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Longitudinal Changes in Insulin Sensitivity and Body Composition of Small-For-Gestational-Age Adolescents after Cessation of Growth Hormone Treatment

Deptartment of Pediatrics (R.H.W., A.C.S.H.-K.), Division of Endocrinology, Erasmus Medical Center Sophia, 3015 GJ Rotterdam, The Netherlands; and Department of Epidemiology and Biostatistics (S.P.W.), Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Ruben Willemsen, MD, Erasmus MC Sophia, Room number SB-2603, 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

 
Context: GH treatment reduces insulin sensitivity (Si). For small-for-gestational-age (SGA) subjects, who might have an increased risk to develop cardiovascular disease and type 2 diabetes, it is still uncertain how Si, β-cell function, and body composition change over time after stopping GH treatment.

Objective: Our objective was to investigate longitudinal changes in Si, β-cell function, and body composition after cessation of long-term GH treatment.

Design and Patients: We conducted a longitudinal study that included 48 SGA adolescents studied at adult height, while still on GH, and 6 months after GH stop and compared them with 38 appropriate-for-gestational-age (AGA) controls at both time points.

Outcome Measure: We took paired measurements of Si and β-cell function, assessed by frequently sampled iv glucose tolerance tests with tolbutamide, and body composition, measured by dual-energy x-ray absorptiometry.

Results: After stopping GH, Si (P = 0.006), glucose effectiveness (Sg; P = 0.009) and β-cell function (disposition index; P = 0.024) increased, whereas insulin secretion (acute insulin response; not significant) decreased. Fat percentage increased (P < 0.0005), and lean body mass decreased (P < 0.0005), but fat distribution remained unaltered, and body composition remained within the normal range. Compared with AGA controls, Si was lower during GH and became similar after GH stop, acute insulin response was higher at both time points, and glucose effectiveness and disposition index became higher.

Conclusions: The GH-induced lower Si in SGA adolescents increases after stopping long-term GH treatment and becomes similar to that of AGA controls. Discontinuation of GH treatment is, however, also associated with an increase in percent body fat and with a decrease in lean body mass, without changes in fat distribution.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
It is well known that GH treatment reduces insulin sensitivity (Si). Because short children born small-for-gestational-age (SGA) have a lower Si than normal children before start of GH treatment, concern has been expressed regarding the long-term effects of GH treatment on the insulin-glucose homeostasis of SGA children (1, 2, 3).

Previously, we showed that the insulin response during an oral glucose tolerance test (OGTT) normalized after stopping GH treatment (4). An OGTT is, however, dependent on the uptake of glucose in the digestive system and does not provide any information regarding changes in Si and β-cell function.

Two studies reported conflicting results regarding the change of Si after discontinuation of GH treatment (5, 6). In the first study in nine short SGA children, the observed decrease in Si during GH treatment was reversible (5). In the second study in 12 children, Si did not recover after stopping GH treatment (6). Both studies investigated Si after stopping GH treatment but before adult height was achieved. Besides, in one study, it was unclear whether some children had already entered puberty (5), which can reduce Si as well (7, 8). Furthermore, it is questionable whether the number of subjects was sufficient to draw definite conclusions. Thus, to date, it is not known how Si and insulin secretion change longitudinally in SGA adolescents after adult height has been attained and GH treatment has been stopped. Regarding body composition, there are no data on changes after stopping GH treatment.

We hypothesized that the GH-induced reduction in Si recovers after stopping GH treatment and that the changes in body composition, if any, would be limited. We performed paired measurements of Si and β-cell function, using the frequently sampled iv glucose tolerance test (FSIGT) in 48 GH-treated SGA adolescents, at near adult height and 6 months after cessation of GH. We also measured body composition by dual-energy x-ray absorptiometry (DXA) at the same time points. In addition, we compared the data of the SGA subjects at both time points with those of 38 AGA controls and hypothesized that the changes in Si, β-cell function, and body composition after stopping GH treatment would result in values resembling those of AGA controls.

	Subjects and Methods

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Subjects

The study group comprised 48 adolescents born SGA, who participated in a GH trial, of which the inclusion criteria have previously been described (9). In short, the children were prepubertal, had a birth length and height SD score (SDS) below –2.0, did not show catch-up growth in height, and had no growth failure caused by other disorders. Once daily at bedtime, 1 mg biosynthetic GH (r-hGH Norditropin; Novo Nordisk A/S, Bagsværd, Denmark) per square meter body surface area was given sc. Every 3 months, the GH dose was adjusted to the calculated body surface area. GH treatment was discontinued when height velocity dropped less than 0.5 cm over the last 6 months and/or bone age (according to Greulich and Pyle) (10) was at least 15 yr for girls and at least 16.5 yr for boys, as described in the original protocol of the study. SGA subjects were compared with 38 healthy normal-statured AGA (defined as birth length and height > –2 SDS) (11, 12) controls, which were matched for gestational age and sex. The GH trial was approved by the Medical Ethics Committees of the participating centers (see Acknowledgments). When the subjects had reached adult height, they were asked to participate in the current follow-up study, which was performed at Erasmus Medical Center and approved by its Medical Ethics Committee. Written informed consent was obtained from all controls and subjects and, if they were younger than 18 yr, also from the parents or custodians of each adolescent.

Study design

Subjects were studied twice after an overnight fast: 1) at near adult height, while still on GH, and 2) 6 months thereafter, without GH. Standing height and weight were measured, and body mass index (BMI) was calculated. Height and BMI were expressed as SDS adjusting for sex and age according to Dutch reference data (11, 13). A modified FSIGT with tolbutamide was performed, as previously described (14, 15). Si, glucose effectiveness (Sg), acute insulin response (AIR), and disposition index (DI) were calculated using Bergman’s MINMOD MILLENNIUM software (16). Si quantifies the capacity of insulin to promote glucose disposal, and Sg reflects the capacity of glucose to mediate its own disposal. The AIR, an estimate of insulin secretory capacity, was measured as the area under the curve from 0–10 min corrected for baseline insulin levels. DI equals AIR x Si and is an estimate of β-cell function.

Body composition was measured with DXA scans on one machine (Lunar Prodigy; GE Healthcare, Chalfont St. Giles, UK). Lean body mass (LBM), fat mass (FM), and percent fat were determined. Percent fat was transformed into SDS for sex and age using Dutch reference values (17, 18). Because body composition is strongly related to height, LBM and FM expressed as SDS for age and sex might result in an underestimation in case of short stature. Therefore, LBM and FM were expressed as SDS for height and sex. Height-adjusted SDS were calculated as previously described (19).

Assays

All serum glucose levels were determined on a VITROS analyzer 750 (Orthoclinical Diagnostics, Johnson & Johnson Co., Beerse, Belgium). The intraassay coefficient of variation (CV) was 0.4%, and the interassay CV was 0.7%. All serum insulin levels were measured by immunoradiometric assay (Medgenix, Biosource Europe, Nivelles, Belgium). The intraassay CV was 1.9%, and the interassay CV was 6.3%. All assays were performed in one central laboratory.

Statistics

To normalize the distribution, all FSIGT parameters and fasting insulin levels were logarithmically transformed before analyses. With respect to body composition data, a value of –2 to 2 SDS corresponds with a normal body composition corrected for age and sex (SDS) or height and sex (SDS_height). To test the time effect of discontinuation of GH treatment on FSIGT and body composition parameters, mixed-model analyses of variance were performed. There were no interactions between sex and time and oral contraceptive use and time. Therefore, these data were not entered in the model. Differences between SGA subjects and controls were tested by one-way ANOVA with a least significant difference post hoc test. Clinical data are presented as mean (SD), model estimates as geometric mean (95% confidence interval) for FSIGT parameters and fasting insulin, and mean (95% confidence interval) for body composition data and fasting glucose. Level of significance was determined at P < 0.05. Statistics were performed using the computer statistical package SPSS (version 11.0.1; SPSS Inc., Chicago, IL).

	Results

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Clinical characteristics

Table 1 shows the clinical characteristics of the SGA subjects and AGA controls at various time points. SGA subjects had a mean age of 8.6 yr at start of GH treatment and 16.1 yr at stop of GH treatment. After a mean duration of 7.5 yr of GH treatment, height had increased from –2.8 SDS at start of GH treatment to –1.3 SDS at adult height.

Figure 1 shows baseline fasting glucose and insulin levels and FSIGT parameters of the serial FSIGT tests at stop of GH treatment (SGA on GH) and 6 months thereafter (SGA after stop GH) in comparison with AGA controls. Fasting glucose levels decreased moderately after stop of GH treatment and became comparable with those of AGA controls [Fig. 1A: 5.1 (4.9–5.2) to 4.7 (4.6–4.8) mmol/liter; P < 0.0005]. Fasting insulin levels also decreased after stop of GH treatment and became comparable with levels in AGA controls [Fig. 1B: 15 (13, 14, 15, 16, 17) to 11 (9, 10, 11, 12) mU/liter]. Si increased significantly after stop of GH treatment [Fig. 1C: 3.8 (3.3–4.4) to 5.1 (4.2–6.3) x 10^–4 min^–1 (mU/liter); P = 0.006]. Si was significantly lower in SGA subjects on GH than in AGA controls (P = 0.001) but became comparable after GH treatment was stopped. Also, Sg improved significantly after stop of GH treatment [Fig. 1E: 1.5 (1.3–1.8) to 1.9 (1.8–2.1) x 10^–2 min^–1 (mg/d); P = 0.009] and became significantly higher than Sg in AGA controls (P = 0.024). After stop of GH treatment, insulin secretion decreased [Fig. 1D: 699 (577–848) to 623 (514–754) mU/liter; P = 0.130] and DI increased significantly (Fig. 1F: 2561 (2063–3178) to 3258 (2768–3835); P = 0.024]. Compared with AGA controls, SGA subjects had a significantly higher insulin secretion at both time points (on GH and after stop of GH; P < 0.0005) and a significantly higher DI 6 months after stop of GH (P = 0.004).

View larger version (31K): [in this window] [in a new window]   FIG. 1. Longitudinal changes in FSIGT parameters of SGA adolescents from stop of GH treatment to 6 months thereafter in comparison with AGA controls. A, Fasting glucose; B, fasting insulin; C, Si; D, insulin secretion; E, Sg; F, DI. AIRg, AIR to glucose; NS, not significant.

Table 2 shows the changes in body composition from stop (SGA on GH) to 6 months after stop of GH treatment (SGA after stop GH). Percent fat SDS and FM corrected for height and sex increased significantly after stop of GH treatment (P < 0.0005), and LBM corrected for height and sex decreased significantly after stop of GH treatment (P < 0.0005). Trunk to total FM ratio did not significantly change and remained within the normal range at both time points. Body composition of SGA subjects was comparable with AGA controls at both time points, with the exception of a higher trunk to total FM ratio in SGA subjects on GH. Body mass index (BMI) SDS did not change after discontinuation of GH.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

This is the first study describing serial measurements of Si and secretion in SGA subjects on GH and 6 months after stop of GH treatment due to attainment of adult height. Our data are in contrast to those of Cutfield et al. (6), who reported that the decrease of Si during GH treatment was irreversible after its discontinuation. However, they studied only five children after stop of GH treatment, and the definition of SGA (birth weight < 10th percentile) was different from the definition used by us and suggested by the international consensus meetings (birth weight and/or length < –2 SDS) (20, 21). De Zegher et al. (5) reported a reversible decrease of Si after stop of GH treatment in nine children, but in this study, it was unclear whether the children remained prepubertal. Finally, both studies investigated Si before adult height had been attained.

Previously, we investigated glucose tolerance with OGTT in another group of GH-treated SGA subjects and showed that the glucose and insulin response during OGTT normalized after stop of GH treatment (4). Unfortunately, OGTT does not provide information on Si and β-cell function. Our current data show that the decrease in Si during GH treatment is reversible after discontinuation of GH. Van Dijk et al. (22) investigated Si in previously GH-treated young adults who had discontinued GH treatment for 6.5 yr and found that their Si and β-cell function were similar to those of untreated SGA controls. However, Si and β-cell function were not measured in these subjects during GH treatment. Therefore, that study was unable to study longitudinal changes in Si and β-cell function.

To the best of our knowledge, this is the first study investigating changes in body composition in SGA after stop of GH. Interestingly, we found significant changes in body composition after stop of GH treatment, which could not be detected with BMI SDS. Percent fat SDS and FM SDS increased, whereas LBM SDS decreased. These changes are opposite to those that occur when GH treatment is started in SGA children (19). At this moment, the clinical relevance of the observed changes is unclear. One would expect a decrease of Si as a consequence of an increase in FM, but instead, Si improved. Si is known to have a strong correlation with percent fat. Despite the increase in percent fat SDS after stop of GH, Si increased. This indicates that discontinuation of GH treatment has a beneficial effect on Si, which is greater than the opposite effect on Si due to gaining more FM. It remains to be elucidated how body composition changes in the longer term after GH has been discontinued.

An unexpected finding was the increase in Sg after stop of GH treatment. Sg is a measure for insulin-independent glucose disposal. The increased Sg after stop of GH cannot be a consequence of a higher basal glucose concentration driving its uptake, because fasting glucose after stop of GH was comparable with AGA controls and decreased in SGA subjects after stop of GH, whereas Sg increased. In previous studies, Sg was not significantly different, albeit lower in short SGA than in normal AGA children (1). During GH treatment, Sg did not change in the short term (6), but the long-term effects are not known. In first-degree relatives of type 2 diabetic individuals, who were followed longitudinally, Sg was lower at the first assessment in those subjects, who progressed from normal glucose tolerance to impaired glucose tolerance (IGT) (23). In another follow-up study on first-degree relatives of type 2 diabetics, Sg was found to be an independent predictor for the development of type 2 diabetes mellitus (DM2) (24). The combination of a low Si and a low Sg was associated with the highest cumulative risk of DM2 (24). Importantly, in our study, Sg was similar for GH-treated SGA subjects and AGA controls and improved significantly when GH treatment was stopped, indicating that Sg in SGA subjects, both on and off GH, is not worse than that in AGA controls.

Interestingly, insulin secretion remained significantly higher in SGA subjects, also after GH was discontinued. This might indicate that the mechanisms that increased insulin secretion during GH treatment have not been fully reversed in this 6-month interval. Therefore, follow-up of these SGA subjects remains important. It has been suggested by some physicians that the β-cells need to secrete relatively large amounts of insulin to maintain glucose homeostasis, leading to a possible exhaustion of the β-cells and thus DM2 in the longer term (5). We do not support this view, because the available literature on the development of DM2 in persons at risk indicates that low rather than high first-phase insulin secretion is associated with progression from normal glucose tolerance to IGT as well as progression from IGT to DM2 (25, 26). Moreover, the decline in glucose tolerance over time in relatives of type 2 diabetic individuals was strongly related to the loss of β-cell function, measured by DI (23). In our study, DI was even higher in SGA subjects than in controls. Nevertheless, our data cannot guarantee that glucose homeostasis remains unaffected in the longer term. Therefore, long-term follow-up of previously GH-treated SGA subjects remains important.

A limitation of our study is that the AGA controls had a mean age of 19 yr, whereas the SGA subjects were on average 16 yr. The recruitment of healthy AGA subjects younger than 18 yr for an invasive test, such as a FSIGT, was not allowed by the medical ethics committee. However, because all SGA subjects were postpubertal and had reached adult height, it is unlikely that this age difference had a major effect on the results. Furthermore, the AGA controls had values for body composition z-scores that tended to be significantly different from zero. It might well be that children have become fatter in the last decade and therefore have values further from the predicted values based on the reference data from 1997.

In conclusion, the GH-induced reduction in Si in SGA adolescents is reversible after stop of long-term GH-treatment, and Si becomes similar to that of AGA controls, which is reassuring. Discontinuation of GH treatment was, however, also associated with a significant increase in percent body fat and a decrease in LBM, without changes in fat distribution. It remains to be elucidated how body composition changes in the longer term after GH has been discontinued. Our data underscore the importance of follow-up studies after discontinuation of GH treatment.

	Acknowledgments

 
We thank all the participants and their parents. Mrs. M. Huibregtse-Schouten and Mrs. E. Lems, research nurses, are greatly acknowledged for their assistance during the study. We also thank all the participating centers that participated in the GH trial: Beatrix Children’s Hospital, Groningen; Wilhelmina Children’s Hospital, Utrecht; Free University Medical Center, Amsterdam; Rijnstate Hospital, Arnhem; Catharina Hospital, Eindhoven; Juliana Children’s Hospital, The Hague; Canisius Wilhelmina Hospital, Nijmegen; and Leiden University Medical Center, Leiden. W. Hackeng is greatly acknowledged for performing laboratory analyses. Mrs. J. Sluimer is greatly acknowledged for checking the DXA analyses and E. P. Krenning, Head of the Department of Nuclear Medicine, for use of the facilities and equipment.

	Footnotes

 
This study was supported by Novo Nordisk Farma B.V., The Netherlands.

The trial registration number of this study is ISRCTN96883876.

Disclosure Statement: The authors have nothing to disclose.

First Published Online June 17, 2008

Abbreviations: AGA, Appropriate-for-gestational-age; AIR, acute insulin response; BMI, body mass index; CV, coefficient of variation; DI, disposition index; DM2, type 2 diabetes mellitus; DXA, dual-energy x-ray absorptiometry; FM, fat mass; FSIGT, frequently sampled iv glucose tolerance test; IGT, impaired glucose tolerance; LBM, lean body mass; OGTT, oral glucose tolerance test; SDS, SD score; Sg, glucose effectiveness; SGA, small for gestational age; Si, insulin sensitivity.

Received March 18, 2008.

Accepted June 5, 2008.

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Top Abstract Introduction Subjects and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Willemsen, R. H. Articles by Hokken-Koelega, A. C. S. Search for Related Content PubMed PubMed Citation Articles by Willemsen, R. H. Articles by Hokken-Koelega, A. C. S. Related Collections Pediatric Endocrinology Diabetes and Insulin Metabolism