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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0308
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 8 3033-3039
Copyright © 2007 by The Endocrine Society

Growth Hormone Treatment in Adolescent Males with Idiopathic Short Stature: Changes in Body Composition, Protein, Fat, and Glucose Metabolism

Tamara S. Hannon, Kapriel Danadian, Chittiwat Suprasongsin and Silva A. Arslanian

Division of Pediatric Endocrinology, Metabolism, and Diabetes Mellitus and Division of Weight Management and Wellness (T.S.H., S.A.A.), Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213; Oneida Pediatric Group (K.D.), Oneida New York 13421; and Ramathibodi Hospital (C.S.), Mahidol University, Bangkok 10400, Thailand

Address all correspondence and requests for reprints to: Tamara S. Hannon, M.D., Children’s Hospital of Pittsburgh, 3705 5th Avenue at DeSoto Street, 4A, Room 424, Pittsburgh, Pennsylvania 15213. E-mail: tamara.hannon{at}chp.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Cross-sectional observations show an inverse relationship between pubertal increase in GH and insulin sensitivity, suggesting that pubertal insulin resistance may be mediated by GH.

Objective: Our objective was to assess longitudinally the effects of short-term GH supplementation in adolescent males with non-GH-deficient idiopathic short stature (ISS) on body composition, substrate metabolism, and insulin sensitivity. Children with ISS were studied to simulate the pubertal increase in GH secretion.

Participants and Setting: Eight males with ISS (10.8–16.5 yr) were recruited from pediatric endocrinology clinics at an academic medical center.

Study Design: Participants were evaluated in the General Clinical Research Center before and after 4 months of GH supplementation (0.3 mg/kg·wk). Body composition was assessed with dual-energy x-ray absorptiometry. Whole-body glucose, protein, and fat turnover were measured using stable isotopes. In vivo insulin action was assessed during a 3-h hyperinsulinemic (40 mU/m2·min) euglycemic clamp.

Results: GH supplementation led to 1) increase in hepatic glucose production and fasting insulin levels, 2) increase in lean body mass and decrease in fat mass, and 3) improvement in cardiovascular lipid risk profile. Plasma IGF-I levels correlated positively with insulin levels.

Conclusions: Four months of GH supplementation in adolescent males with ISS is associated with significant body composition changes and hepatic insulin resistance.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PUBERTY IS CHARACTERIZED by an acceleration in growth rate and lean body mass accretion driven by hormonal and metabolic changes, including doubling of GH secretion, increased sex steroids, and insulin resistance (1, 2, 3). The insulin resistance of puberty is characterized by approximately 25–30% lower insulin-stimulated glucose disposal in pubertal adolescents compared with prepubertal children (1, 4, 5). Whether pubertal insulin resistance is the result of sex steroids or GH, or a combination of both, has been investigated in our laboratory. We have demonstrated that neither testosterone nor dihydrotestosterone treatment for 4 months in boys with short stature and delayed puberty resulted in deterioration of insulin sensitivity despite improvements in body composition and anabolism (6, 7). Because cross-sectional observations show an inverse relationship with GH levels and insulin action (8), and because of the antiinsulin actions of GH, we hypothesized that pubertal insulin resistance is driven by the increased GH secretion. The aim of the present study was to assess longitudinally the effects of 4 months of GH supplementation (0.3 mg/kg·wk) in adolescent males with non-GH-deficient idiopathic short stature (ISS) on body composition; protein, fat, and glucose metabolism; and insulin sensitivity. We elected to evaluate children with ISS instead of GH-deficient children in an effort to simulate the pubertal increase in GH secretion because the intent was not to study the effects of GH in GH-deficient children.


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

The studies were approved by the Human Rights Committee of Children’s Hospital of Pittsburgh/Institutional Review Board, University of Pittsburgh, and parental informed consent and child assent were obtained for all participants. Eight males with non-GH-deficient ISS (age range 10.8–16.5 yr) were recruited from the pediatric endocrinology clinics at Children’s Hospital of Pittsburgh for participation. All participants had a height less than 2.25 SD below the mean for age and sex (mean height SD, –0.5 ± 0.2) normal IGF-I levels and were otherwise healthy as assessed by medical history, physical examination, and routine hematological and biochemical tests. None of the participants were taking chronic medications or had a chronic disease known to influence growth, body composition, or insulin action. Pubertal development was assessed according to the criteria of Tanner by a single pediatric endocrinologist and with plasma testosterone levels. Six participants were Tanner stage II or III, two were Tanner stage I, and these stages did not change after 4 months of GH supplementation (Table 1Go).


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  		TABLE 1. Body composition and hormonal profile before and after 4 months of GH (0.3 mg/kg·wk) supplementation

 
Experimental design

Each participant was studied twice in the General Clinical Research Center at Children’s Hospital of Pittsburgh, with identical evaluations before and after 4 months of daily sc human GH supplementation (0.3 mg/kg·wk). All subjects were in good health during both study periods as assessed by medical history, physical examination, and routine hematological and biochemical tests. Participants were prescribed a weight-maintaining diet containing 55% carbohydrate, 30% fat, and 15% protein for a week before and during their hospital stay. All participants were admitted to the General Clinical Research Center in the afternoon in preparation for testing the following morning. Clamp experiments were performed after a 10- to 12-h overnight fast, and the posttreatment study was performed 10–12 h after the last dose of GH and after overnight fasting. For each study, two iv catheters were inserted, one in a forearm vein for administration of stable isotopes, insulin, and exogenous glucose and the second on the dorsum of the contralateral heated hand for sampling of arterialized venous blood (6). Fasting blood was obtained for determination of plasma leptin, testosterone, lipid profile, IGF-I, and IGF-binding protein 3 (IGFBP-3). Body composition was determined before and after 4 months of GH supplementation with dual-energy x-ray absorptiometry (Lunar DPX-L; Lunar Radiation Corp., Madison, WI).

Stable isotope infusions for the evaluation of glucose, protein, and fat turnover

From 0730–0930 h, stable isotope infusions of [6,6-2H2]glucose, [1-13C]leucine, and [2H5]glycerol were given to evaluate baseline substrate turnover as previously described (7). After this baseline period, a 3-h hyperinsulinemic-euglycemic clamp procedure was performed between 0930 and 1230 h, during which stable isotope infusions of glycerol and leucine were continued to assess insulin action in suppressing lipolysis and proteolysis (7). Total-body lipolysis was measured at baseline and during the 3-h hyperinsulinemic-euglycemic clamp procedure with a primed (1.2 µmol/kg) constant rate (0.08 µmol/kg·min) infusion of [2H5]glycerol as described by us previously (6, 9). Whole-body protein turnover was evaluated by a primed (5 µmol/kg) constant rate (6 µmol/kg·h) infusion of [1-13C]leucine according to our published protocols (6, 7, 10).

Fasting hepatic glucose production was evaluated by a primed (2.2 µmol/kg) constant rate (0.22 µmol/kg·min) infusion of [6,6-2H2]glucose for a total of 2 h before the clamp experiment. A 3-h hyperinsulinemic-euglycemic clamp procedure was performed to evaluate in vivo glucose metabolism and insulin sensitivity (6, 7, 11). The iv crystalline insulin (Humulin R; Lilly, Indianapolis, IN) was infused at a constant rate of 40 mU/m2·min. Insulin at this dose inhibits hepatic glucose production in prepubertal and pubertal children (4). Therefore, [6,6-2H2]glucose was not used during the clamp procedure to assess hepatic glucose production because it was assumed that endogenous glucose production during the clamp was zero. Plasma glucose was clamped at 5.5 mmol/liter with a variable rate infusion of 20% dextrose. The rate of glucose infusion was adjusted based on arterialized plasma glucose concentrations every 5 min. Blood was sampled every 10–15 min for the determination of plasma insulin, glycerol, free fatty acids, and plasma isotopic enrichments.

Indirect calorimetry

Continuous indirect calorimetry by a ventilated hood (Deltratrac Metabolic Monitor; Sensormedics, Anaheim, CA) was used to measure CO2 production, O2 consumption, and respiratory quotient (6). Measurements were made for 30 min at baseline before insulin infusion and for 30 min at the end of the clamp procedure (7).

Analytical methods

Laboratory analyses were performed as described by us previously (6, 7). Plasma glucose was measured at the bedside by the glucose oxidase method using a YSI, Inc. (Yellow Springs, OH) glucose analyzer. Plasma insulin was measured by RIA, IGF-I was measured by RIA after acid ethanol extraction, and estradiol was measured by double-antibody RIA. Cholesterol, high-density lipoprotein (HDL), and triglyceride measurements were performed using U.S. Centers for Disease Control and Prevention protocols (12). Low-density lipoprotein (LDL) cholesterol levels were estimated with the Friedewald equation. Testosterone was analyzed by double-antibody RIA, and IGFBP-3 was analyzed by RIA at Esoterix, Inc. (Calabasas Hills, CA; formerly Endocrine Sciences, Inc.).

The isotopic enrichments of plasma ketoisocaproate (KIC), glycerol, and glucose were determined as described by us previously (6, 9). Standard curves of known enrichments of KIC, glycerol, and glucose were performed with each assay. Pre- and post-GH supplementation samples were analyzed simultaneously in the same assay. Free fatty acid levels were measured with the commercially available Wako NEFA C kit (Wako Pure Chemical Industries Ltd., Osaka, Japan) that uses the in vitro enzymatic colorimetric method.

Calculations

Calculations were made at baseline during the last 30 min of the 2-h postabsorptive isotope infusion period and during hyperinsulinemia during the last 30 min of the clamp period as previously described (7). Total-body lipolysis was estimated from the rate of appearance of endogenous glycerol (6). Leucine turnover was calculated with the reciprocal pool model from the plasma rate of appearance of KIC (6, 13). Leucine turnover was extrapolated to whole-body proteolysis with the assumption that 1 g protein contains 590 µmol leucine (14). Protein synthesis was calculated as the difference between whole-body proteolysis and protein oxidation (6, 7). Fasting hepatic glucose production was calculated from the rate of appearance of [6,6-2H2]glucose (9). A steady-state plateau of isotopic enrichment was achieved for KIC, glycerol, and glucose in the participants before the start and during the last 30 min of the hyperinsulinemic-euglycemic clamp.

The rate of insulin-stimulated glucose disposal (Rd) was calculated during the last 30 min of the 40 mU/m2·min hyperinsulinemic-euglycemic clamp. Under steady-state conditions of euglycemia, the rate of exogenous glucose infusion is equal to the rate of insulin-stimulated glucose disposal. Insulin infusion at this dose (40 mU/m2·min) inhibits hepatic glucose production in prepubertal and pubertal children (4). Glucose disposal was expressed in milligrams per kilogram per minute. Basal and insulin-stimulated carbohydrate oxidation rates and lipid oxidation rate were calculated according to the formulas of Frayn (15) from the indirect calorimetry data by averaging the data for 30 min before the beginning of the insulin infusion and for the last 30 min of the insulin infusion. Nonoxidative glucose disposal was estimated by subtracting the rate of glucose oxidation from the total body insulin-stimulated glucose disposal during the last 30 min of the clamp period. Peripheral insulin sensitivity was calculated as insulin-stimulated glucose disposal at the end of the clamp divided by the steady-state plasma insulin concentration (6, 7, 11). Hepatic insulin sensitivity was calculated as the inverse of the product of hepatic glucose production (HGP) and the fasting plasma insulin (1000/HGP x fasting insulin) as described previously (16, 17).

Statistical analysis

Statistical analyses were performed using paired two-tailed Student’s t test to assess within-subject changes, before vs. after GH supplementation. Pearson or Spearman correlation analysis was used, where appropriate, to examine bivariate relationships. Data are presented as means ± SEM unless otherwise indicated. A P value of ≤0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Body composition (Table 1Go)

After 4 months of GH supplementation, both IGF-I and IGFBP-3 increased, indicating that participants were compliant with therapy. Pubertal stages of the participants did not change during the study. Both height and weight increased significantly in response to treatment. In all participants, fat-free mass increased, and fat mass, percent body fat, and leptin level decreased.

Glucose metabolism and insulin sensitivity (Figs. 1Go and 2Go)

Fasting hepatic glucose production and fasting insulin levels increased, and hepatic insulin sensitivity and fasting glucose to insulin ratio decreased after 4 months of GH supplementation (Fig. 1Go). Fasting glucose levels were not different before [95.9 ± 1.0 mg/dl (5.3 ± 0.06 mmol/liter)] vs. after [97.2 ± 1.5 mg/dl (5.4 ± 0.06 mmol/liter), P = 0.15] GH supplementation. During the hyperinsulinemic-euglycemic clamp, steady-state insulin and glucose levels were not different before and after GH [steady-state insulin, 95.2 ± 6.6 vs. 93.2 ± 2.3 µU/ml (571.2 ± 39.6 vs. 559.2 ± 13.8 pmol/liter); glucose, 102.8 ± 0.7 vs. 102.2 ± 0.5 mg/dl (5.7 ± 0.04 vs. 5.7 ± 0.3 mmol/liter)]. Insulin-stimulated total glucose disposal, glucose oxidation, and nonoxidative glucose disposal did not change significantly after GH supplementation (Fig. 2Go). Similarly, in vivo peripheral insulin sensitivity did not change significantly (Fig. 2Go). The subject with the lowest IGF-I level was an outlier for baseline hepatic and peripheral insulin sensitivity. Calculations performed with and without the outlier yielded similar results.


Figure 1
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  		FIG. 1. Fasting glucose metabolism and hepatic insulin sensitivity before (gray bars, n = 8) and after 4 months of GH supplementation (black bars).

 

Figure 2
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  		FIG. 2. Insulin-stimulated glucose metabolism (top) and peripheral insulin sensitivity (bottom, horizontal bars indicate the mean) before and after GH supplementation (n = 8).

 
Plasma lipid concentrations and substrate levels (Table 2Go)

After 4 months of GH supplementation, fasting plasma cholesterol, LDL, and LDL/HDL ratio were significantly lower. Very-low-density lipoprotein was higher. There was a trend toward higher triglyceride levels with no difference in free fatty acid levels.


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  		TABLE 2. Fasting lipid profile before and after 4 months of GH (0.3 mg/kg·wk) supplementation

 
Protein metabolism (Table 3Go)

After 4 months of GH supplementation, the endogenous Ra for leucine, reflecting proteolysis, was not significantly different while fasting or during the clamp. Expressed in grams per kilogram fat-free mass per hour, protein breakdown, protein oxidation (pre-GH, 0.06 ± 0.01; post-GH, 0.09 ± 0.02), and protein synthesis (pre-GH, 0.33 ± 0.04; post-GH, 0.28 ± 0.03) were not significantly different.


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  		TABLE 3. Leucine Ra (proteolysis) and glycerol Ra (lipolysis) expressed for whole body, per kilogram body weight, per kilogram fat-free mass, and per kilogram fat mass before and after 4 months of GH (0.3 mg/kg·wk) supplementation

 
Fat metabolism (Table 3Go)

After 4 months of GH supplementation, there was no significant change in fasting fat oxidation (pre-GH, 3.36 ± 0.52; post-GH, 2.48 ± 0.41 µmol/kg·min, P = 0.5). There was no significant change in glycerol rate of appearance, reflecting lipolysis, when rates were expressed as total, per kilogram, or per kilogram fat-free mass. When the data were expressed per fat mass, there was a doubling in total-body lipolysis after GH (7.1 ± 1.6 vs. 13.9 ± 5.1 µmol/kg fat mass·min, P = 0.12, two-tailed; P = 0.06, one-tailed). During the clamp, rates of lipolysis and fat oxidation were not different after GH (data not shown).

Correlations (Fig. 3Go)

Throughout the study, IGF-I levels were positively correlated with fasting insulin levels and negatively correlated with glucose to insulin ratio (Fig. 3Go). Correlations of measures of insulin sensitivity with IGF-I values were calculated with and without the outlier (reported with the outlier in Fig. 3Go). The correlations were similar, except for the correlation of peripheral insulin sensitivity with IGF-I levels, which increased when calculated without the outlier (pre-GH, r = –0.79 and P = 0.04; post-GH, r = –0.54 and P = 0.22; pre and post combined, r = –0.61 and P = 0.02).


Figure 3
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  		FIG. 3. Correlation of plasma IGF-I levels with fasting insulin levels, glucose/insulin ratio, hepatic insulin sensitivity, and peripheral insulin sensitivity.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Whether or not pubertal insulin resistance is mediated by sex steroids, GH/IGF-I, or both is incompletely understood. Our previous investigations support the hypothesis that physiological insulin resistance of puberty may be mediated by the actions of GH (5, 6, 7, 18). The objective of the present study was to longitudinally assess the effects of 4 months of GH (0.3 mg/kg·wk) supplementation in adolescent males with ISS on body composition; protein, fat, and glucose metabolism; and insulin sensitivity. We investigated GH supplementation in children with ISS rather than GH-deficient children in an effort to simulate the pubertal increase in GH secretion. Results of this study indicate that 4 months of GH supplementation in adolescent boys with ISS was associated with 1) increase in hepatic glucose production and fasting insulin level, 2) hepatic insulin resistance, 3) increase in lean body mass and decrease in fat mass and leptin levels, and 4) improvement in cardiovascular lipid risk profile. Plasma IGF-I levels correlated positively with insulin levels.

In addition to GH and sex steroids, insulin is an anabolic hormone that significantly increases during puberty due to physiological insulin resistance (1, 5, 18, 19). Cross-sectional studies have shown that pubertal insulin resistance is present during all stages of puberty and subsides after full sexual development has been attained (1, 4). Results of previous studies support the concept that the GH/IGF-I axis is an important contributor to pubertal insulin resistance (5, 6, 7, 20, 21). It has been shown that GH-deficient children on exogenous GH therapy exhibit GH-induced changes in insulin-mediated glucose metabolism similar to those observed among pubertal children (22). In our previous longitudinal study of insulin action in healthy children transitioning from prepuberty to puberty, peripheral insulin sensitivity decreased by about 50%, with IGF-I levels explaining 34% of the variance in insulin sensitivity (18). Conversely, there was not a significant relationship between levels of sex steroids and insulin sensitivity (18). In the present study, IGF-I levels were positively correlated with fasting insulin levels and negatively correlated with fasting glucose to insulin ratio, whereas testosterone levels remained unchanged during the pre- and post-GH periods.

A cross-sectional study of prepubertal and pubertal children performed by Amiel et al. (4) demonstrated that peripheral insulin sensitivity decreased during puberty, whereas hepatic insulin sensitivity was not different in prepubertal and pubertal participants. This is consistent with our previous longitudinal data in healthy children, which demonstrate a decline in peripheral insulin sensitivity and preservation of hepatic insulin sensitivity during puberty (18). In the present study, hepatic insulin sensitivity decreased after GH supplementation, whereas peripheral insulin sensitivity remained unchanged. The increase in hepatic glucose production during GH supplementation did not result in a significant increase in fasting blood glucose concentration, likely because insulin levels were significantly higher.

In adults, acute iv administration of GH has been shown to promote insulin resistance due to decreases in hepatic and extrahepatic effects of insulin (23). There are few studies in pediatrics to evaluate in vivo insulin sensitivity before and after GH supplementation, and the majority are in patients with GH deficiency or chronic disease. In the present study, six of eight participants had entered puberty before the onset of GH supplementation. Therefore, some degree of pubertal insulin resistance may have been present at baseline. An important limitation of the study is the small sample size, which limited the power to confirm that there was not a significant change in peripheral insulin sensitivity. Longitudinal metabolic studies such as this are not easy to perform for a variety of reasons; thus, pediatric clinical studies such as this are few. Additionally, the body composition changes that occurred during the course of this study (decreased adiposity/increased lean body mass) were so robust that this may have tempered the expected decrease in insulin sensitivity with GH treatment.

The effect of administration of sex steroids (testosterone/dihydrotestosterone) on pubertal insulin resistance in adolescent males has been previously investigated in our laboratory (6, 7). Neither 4 months of testosterone treatment (50 mg im every 2 wk) nor 4 months of dihydrotestosterone treatment (50 mg im every 2 wk) in adolescent males with delayed puberty was associated with deterioration in insulin sensitivity (6, 7). In the testosterone study, GH/IGF-I levels doubled during the course of the treatment; thus, any separate effects that testosterone might have had on insulin action could not be determined with certainty (6). However, in the dihydrotestosterone study, GH/IGF-I levels did not change during the course of the treatment, indicating that treatment with dihydrotestosterone does not promote insulin resistance in adolescent boys with delayed puberty (7). Moreover, testosterone replacement in hypogonadal adult men has been demonstrated to improve insulin sensitivity (24). In combination, results of the present study and previous investigations support the hypothesis that physiological insulin resistance of puberty is mediated by the actions of GH rather than sex steroids.

GH administration is known to have anabolic effects on protein metabolism (25, 26). Previously, we have shown that pubertal children have lower rates of total-body proteolysis and protein oxidation, in comparison with prepubertal children, allowing for net protein accretion (10). In the present study, there was no change in total-body protein breakdown, oxidation, or synthesis in response to 4 months of GH supplementation. Taking into account the higher fasting insulin levels post-GH, the suppression in total-body proteolysis per unit of insulin was lower, which could be indicative of insulin resistance in suppressing proteolysis. Despite no change in total-body protein synthesis, significant increases in lean body mass were observed, indicative of protein accretion. In a state of dynamic and rapid change in body composition, small changes in protein turnover may be difficult to assess. We speculate that increased protein accretion was hallmarked by the high protein turnover state that was maintained during GH supplementation.

There is sufficient evidence to support that short-term treatment with GH promotes nitrogen retention and increases measures of whole-body protein synthesis (26, 27, 28, 29). These studies were performed largely in individuals with GH deficiency or catabolic disease states. The effects of GH supplementation on protein metabolism in a relatively healthy group of non-GH-deficient adolescents may be attenuated in comparison with studies in subjects with GH deficiency. Moreover, the acute protein-anabolic effects of GH may not be sustained with prolonged therapy, and the balance between protein synthesis and protein breakdown may have returned to a near normal steady state by the end of 4 months of GH supplementation (30). We did not measure protein turnover or splanchnic uptake of amino acids during the fed state. Increased protein accretion in conjunction with meals is likely to lead to increased protein synthesis.

In GH-deficient children, treatment with GH is known to have positive effects on body composition, promoting accretion of lean body mass and reduction of fat mass (31, 32, 33, 34). In the present study, children with ISS demonstrated significant increases in lean body mass and reduction in total body fat in response to short-term GH supplementation. Although there was not a significant change in lipolysis per kilogram body weight pre- and post-GH supplementation, GH supplementation was associated with a doubling in lipolysis per kilogram fat mass. This is consistent with what has been shown in in vitro studies of adipose tissue from children with ISS before and after 3 months of GH supplementation (35), where GH supplementation was associated with a significant reduction in abdominal adipocyte volume and a significant increase in the responsiveness of adipose tissue to the lipogenic actions of insulin (35, 36). In our previous study of dihydrotestosterone treatment in adolescents with delayed puberty, rates of lipolysis were not affected by 4 months of dihydrotestosterone (50 mg im every 2 wk) (7). Additional study is required to expand our knowledge of the integration of hormonal and metabolic processes that take place during normal pubertal growth.

In the present study, 4 months of GH supplementation was associated with significant improvement in cardiovascular disease risk profile with decreases in total and LDL cholesterol levels and LDL/HDL ratio. This improvement in cardiovascular disease risk is consistent with what has been reported previously in the adult literature (37, 38, 39). Adults with GH deficiency have increased body fat, dyslipidemia with high total and LDL cholesterol and low HDL cholesterol levels, and increased mortality from cardiovascular disease (37, 38, 40, 41). Among children with GH deficiency, treatment with GH has also been reported to have positive effects on total cholesterol to HDL ratio (32, 34, 42, 43).

In conclusion, the present study demonstrates that 4 months of GH supplementation in adolescent males with ISS is associated with significant body composition changes and hepatic insulin resistance. Based on these results and results of our past studies of the metabolic effects of testosterone/dihydrotestosterone treatment in adolescent males with delayed puberty (6, 7), we conclude that during male puberty, insulin resistance/hyperinsulinemia is likely attributable to increased GH/IGF-I and not sex steroids. Longer periods of GH supplementation are needed to assess the long-term outcomes on peripheral insulin sensitivity when the dramatic changes in body composition decline. Potential gender-related differences should be investigated as well.


   Acknowledgments
 
These studies would not have been possible without the nurses and staff of the General Clinical Research Center and commitment of the study volunteers and their parents.


   Footnotes
 
This work was supported by U.S. Public Health Service Grants R01 HD27503, K24-HD01357, K23 RR17250, and M01-RR00084 from the National Center for Research Resources through the General Clinical Research Center at the Children’s Hospital of Pittsburgh, the Genentech Foundation for Research, and the Renziehausen Fund.

Disclosure Statement: The authors have nothing to disclose.

First Published Online May 22, 2007

Abbreviations: HDL, High-density lipoprotein; IGFBP-3, IGF-binding protein 3; ISS, idiopathic short stature; KIC, ketoisocaproate; LDL, low-density lipoprotein.

Received February 9, 2007.

Accepted May 14, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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S. Surya, J. F. Horowitz, N. Goldenberg, A. Sakharova, M. Harber, A. S. Cornford, K. Symons, and A. L. Barkan
The Pattern of Growth Hormone Delivery to Peripheral Tissues Determines Insulin-Like Growth Factor-1 and Lipolytic Responses in Obese Subjects
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