is not surprising to also find partial insulin resistance to IGFBP-1 suppression, particularly given the role of IGFBP-1 in glucose regulation (44).

Clonidine-stimulated peak GH levels were the same in the IUGR and control study groups. Boguszewski et al. (5) have also demonstrated that peak GH levels, after arginine and insulin stimulation, were no different when short IUGR children were compared with short normal children. The increased IGF-I values observed in our short, thin IUGR group cannot be explained by increased GH secretion, which indirectly adds further weight to our proposal that hyperinsulinism and not hypersommatotropism is the cause of the observed elevated IGF-I levels in short IUGR children.

In summary, this study has demonstrated increased plasma IGF-I, IGF-II, and IGFBP-3 levels in short, thin prepubertal IUGR children when compared with normal children closely matched for height, weight, and pubertal status. We propose that these changes can be attributed to hyperinsulinism observed in the IUGR group. Despite a marked increase in the AIR, there was a lack of influence on the fall in IGFBP-1 levels, suggesting that there is also insulin resistance to IGFBP-1 regulation in the IUGR group.

	Acknowledgments

 

	Footnotes

 
This work was supported by grants from the Auckland Medical Research Foundation and Pharmacia \|[amp ]\| Upjohn, Inc.

Abbreviations: AIR, Acute insulin response; IGFBP, IGF binding protein; IUGR, intrauterine growth retardation; WLI, weight for length index.

Received May 17, 2000.

Accepted October 10, 2001.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Fitzhardinge P, Steven E 1972 The small-for-date-infant I; later growth patterns. Pediatrics 46:671–681
2. Sung I, Vohr B, Oh W 1993 Growth and neurodevelopmental outcome of very low birth weight infants with intrauterine growth retardation: comparison with control subjects matched by birth weight and gestational age. J Pediatr 123:618–624[CrossRef][Medline]
3. Westwood M, Kramer M, Munz D, Lovett J, Watters G 1983 Growth and development of full-term, nonasphyxiated small-for-gestational-age newborns; followup through adolescence. Pediatrics 71:376–382[Abstract/Free Full Text]
4. Albertsson-Wikland K, Karlberg J 1994 Natural growth in children born small for gestational age with and without catch-up growth. Acta Paediatr Suppl 399:64–70[Medline]
5. Boguszewski M, Rosberg S, Albertsson-Wikland K 1995 Spontaneous 24-hour growth hormone profiles in prepubertal small for gestational age children. J Clin Endocrinol Metab 80:2599–2606[Abstract]
6. Ackland EM, Stanhope R, Eyre C, Hamill G, Jones J, Preece MA 1988 Physiological growth hormone secretion in children with short stature and intra-uterine growth retardation. Horm Res 30:241–245[Medline]
7. Straus DS, Ooi GT, Orlowski CC, Rechler MM 1991 Expression of the genes for insulin-like growth factor-I (IGF-I), IGF-II, and IGF-binding proteins-1 and –2 in fetal rat under conditions of intrauterine growth retardation caused by maternal fasting. Endocrinology 128:518–525[Abstract/Free Full Text]
8. Unterman TG, Simmons RA, Glick RF, Ogata RS 1993 Circulating levels of insulin, insulin-like growth factor-I (IGF-I), IGF-II and IGF-binding proteins in the small for gestational age fetal rat. Endocrinology 132:327–336[Abstract/Free Full Text]
9. Tapanainen PJ, Bang P, Wilson, Unterman TG, Vreman HJ, Rosenfeld RG, Maternal hypoxia as a model for intrauterine growth retardation: effects on insulin-like growth factors and their binding proteins. Pediatr Res 36:152–158
10. Wang HS, Lim J, English J, Irvine L, Chard T 1991 The concentration of insulin-like growth factor-1 and insulin-like growth factor-binding protein-1 in human umbilical cord serum at delivery: relation to fetal weight. J Endocrinol 129:459–464[Abstract/Free Full Text]
11. Leger J, Oury JF, Noel M, Baron S, Benali P, Blot P, Czernichow P 1996 Growth factors and intrauterine growth retardation. I. Serum growth hormone, insulin-like growth factor (IGF)-I, IGF-II, and IGF binding protein 3 in normally grown and growth-retarded human fetuses during the second half of gestation. Pediatr Res 40:94–100[Medline]
12. De Waal WJ, Hokken-Koelega AC, Stijnen T, de Muinck Keizer-Schrama SM, Drop SL 1994 Endogenous and stimulated GH secretion, urinary GH excretion, and plasma IGF-I and IGF-II levels in prepubertal children with short stature after intrauterine growth retardation. The Dutch Working Group on Growth Hormone. Clin Endocrinol (Oxf) 41:621–630[Medline]
13. Leger J, Noel M, Limal JM, Czernichow P, on behalf of the Study Group of IUGR 1996 Growth factors and intrauterine growth retardation. II. Serum growth hormone, insulin-like growth factor (IGF-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[Medline]
14. Boguszewski M, Jansson C, Rosberg S, Albertsson-Wikland K 1996 Changes in serum IGF-I and IGFBP-3 levels during growth hormone treatment in prepubertal short children born small for gestational age. J Clin Endocrinol Metab 81:3902–3908[Abstract/Free Full Text]
15. Barker D 1994 Mothers, babies and diseases in later life. London: BMJ Publishing
16. Robinson S, Walton R, Clark P, Barker D, Hales C, Osmond C 1992 The relation of foetal growth to plasma glucose in young men. Diabetologia 35:444–446[CrossRef][Medline]
17. Barker DJ, Hales CN, Fall CH, Osmond C, Phipps K, Clark PM 1993 Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidemia (Syndrome X): relation to reduced foetal growth. Diabetologia 36:62–67[CrossRef][Medline]
18. Law CM, Barker DJ, Bull AR, Osmond C 1991 Maternal and foetal influences on blood pressure. Arch Dis Child 66:1291–1295[Abstract/Free Full Text]
19. Hofman PL, Cutfield WS, Robinson EM, Bergman RN, Menon RK, Sperling MA, Gluckman PD 1997 Insulin resistance in short children with intrauterine growth retardation. J Clin Endocrinol Metab 82:402–406[Abstract/Free Full Text]
20. Martin BC, Warram JH, Krolewski AS, Bergman RN, Soeldner JS, Kahn CR 1992 Role of glucose and insulin resistance in development of type 2 diabetes mellitus; results of a 25-year follow-up study. Lancet 340:925–929[CrossRef][Medline]
21. Tanner JM, Whitehouse RH, Takaishi M 1966 Standards from birth to maturity for height, weight, height velocity and weight velocity: British children. Arch Dis Child 41:454–471, 613–635
22. Guaran R, Wein R, Sheedy M, Walstab J, Beischer N 1995 Update of growth percentiles for infants born in Australian population. Aust NZ J Obstet Gynaecol 34:39–50[CrossRef]
23. McLauren D, Read W 1975 Weight/length classification of nutritional status. Lancet 2:219–221[CrossRef][Medline]
24. Durant R, Linder C 1981 An evaluation of five indexes of relative body weight for use with children. Br J Nutr 78:24–41
25. Cutfield W, Bergman RN, Menon RK, Sperling MA 1990 The modified minimal model: application to measurement of insulin sensitivity in children. J Clin Endocrinol Metab 70:1644–1650[Abstract/Free Full Text]
26. Trinder P 1995 Determination of blood glucose using an oxidase-peroxidase system with a non-carcinogenic chromogen. J Clin Pathol 22:158–161[Abstract/Free Full Text]
27. Blum WF, Breier BH 1994 Radioimmunoassay for IGFs and IGFBPs. Growth Regul 4:11–19
28. Breier BH, Milsom SR, Blum WF, Schwander J, Gallaher BW, Gluckman PD 1993 Insulin-like growth factors and their binding proteins in plasma and milk after growth hormone stimulated galactopoiesis in normally lactating women. Acta Endocrinol (Copenh) 129:427–435[Abstract/Free Full Text]
29. Blum WF, Ranke MB, Bierich JR 1988 A specific radioimmunoassay for insulin-like growth factor II. The interference of IGF binding proteins can be blocked by excess IGF-I. Acta Endocrinol (Copenh) 118:374–380[Abstract/Free Full Text]
30. Blum WF, Albertsson-Wikland K, Rosberg S, Ranke MB 1993 Serum levels of IGF-I and IGFBP-3 reflect spontaneous GH secretion. J Clin Endocrinol Metab 76:1610–1616[Abstract]
31. Vardi P, Dib SA, Tuttleman M, Connelly JE, Grinbergs M, Radizabeh A, Riley WJ, Maclaren NK, Eisenbarth GS, Soeldner JS 1987 Prospective evaluation of subjects at high risk for development of type 1 diabetes mellitus. Diabetes 36:1286–1291[Abstract]
32. Pilcher C, Elliott R 1990 A sensitive and reproducible method for the assay of human islet cell antibodies. J Immunol Methods 129:111–117[CrossRef][Medline]
33. Juul A, Dalgard P, Blum WF, Bang P, Hall K, Michaelsen KF, Muller J, Skakkebaek NE 1995 Serum levels of insulin-like growth factor binding protein-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 80:2534–2542[Abstract]
34. Soliman AT, Hassen AE, Aref MK, Hintz RL, Rosenfeld RG, Rogol AD 1986 Serum insulin-like growth factors I and II concentrations and growth hormone and insulin responses to arginine infusion in children with protein-energy malnutrition before and after nutritional rehabilitation. Pediatr Res 20:1122–1130[Medline]
35. Hansen AP 1972 Serum growth hormone patterns in juvenille diabetes. Dan Med Bull 19(Suppl 1):1–32
36. Horner JM, Kemp SF, Hintz RL 1981 Growth hormone and somatomedin in insulin dependent diabetes mellitus. J Clin Endocrinol Metab 53:1148–1153[Abstract/Free Full Text]
37. Amiel SA, Sherwin RS, Hintz RL, Gertner JM, Press M, Tambourlane WV 1984 Effect of diabetes and its control on insulin-like growth factors in the young subject with type 1 diabetes. Diabetes 33:1175–1179[Abstract]
38. Tamborlane WV, Hintz RL, Bergman M, Genel M, Felig P, Sherwin RS 1981 Insulin infusion pump treatment of diabetics. Influence of improved metabolic control on plasma somatomedin levels. N Eng J Med 305:303–307[Abstract]
39. Zapf J, Kiefer M, Merryweather J, Masiarz F, Bauer D, Born W, Fisher JA, Froesch ER 1990 Isolation from adult serum of four insulin like growth factor (IGF) binding proteins and molecular cloning of one of them that is increased by IGF-I administration and tumour hypoglycaemia. J Biol Chem 265:14892–14898[Abstract/Free Full Text]
40. Boni-Schnetzler M, Schmid C, Meier PJ, Froesch ER 1991 Insulin regulates insulin like growth factor-1 mRNA in rat hepatocytes. Am J Physiol 260:E846–E851
41. O’Brien RM, Granner DK 1991 Regulation of gene expression by insulin. Biochem J 278:609–619
42. 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[Abstract]
43. Baxter RC, Martin JL 1986 Radioimmunoassay of growth hormone-dependent insulin like growth factor binding protein in human plasma. J Clin Invest 78:1504–1512
44. Yeoh SI, Baxter RC 1988 Metabolic regulation of the growth hormone independent insulin-like growth factor binding protein in human plasma. Acta Endocrinol (Copenh) 119:465–473[Abstract/Free Full Text]
45. Cotterill AM, Cowell CT, Baxter RC, McNeil D, Silink M 1988 Regulation of the growth hormone independent growth factor-binding protein in children. J Clin Endocrinol Metab 67:882–887[Abstract/Free Full Text]

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				D. Meyre, P. Boutin, A. Tounian, M. Deweirder, M. Aout, B. Jouret, B. Heude, J. Weill, M. Tauber, P. Tounian, et al. Is Glutamate Decarboxylase 2 (GAD2) a Genetic Link between Low Birth Weight and Subsequent Development of Obesity in Children? J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2384 - 2390. [Abstract] [Full Text] [PDF]

				S. Tenhola, P. Halonen, J. Jaaskelainen, and R. Voutilainen Serum markers of GH and insulin action in 12-year-old children born small for gestational age Eur. J. Endocrinol., March 1, 2005; 152(3): 335 - 340. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, A. D. Rogol, J. C. Lovejoy, M. Sheffield-Moore, N. Mauras, and C. Y. Bowers Endocrine Control of Body Composition in Infancy, Childhood, and Puberty Endocr. Rev., February 1, 2005; 26(1): 114 - 146. [Abstract] [Full Text] [PDF]

				P. A. Lee, J. W. Kendig, and J. R. Kerrigan Persistent Short Stature, Other Potential Outcomes, and the Effect of Growth Hormone Treatment in Children Who Are Born Small for Gestational Age Pediatrics, July 1, 2003; 112(1): 150 - 162. [Full Text] [PDF]

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