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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-0852
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 1 117-123
Copyright © 2007 by The Endocrine Society

Effect of Growth Hormone Therapy on Serum Adiponectin and Resistin Levels in Short, Small-for-Gestational-Age Children and Associations with Cardiovascular Risk Parameters

Ruben H. Willemsen, Marije van Dijk, Yolanda B. de Rijke, Albert W. van Toorenenbergen, Paul G. Mulder and Anita C. Hokken-Koelega

Department of Pediatrics (R.H.W., M.v.D., A.C.H.-K.), Division of Endocrinology, Erasmus Medical Centre Sophia, 3015 GJ Rotterdam, The Netherlands; and Department of Internal Medicine (Y.B.d.R.), Diagnostic Laboratory Endocrinology, Department of Clinical Chemistry (Y.B.d.R., A.W.v.T.), University Medical Centre Rotterdam, and Department of Epidemiology and Biostatistics (P.G.M.), Erasmus Medical Centre, 3000 CA Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Ruben Willemsen, M.D., Erasmus Medical Center Sophia, Room SP-3435, Dr. Molenwaterplein 60, 3015 GJ Rotterdam, The Netherlands. E-mail: r.h.willemsen{at}erasmusmc.nl.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Background: Adiponectin and resistin are fat cell-derived hormones, which are thought to be respectively protective and disadvantageous with regard to the development of cardiovascular disease and diabetes mellitus type 2. Low birth weight has been associated with increased risks for the development of these diseases. In short, small-for-gestational-age (SGA) children, GH therapy has several positive effects regarding cardiovascular risk factors. On the other hand, concern has been expressed about the effects of GH therapy on insulin sensitivity.

Methods: We measured adiponectin and resistin levels in 136 short prepubertal children born SGA and their association with cardiovascular risk parameters and growth factors. Also, we compared the levels with normal-statured controls. The effect of GH treatment was evaluated in 50 short SGA children vs. baseline and vs. an untreated sex- and age-matched SGA control group.

Results: Short SGA children had similar adiponectin and lower resistin levels, compared with normal-statured controls. In GH-treated SGA children, neither adiponectin nor resistin levels changed significantly during 2 yr of GH treatment. Compared with untreated sex- and age-matched SGA controls, GH-treated SGA children had similar adiponectin and lower resistin levels. Adiponectin correlated inversely with age but not any cardiovascular risk parameter or growth factor. Higher IGF-I levels in GH-treated children were associated with lower resistin levels.

Conclusions: Compared with normal-statured controls, short prepubertal SGA children had similar adiponectin and lower resistin levels. Two years of GH treatment had no effect on their adiponectin and resistin levels.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE IDENTIFICATION OF so-called adipocytokines has brought challenging opportunities in metabolic research. Adipocytokines are fat cell-derived hormones, which are thought to have an influence on metabolism and might predict susceptibility to cardiovascular disease.

Adiponectin was first described in 1995 as a novel adipocytokine, synthesized exclusively by adipocytes and secreted in relatively large amounts into plasma (1). Adiponectin has been inversely associated with insulin resistance and parameters of obesity in both animal models and human studies (2, 3, 4, 5, 6, 7, 8, 9). Adiponectin knockout mice developed insulin resistance when fed a high-fat/high-sucrose diet (8), whereas in obese children, weight loss resulted in an increase of serum adiponectin levels (2). Although its mechanism of action is largely unknown, adiponectin is regarded as one of the factors related to the metabolic syndrome (9).

Resistin was recently discovered as an adipocytokine that was down-regulated by thiazolidinediones (a class of peroxisome proliferator-activated receptor-{gamma} agonists) (10). Thiazolidinediones are used in the treatment of type 2 diabetes mellitus and are known to enhance insulin sensitivity in vivo. Increased resistin levels were found in genetically and diet-induced animal models of obesity (10). In animals, inverse associations were described between resistin levels and glucose tolerance and positive correlations with obesity (10). In humans, however, the associations with insulin resistance and obesity are less clear and often cannot be reproduced (7, 11, 12, 13, 14). Data on resistin levels in children and adolescents are very scarce (13, 14).

Low birth weight has been associated with increased risk for the development of adult cardiovascular disease and type 2 diabetes mellitus (15). Because GH therapy has effects on insulin sensitivity, concern has been expressed about the long-term effects of GH therapy in short children born small for gestational age (SGA). GH therapy has various positive effects on cardiovascular risk factors, such as a reduction in blood pressure SD score (SDS), the atherogenic index, and a more favorable body composition with particularly more lean body mass (16). On the other hand, lower insulin sensitivity with higher insulin levels has been described during GH therapy (17, 18), which appeared to normalize after discontinuation of GH (19). Contrasting data about adiponectin levels have been reported for SGA infants and children (20, 21, 22, 23). Some found positive correlations with birth weight (20, 22, 24, 25, 26), but others did not (21, 27, 28, 29). Importantly, birth weight was not adjusted for gestational age in all of these studies, whereas adiponectin has been shown to increase impressively with gestational age (30).

To the best of our knowledge resistin levels have not been described in SGA children. Besides, adiponectin and resistin levels have not been described in relation to cardiovascular risk parameters in short SGA children.

The aims of the present study were: 1) to evaluate adiponectin and resistin levels in prepubertal short SGA children before and after 24 months of GH therapy, 2) to compare the levels of the GH-treated short SGA children with a sex- and age-matched untreated short SGA control group, and 3) to describe the relation between adipocytokine levels and parameters of obesity, blood lipids, glucose, insulin, blood pressure, and growth factors.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The study group comprised 136 prepubertal short children born SGA. All children fulfilled the same inclusion criteria: 1) birth length and/or birth weight SDS below –2 for gestational age (31); 2) height SDS below –2 according to Dutch standards (32); 3) height velocity SDS below zero to exclude children with spontaneous catch-up growth (32); 4) prepubertal stage, defined as Tanner breast stage 1 for girls and testicular volume less than 4 ml for boys (33); and 5) an uncomplicated neonatal period without signs of severe asphyxia (defined as Apgar score < 3 after 5 min), sepsis, or long-term complications of respiratory ventilation such as bronchopulmonary dysplasia. Children with endocrine or metabolic disorders, chromosomal defects, syndromes, and growth failure caused by other conditions (e.g. emotional deprivation, severe chronic illness, chondrodysplasia) were excluded, with the exception of Silver-Russell syndrome. In 50 of the 136 children, adiponectin and resistin levels were tested before and after 24 months GH therapy (while still receiving GH therapy). Baseline cardiovascular data and GH effects on height SDS, IGF-I SDS, and IGF binding protein (IGFBP)-3 SDS of 28 of these 50 children have been published before (34, 35). To study the effect of GH, the GH-treated children were also compared with 27 untreated short prepubertal SGA children. These 27 children were selected from the 86 children at baseline, which did not have a repeat measurement, to match in age and sex with the 50 GH-treated children. Biosynthetic GH (r-hGH Norditropin; Novo Nordisk A/S, Bagsværd, Denmark) was given sc once daily at bedtime. Thrice monthly, the GH dose was adjusted to the calculated body surface area (BSA). GH dose was 1 mg/m2 BSA for all children, except for a subgroup of 19 children, who received 2 mg/m2 BSA for the first 6 months of treatment followed by 1 mg/m2 BSA thereafter. Because the 2-yr change in adiponectin and resistin was similar for children receiving 1 or 2 mg/m2 BSA in the first 6 months of GH treatment (data not shown), they were analyzed together. The study was approved by the ethics committees. Written informed consent was obtained from the parents or custodians of each child.

Anthropometry

Standing height was measured using a Harpenden stadiometer and was expressed as SDS for sex and chronological age using Dutch references (32). Body mass index (BMI) was calculated according to the formula weight/(height)2 and was expressed as SDS for sex and age (36). Biceps, triceps, subscapular and suprailiacal skinfold thickness were measured using a Holtain skinfold caliper; the sum of four skinfolds was calculated, and these were expressed as SDS using references for healthy Dutch children (37). Systolic and diastolic blood pressure (BP) was measured twice on the left arm. The mean of two measurements was used for analysis. BP was expressed as SDS adjusted for age and sex (38). Because height is an important determinant of BP in childhood and adolescence, BP was also expressed as SDS adjusted for height and sex (38).

Hormone and biochemical assays

All blood samples were taken after an overnight fast. Serum glucose and total cholesterol levels were measured as described previously (19). Insulin levels were all measured in one laboratory using the same method (immunoradiometric assay; Medgenix, Biosource Europe, Nivelles, Belgium). The intraassay coefficient of variation (CV) was 2–4.7% (19–405 pmol/liter) and the interassay CV was 4.2–11.3% (32–375 pmol/liter). Triglycerides were measured on the Chem-1 analyzer according to the manufacturer’s instructions (Technicon Instruments, Tarrytown, NY) and after 1998 on the Hitachi 917 analyzer according to the manufacturer’s instructions (Roche Diagnostics, Mannheim, Germany). Both methods were comparable (y = x – 0.030).

Dehydroepiandrosterone sulfate (DHEAS) levels were measured in 79 consecutive children recruited between 1991 and 2000 using a chemiluminescence-based competitive immunoassay (Immulite1; Diagnostic Products Corp., Los Angeles, CA). The interassay coefficient was 8%. The limit of detection was 0.2 µmol/liter. Values below this limit of detection were considered to be 0.2 µmol/liter.

IGF-I and IGFBP-3 serum levels were measured as described previously (39). IGF-I and IGFBP-3 levels were adjusted for age and sex as SDS (40, 41).

Adiponectin and resistin levels were measured before and after 2 yr of GH therapy after an overnight fast. All samples were assayed in duplicate and the mean of these two measures used for analysis. Serum adiponectin levels were determined by ELISA (R&D Systems Inc., Minneapolis, MN; intraassay CV < 7%; interassay CV < 7%). Serum resistin levels were determined by ELISA (R&D Systems; intra- and interassay CVs < 6% and < 7%, respectively). Adiponectin and resistin reference values were obtained from 40 healthy normal-statured prepubertal children (23 boys and 17 girls), aged 5.0–10.1 yr, attending the outpatient clinic for a minor surgical procedure. Children suffering from any systemic illness, syndrome, or dysmorphic features were excluded. Normal stature was defined as a height SDS above –2 and below +2 according to Dutch standards (32).

Statistical analysis

All data are presented as mean ± SD, except for serum adiponectin and resistin levels, which are presented as median and interquartile range. The nonnormally distributed levels of adiponectin and resistin were logarithmically transformed. Differences between groups were tested using the independent Student’s t test. Differences in time within the same subjects (i.e. before and after 2 yr of GH therapy) were calculated using a paired Student’s t test. Correlations were analyzed using Spearman’s correlation coefficient in the total group at baseline and in 55 children (50 GH treated and five untreated) with a repeat measurement after 2 yr. Backward multiple regression analyses with logarithmically transformed adiponectin and resistin as the dependent variable were used to assess multivariate relationships. Factors showing a linear correlation with adiponectin or resistin were entered in the model together with age and sex. Level of significance was determined at P < 0.05. Statistics were performed using SPSS for Windows (version 11.0.1; SPSS Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline data

Table 1Go shows the clinical and laboratory parameters of the total study population. Adiponectin did not significantly differ from the normal-statured control group of the same age. Resistin levels were significantly lower in SGA children (P < 0.001), when compared with normal-statured controls. BMI SDS and sum of skinfold SDS were significantly lower than zero SDS. Also, IGF-I SDS and IGFBP-3 SDS were significantly lower than zero SDS. Whereas diastolic BP SDS was in the normal range, systolic BP SDS was significantly higher than zero SDS. Lipid, fasting glucose, and insulin levels were in the normal range. Adiponectin and resistin levels at baseline were not different for girls and boys (data not shown). Table 2Go shows anthropometric and laboratory parameters for the GH-treated SGA children vs. the sex- and age-matched untreated SGA controls. Gestational age, birth weight SDS, birth length SDS, height SDS at baseline, age, and sex were similar for the GH-treated SGA children and the untreated SGA controls.


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  		TABLE 1. Baseline clinical and fasting laboratory parameters in 136 short SGA children

 

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  		TABLE 2. GH effects on anthropometric and laboratory parameters

 
Correlations at baseline

At baseline, serum adiponectin levels in 136 short SGA children did not correlate with BMI SDS or sum of four skinfold SDS. There was no correlation between adiponectin levels and systolic and diastolic BP SDS (either corrected for age and sex or for height and sex). There was a weak but significant negative correlation between age and adiponectin (r = –0.229, P < 0.01). Adiponectin levels did not correlate with height SDS, fasting insulin, glucose, insulin to glucose-ratio, IGF-I SDS, IGFBP-3 SDS, DHEAS, total cholesterol, triglyceride levels, birth weight SDS, birth length SDS, and birth head circumference SDS. Resistin levels in all SGA children at baseline did not correlate with BMI SDS, sum of skinfold SDS, systolic or diastolic BP SDS, age, height SDS, fasting insulin and glucose, IGF-I SDS, IGFBP-3 SDS, DHEAS, total cholesterol, triglyceride levels, birth weight SDS, birth length SDS, and birth head circumference SDS.

Adiponectin and resistin levels during 2 yr of GH therapy

In the 50 GH-treated children, neither adiponectin nor resistin levels changed significantly during 2 yr of GH treatment (Figs. 1Go and 2Go and Table 2Go). Height and BMI SDS increased significantly, compared with baseline, in the GH-treated children, whereas the sum of skinfolds SDS decreased significantly. IGF-I SDS, IGFBP-3 SDS, and fasting insulin increased significantly, compared with baseline. Twenty-seven SGA children were selected from the remaining 86 untreated on the basis of matching sex and age with the treated group. Compared with these untreated sex- and age-matched SGA controls, the GH-treated SGA children had similar levels of adiponectin and lower resistin levels (Fig. 2Go). Compared with the untreated SGA controls, they had a significantly higher height SDS, systolic BP SDS, IGF-I SDS, and IGFBP-3 SDS but lower cholesterol levels and sum of skinfold SDS.


Figure 1
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  		FIG. 1. Adiponectin levels of GH-treated children vs. baseline, untreated SGA, and normal-statured controls.

 

Figure 2
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  		FIG. 2. Resistin levels of GH-treated children vs. baseline, untreated SGA, and normal-statured controls.

 
In the five untreated children with a repeat measurement after 2 yr, adiponectin levels did also not change, but resistin levels tended to increase [8.6 (0.8) ng/ml at baseline to 13.0 (3.5) ng/ml after 2 yr; P = 0.08].

Correlations after 2 yr

In the 55 children with a second measurement after 2 yr (50 GH treated and five untreated), adiponectin correlated weakly with fasting glucose (r = –0.278; P < 0.05) but did not correlate with age, height SDS, IGF-I SDS, and IGFBP-3 SDS. There were also no correlations with BMI SDS, sum of skinfold SDS, systolic and diastolic BP SDS, fasting insulin, insulin to glucose-ratio, total cholesterol, and triglyceride levels.

Resistin levels correlated inversely with IGF-I SDS (r = –0.291; P < 0.05) but not with age and IGFBP-3 SDS. Resistin levels did not correlate with height SDS, BMI SDS, sum of skinfold SDS, BP SDS, fasting glucose, insulin, insulin to glucose ratio, total cholesterol, and triglyceride levels.

Multiple regression analysis

In multiple regression analyses on the data of 55 children, with a repeat measurement after 2 yr (50 GH treated and five untreated), the correlation between serum adiponectin levels and fasting glucose lost significance after adjustment for GH therapy (coded as yes/no), age, and sex.

For serum resistin levels, a model containing IGF-I SDS (beta = –0.123; P < 0.01) explained 14.7% of the variance in resistin levels, after adjustment for GH therapy, age, and sex.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our study reports serum adiponectin and resistin levels in 136 short prepubertal SGA children. The effect of 2 yr of GH treatment was evaluated by testing 50 children before and after 24 months of GH treatment. In addition, we compared the GH-treated children with an untreated sex- and age-matched SGA control group and a normal-statured reference group. At baseline, no strong relations were present between either adiponectin or resistin levels and known cardiovascular parameters, such as BMI and sum of four skinfold SDS, BP, lipids, fasting glucose, and insulin. There was a weak inverse correlation between age and adiponectin levels. Compared with normal-statured controls, SGA children had similar levels of adiponectin but lower resistin levels. Compared with baseline, neither serum adiponectin nor resistin levels changed significantly in 50 SGA children during 2 yr of GH treatment. Compared with untreated sex- and age- matched SGA controls, the GH-treated children had comparable levels of adiponectin and lower resistin levels. In multivariable analyses in the children who were also measured after 2 yr, higher IGF-I levels were associated with lower resistin levels after adjustment for age, sex, and GH treatment.

At baseline, we did not find correlations between serum adiponectin levels and variables, such as BMI SDS, sum of skinfold SDS, blood lipids, fasting glucose, insulin, and BP. Martin et al. (42) investigated relationships among adiponectin, fasting insulin, and lipids and found that the association between adiponectin and fasting insulin could be demonstrated only in obese individuals, whereas the associations between adiponectin and lipid levels were very weak in lean children. Also, Knobler et al. (43) found the association between adiponectin and measures of insulin sensitivity to be not present in nonobese coronary artery disease patients when stratifying the total group by their BMI. Because short SGA children typically have a very lean appearance with a low muscle mass and fat mass (44), it is very plausible that associations between adiponectin and fasting insulin and blood lipids were not present in our study group.

We found adiponectin levels in short SGA children not to be different from those in normal-statured controls. Some authors reported adiponectin levels in SGA children and found lower (20, 22), similar (23), or higher (21) levels when compared with appropriate-for-gestational-age children. However, the studied SGA groups for which lower adiponectin levels were reported all consisted of a mixture of short SGA children and SGA children with catch-up growth (20, 22). Ibanez et al. (23) reported adiponectin levels in a group of exclusively short SGA children and also found normal levels. Lopez-Bermejo et al. (21) found higher levels in lean SGA children and lower levels in overweight SGA children. Our SGA children were all short. More recent data indicate that SGA children with spontaneous catch-up growth, particularly those who become overweight, are probably more at risk than those who remain short (45). We did not find reduced adiponectin levels in our population of exclusively short SGA children, which is in agreement with this hypothesis.

Our study showed that 2 yr of GH treatment in a group of short SGA children did not affect adiponectin levels. A previous study reported a decline in adiponectin levels during GH treatment of 16 short SGA children (23). However, numbers were smaller, the study period lasted 6 months instead of 2 yr, and the study population had a different ethnicity. Because the decline of adiponectin levels in the latter study was accompanied by an increase of DHEAS levels, as opposed to our population (46), we wanted to investigate whether DHEAS levels were associated with adiponectin levels. We could, however, not detect such a correlation. The longer duration of GH treatment in our study might also be important, due to possible time-dependent effects of GH on insulin sensitivity and growth factors, resulting in a different net outcome of adiponectin levels.

Data on the effects of GH and IGF-I on adiponectin levels, as reported in the literature up to date, have been inconclusive. Acromegalic patients have been reported to have increased, similar as well as decreased levels when compared with healthy controls (47, 48, 49, 50). In GH-deficient patients, substitution therapy led to either an increase in adiponectin levels or no change (51, 52, 53, 54, 55). In accordance with the reports in GH-deficient patients, GH therapy in our SGA patients did not affect adiponectin levels.

The first reports on resistin levels in animals suggested that resistin could be a marker of insulin resistance (8, 10). In accordance with other reports in humans (12, 13, 56, 57), we did not find positive correlations between resistin and fasting glucose and insulin levels. Strikingly, short SGA children had reduced resistin levels. One of the explanations might be that short SGA children typically have a very lean appearance and low fat mass (44, 58). GH therapy, which has been reported to attenuate insulin sensitivity (17, 18), did not change resistin levels in the GH-treated group. The untreated SGA control group, which is expected to be less insulin resistant, showed even higher resistin levels. After 2 yr, resistin levels correlated inversely with IGF-I SDS. In multiple regression analysis with resistin levels as the dependent variable, IGF-I SDS had a negative association with resistin, independently of GH therapy, age, and sex. This is in line with a report showing that in vitro IGF-I down-regulates resistin gene expression and protein secretion (59). The IGF-I/IGFBP-3 axis has been repeatedly linked with insulin sensitivity as well as the pathogenesis of atherosclerosis (60, 61). Underlying associations between IGF-I and resistin might have confounded the reported yet inconclusive associations in the literature. On the other hand, we did not find significant changes in resistin levels during 2 yr of GH treatment, suggesting that there are also other factors influencing resistin levels. Recent reports on resistin levels indicate that, instead of being a marker for insulin resistance, it might have proinflammatory properties because it is a member of the cytokine family (62, 63). Our data do not support that resistin is a marker for insulin resistance.

A limitation of our study is the absence of a large untreated control group with a repeat measurement after 2 yr. We had only five untreated children with a repeat measurement after 2 yr. Therefore, we chose to compare the GH-treated children with a sex- and age-matched untreated SGA control group, with the same in- and exclusion criteria as the GH-treated children. We cannot exclude the possibility that this sex- and age-matched group had already higher resistin levels 2 yr before the measurement for this study. However, in our small group of untreated children, a rise in resistin levels was observed, which is in agreement with the higher resistin levels in the sex- and age-matched control group when compared with the GH-treated group.

In conclusion, our study shows that short prepubertal SGA children have normal adiponectin and lower resistin levels, when compared with normal statured controls of the same age. Because of known associations between low birth weight and the development of cardiovascular disease and diabetes mellitus type 2, concern has been expressed about the effects of GH treatment in short SGA children. Our data demonstrate that 2 yr of GH treatment had no effect on their adiponectin and resistin levels. This is reassuring because it shows that GH treatment does not induce disadvantageous changes in these adipocytokines, which have emerged as one of the markers for the development of cardiovascular disease and diabetes mellitus type 2.


   Acknowledgments
 
Mrs. C. Bruinings-Vroombout, Mrs. M. Huibregtse-Schouten, Mrs. J. van Houten, Mrs. E. Lems, Mrs. J. van Nieuwkasteele, and Mrs. I. van Slobbe, research nurses, are greatly acknowledged for their assistance. W. Hackeng, G. Klein Heerenbrink, and H. van Toor are greatly acknowledged for performing laboratory analyses. The participating centers were: P. Voorhoeve, Free University Hospital Amsterdam, The Netherlands; J. C. Mulder, Rijnstate Hospital, Arnhem, The Netherlands; J. J. J. Waelkens, Catharina Hospital, Eindhoven, The Netherlands; R. J. H. Odink and W. M. Bakker-van Waarde, University Medical Center Groningen, Groningen, The Netherlands; W. H. Stokvis, Leiden University Medical Center, Leiden, The Netherlands; C. Noordam, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands; C. Rongen-Westerlaken, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands; N. J. T. Arends, V. H. Boonstra, M. van Dijk, A. C. S. Hokken-Koelega, D. C. van der Kaay, T. C. J. Sas, Erasmus Medical Center Sophia, Rotterdam, The Netherlands; H. M. Reeser and E. C. A. M. Houdijk, Juliana Children’s Hospital, The Hague, The Netherlands; and M. Jansen, Wilhelmina Children’s Hospital, Utrecht, The Netherlands.


   Footnotes
 
This work was supported by Novo Nordisk Farma B.V., The Netherlands, and Novo Nordisk Denmark.

Disclosure Statement: The authors have nothing to disclose.

First Published Online September 26, 2006

Abbreviations: BMI, Body mass index; BP, blood pressure; BSA, body surface area; CV, coefficient of variation; DHEAS, dehydroepiandrosterone sulfate; IGFBP, IGF binding protein; SDS, SD score; SGA, small for gestational age.

Received April 20, 2006.

Accepted September 18, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF 1995 A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 270:26746–26749[Abstract/Free Full Text]
  2. Reinehr T, Roth C, Menke T, Andler W 2004 Adiponectin before and after weight loss in obese children. J Clin Endocrinol Metab 89:3790–3794[Abstract/Free Full Text]
  3. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA 2001 Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86:1930–1935[Abstract/Free Full Text]
  4. Gavrila A, Chan JL, Yiannakouris N, Kontogianni M, Miller LC, Orlova C, Mantzoros CS 2003 Serum adiponectin levels are inversely associated with overall and central fat distribution but are not directly regulated by acute fasting or leptin administration in humans: cross-sectional and interventional studies. J Clin Endocrinol Metab 88:4823–4831[Abstract/Free Full Text]
  5. Stefan N, Bunt JC, Salbe AD, Funahashi T, Matsuzawa Y, Tataranni PA 2002 Plasma adiponectin concentrations in children: relationships with obesity and insulinemia. J Clin Endocrinol Metab 87:4652–4656[Abstract/Free Full Text]
  6. Weiss R, Dziura J, Burgert TS, Tamborlane WV, Taksali SE, Yeckel CW, Allen K, Lopes M, Savoye M, Morrison J, Sherwin RS, Caprio S 2004 Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 350:2362–2374[Abstract/Free Full Text]
  7. Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL, Murphy LJ 2003 Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. Eur J Endocrinol 149:331–335[Abstract]
  8. Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, Furuyama N, Kondo H, Takahashi M, Arita Y, Komuro R, Ouchi N, Kihara S, Tochino Y, Okutomi K, Horie M, Takeda S, Aoyama T, Funahashi T, Matsuzawa Y 2002 Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 8:731–737[CrossRef][Medline]
  9. Spranger J, Kroke A, Mohlig M, Bergmann MM, Ristow M, Boeing H, Pfeiffer AF 2003 Adiponectin and protection against type 2 diabetes mellitus. Lancet 361:226–228[CrossRef][Medline]
  10. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA 2001 The hormone resistin links obesity to diabetes. Nature 409:307–312[CrossRef][Medline]
  11. Silha JV, Krsek M, Skrha J, Sucharda P, Nyomba BL, Murphy LJ 2004 Plasma resistin, leptin and adiponectin levels in non-diabetic and diabetic obese subjects. Diabet Med 21:497–499[Medline]
  12. Heilbronn LK, Rood J, Janderova L, Albu JB, Kelley DE, Ravussin E, Smith SR 2004 Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects. J Clin Endocrinol Metab 89:1844–1848[Abstract/Free Full Text]
  13. Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, Orlova C, Mantzoros CS 2003 Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects. J Clin Endocrinol Metab 88:4848–4856[Abstract/Free Full Text]
  14. Yannakoulia M, Yiannakouris N, Bluher S, Matalas AL, Klimis-Zacas D, Mantzoros CS 2003 Body fat mass and macronutrient intake in relation to circulating soluble leptin receptor, free leptin index, adiponectin, and resistin concentrations in healthy humans. J Clin Endocrinol Metab 88:1730–1736[Abstract/Free Full Text]
  15. Barker DJ, Hales CN, Fall CH, Osmond C, Phipps K, Clark PM 1993 Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 36:62–67[CrossRef][Medline]
  16. Sas T, Mulder P, Hokken-Koelega A 2000 Body composition, blood pressure, and lipid metabolism before and during long-term growth hormone (GH) treatment in children with short stature born small for gestational age either with or without GH deficiency. J Clin Endocrinol Metab 85:3786–3792[Abstract/Free Full Text]
  17. Sas T, Mulder P, Aanstoot HJ, Houdijk M, Jansen M, Reeser M, Hokken-Koelega A 2001 Carbohydrate metabolism during long-term growth hormone treatment in children with short stature born small for gestational age. Clin Endocrinol (Oxf) 54:243–251[CrossRef][Medline]
  18. Cutfield WS, Jackson WE, Jefferies C, Robinson EM, Breier BH, Richards GE, Hofman PL 2003 Reduced insulin sensitivity during growth hormone therapy for short children born small for gestational age. J Pediatr 142:113–116[CrossRef][Medline]
  19. van Pareren Y, Mulder P, Houdijk M, Jansen M, Reeser M, Hokken-Koelega A 2003 Effect of discontinuation of growth hormone treatment on risk factors for cardiovascular disease in adolescents born small for gestational age. J Clin Endocrinol Metab 88:347–353[Abstract/Free Full Text]
  20. Cianfarani S, Martinez C, Maiorana A, Scire G, Spadoni GL, Boemi S 2004 Adiponectin levels are reduced in children born small for gestational age and are inversely related to postnatal catch-up growth. J Clin Endocrinol Metab 89:1346–1351[Abstract/Free Full Text]
  21. Lopez-Bermejo A, Casano-Sancho P, Fernandez-Real JM, Kihara S, Funahashi T, Rodriguez-Hierro F, Ricart W, Ibanez L 2004 Both intrauterine growth restriction and postnatal growth influence childhood serum concentrations of adiponectin. Clin Endocrinol (Oxf) 61:339–346[CrossRef][Medline]
  22. Iniguez G, Soto N, Avila A, Salazar T, Ong K, Dunger D, Mericq V 2004 Adiponectin levels in the first two years of life in a prospective cohort: relations with weight gain, leptin levels and insulin sensitivity. J Clin Endocrinol Metab 89:5500–5503[Abstract/Free Full Text]
  23. Ibanez L, Fucci A, Valls C, Ong K, Dunger D, de Zegher F 2005 Neutrophil count in small-for-gestational age children: contrasting effects of metformin and growth hormone therapy. J Clin Endocrinol Metab 90:3435–3439[Abstract/Free Full Text]
  24. Kotani Y, Yokota I, Kitamura S, Matsuda J, Naito E, Kuroda Y 2004 Plasma adiponectin levels in newborns are higher than those in adults and positively correlated with birth weight. Clin Endocrinol (Oxf) 61:418–423[CrossRef][Medline]
  25. Sivan E, Mazaki-Tovi S, Pariente C, Efraty Y, Schiff E, Hemi R, Kanety H 2003 Adiponectin in human cord blood: relation to fetal birth weight and gender. J Clin Endocrinol Metab 88:5656–5660[Abstract/Free Full Text]
  26. Tsai PJ, Yu CH, Hsu SP, Lee YH, Chiou CH, Hsu YW, Ho SC, Chu CH 2004 Cord plasma concentrations of adiponectin and leptin in healthy term neonates: positive correlation with birthweight and neonatal adiposity. Clin Endocrinol (Oxf) 61:88–93[CrossRef][Medline]
  27. Lindsay RS, Walker JD, Havel PJ, Hamilton BA, Calder AA, Johnstone FD 2003 Adiponectin is present in cord blood but is unrelated to birth weight. Diabetes Care 26:2244–2249[Abstract/Free Full Text]
  28. Kim CS, Park JS, Park J, Nam JS, Kang ES, Ahn CW, Cha BS, Lim SK, Kim KR, Lee HC, Huh KB, Kim DJ 2006 Does birthweight predict adolescent adiponectin levels? Clin Endocrinol (Oxf) 64:162–168[CrossRef][Medline]
  29. Martinez-Cordero C, Amador-Licona N, Guizar-Mendoza JM, Hernandez-Mendez J, Ruelas-Orozco G 2006 Body fat at birth and cord blood levels of insulin, adiponectin, leptin, and insulin-like growth factor-I in small-for-gestational-age infants. Arch Med Res 37:490–494[CrossRef][Medline]
  30. Kajantie E, Hytinantti T, Hovi P, Andersson S 2004 Cord plasma adiponectin: a 20-fold rise between 24 weeks gestation and term. J Clin Endocrinol Metab 89:4031–4036[Abstract/Free Full Text]
  31. Usher R, McLean F 1969 Intrauterine growth of live-born Caucasian infants at sea level: standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation. J Pediatr 74:901–910[CrossRef][Medline]
  32. Fredriks AM, van Buuren S, Burgmeijer RJ, Meulmeester JF, Beuker RJ, Brugman E, Roede MJ,. Verloove-Vanhorick SP, Wit JM 2000 Continuing positive secular growth change in The Netherlands 1955–1997. Pediatr Res 47:316–323[Medline]
  33. Tanner JM, Whitehouse RH 1976 Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child 51:170–179[Abstract/Free Full Text]
  34. Arends NJ, Boonstra VH, Duivenvoorden HJ, Hofman PL, Cutfield WS, Hokken-Koelega AC 2005 Reduced insulin sensitivity and the presence of cardiovascular risk factors in short prepubertal children born small for gestational age (SGA). Clin Endocrinol (Oxf) 62:44–50[CrossRef][Medline]
  35. Arends NJ, Boonstra VH, Mulder PG, Odink RJ, Stokvis-Brantsma WH, Rongen-Westerlaken C, Mulder JC, Delemarre-Van de Waal H, Reeser HM, Jansen M, Waelkens JJ, Hokken-Koelega AC 2003 GH treatment and its effect on bone mineral density, bone maturation and growth in short children born small for gestational age: 3-year results of a randomized, controlled GH trial. Clin Endocrinol (Oxf) 59:779–787[CrossRef][Medline]
  36. Fredriks AM, van Buuren S, Wit JM, Verloove-Vanhorick SP 2000 Body index measurements in 1996–7 compared with 1980. Arch Dis Child 82:107–112[Abstract/Free Full Text]
  37. Gerver WJ, de Bruin R 2001 Paediatric morphometrics, a reference manual. 2nd ed. Maastricht, The Netherlands: University Press
  38. Rosner B, Prineas RJ, Loggie JM, Daniels SR 1993 Blood pressure nomograms for children and adolescents, by height, sex, and age, in the United States. J Pediatr 123:871–886[CrossRef][Medline]
  39. Van Pareren Y, Mulder P, Houdijk M, Jansen M, Reeser M, Hokken-Koelega A 2003 Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose-response GH trial. J Clin Endocrinol Metab 88:3584–3590[Abstract/Free Full Text]
  40. Rikken B, van Doorn J, Ringeling A, Van den Brande JL, Massa G, Wit JM 1998 Plasma levels of insulin-like growth factor (IGF)-I, IGF-II and IGF-binding protein-3 in the evaluation of childhood growth hormone deficiency. Horm Res 50:166–176[CrossRef][Medline]
  41. Cole TJ, Green PJ 1992 Smoothing reference centile curves: the LMS method and penalized likelihood. Stat Med 11:1305–1319[Medline]
  42. Martin LJ, Woo JG, Daniels SR, Goodman E, Dolan LM 2005 The relationships of adiponectin with insulin and lipids are strengthened with increasing adiposity. J Clin Endocrinol Metab 90:4255–4259[Abstract/Free Full Text]
  43. Knobler H, Benderly M, Boyko V, Behar S, Matas Z, Rubinstein A, Raz I, Wainstein J 2006 Adiponectin and the development of diabetes in patients with coronary artery disease and impaired fasting glucose. Eur J Endocrinol 154:87–92[Abstract/Free Full Text]
  44. Boonstra VH, Arends NJ, Stijnen T, Blum WF, Akkerman O, Hokken-Koelega AC 2005 Food intake of children with short stature born small for gestational age before and during a randomized GH trial. Horm Res 65:23–30
  45. Barker DJ, Osmond C, Forsen TJ, Kajantie E, Eriksson JG 2005 Trajectories of growth among children who have coronary events as adults. N Engl J Med 353:1802–1809[Abstract/Free Full Text]
  46. Boonstra VH, Mulder PG, de Jong FH, Hokken-Koelega AC 2004 Serum dehydroepiandrosterone sulfate levels and pubarche in short children born small for gestational age before and during growth hormone treatment. J Clin Endocrinol Metab 89:712–717[Abstract/Free Full Text]
  47. Fukuda I, Hizuka N, Ishikawa Y, Itoh E, Yasumoto K, Murakami Y, Sata A, Tsukada J, Kurimoto M, Okubo Y, Takano K 2004 Serum adiponectin levels in adult growth hormone deficiency and acromegaly. Growth Horm IGF Res 14:449–454[Medline]
  48. Silha JV, Krsek M, Hana V, Marek J, Jezkova J, Weiss V, Murphy LJ 2003 Perturbations in adiponectin, leptin and resistin levels in acromegaly: lack of correlation with insulin resistance. Clin Endocrinol (Oxf) 58:736–742[CrossRef][Medline]
  49. Lam KS, Xu A, Tan KC, Wong LC, Tiu SC, Tam S 2004 Serum adiponectin is reduced in acromegaly and normalized after correction of growth hormone excess. J Clin Endocrinol Metab 89:5448–5453[Abstract/Free Full Text]
  50. Ronchi CL, Corbetta S, Cappiello V, Morpurgo PS, Giavoli C, Beck-Peccoz P, Arosio M, Spada A 2004 Circulating adiponectin levels and cardiovascular risk factors in acromegalic patients. Eur J Endocrinol 150:663–669[Abstract]
  51. Hana V, Silha JV, Justova V, Lacinova Z, Stepan JJ, Murphy LJ 2004 The effects of GH replacement in adult GH-deficient patients: changes in body composition without concomitant changes in the adipokines and insulin resistance. Clin Endocrinol (Oxf) 60:442–450[CrossRef][Medline]
  52. Svensson J, Herlitz H, Lundberg PA, Johannsson G 2005 Adiponectin, leptin, and erythrocyte sodium/lithium countertransport activity, but not resistin, are related to glucose metabolism in growth hormone-deficient adults. J Clin Endocrinol Metab 90:2290–2296[Abstract/Free Full Text]
  53. Giavoli C, Cappiello V, Corbetta S, Ronchi CL, Morpurgo PS, Ferrante E, Beck-Peccoz P, Spada A 2004 Different effects of short- and long-term recombinant hGH administration on ghrelin and adiponectin levels in GH-deficient adults. Clin Endocrinol (Oxf) 61:81–87[CrossRef][Medline]
  54. Schmid C, Bianda T, Zwimpfer C, Zapf J, Wiesli P 2005 Changes in insulin sensitivity induced by short-term growth hormone (GH) and insulin-like growth factor I (IGF-I) treatment in GH-deficient adults are not associated with changes in adiponectin levels. Growth Horm IGF Res 15:300–303[CrossRef][Medline]
  55. Eden Engstrom B, Burman P, Holdstock C, Karlsson FA 2003 Effects of growth hormone (GH) on ghrelin, leptin, and adiponectin in GH-deficient patients. J Clin Endocrinol Metab 88:5193–5198[Abstract/Free Full Text]
  56. Azuma K, Katsukawa F, Oguchi S, Murata M, Yamazaki H, Shimada A, Saruta T 2003 Correlation between serum resistin level and adiposity in obese individuals. Obes Res 11:997–1001[Medline]
  57. Nagaev I, Smith U 2001 Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle. Biochem Biophys Res Commun 285:561–564[CrossRef][Medline]
  58. Leger J, Garel C, Fjellestad-Paulsen A, Hassan M, Czernichow P 1998 Human growth hormone treatment of short-stature children born small for gestational age: effect on muscle and adipose tissue mass during a 3-year treatment period and after 1 year’s withdrawal. J Clin Endocrinol Metab 83:3512–3516[Abstract/Free Full Text]
  59. Chen YH, Hung PF, Kao YH 2005 IGF-I down-regulates resistin gene expression and protein secretion. Am J Physiol Endocrinol Metab 288:E1019–E1027
  60. Dunger D, Yuen K, Ong K 2004 Insulin-like growth factor I and impaired glucose tolerance. Horm Res 62(Suppl 1):101–107
  61. Juul A, Scheike T, Davidsen M, Gyllenborg J, Jorgensen T 2002 Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation 106:939–944
  62. Bokarewa M, Nagaev I, Dahlberg L, Smith U, Tarkowski A 2005 Resistin, an adipokine with potent proinflammatory properties. J Immunol 174:5789–5795[Abstract/Free Full Text]
  63. Reilly MP, Lehrke M, Wolfe ML, Rohatgi A, Lazar MA, Rader DJ 2005 Resistin is an inflammatory marker of atherosclerosis in humans. Circulation 111:932–939



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