| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
From the Clinical Research Centers |
Division of Endocrinology, Department of Pediatrics, The Children’s Hospital (S.H.T.), Division of Biostatistics (B.W.J.), and The Center for Human Nutrition and Division of Endocrinology, Metabolism and Diabetes, Department of Medicine (R.H.E.), University of Colorado Health Sciences Center, Denver, Colorado 80262; and Division of Endocrinology, Department of Pediatrics (J.I.L., S.E.G., R.G.R.), Oregon Health Sciences University, Portland, Oregon, 97201
Address all correspondence and requests for reprints to: Sharon H. Travers, Division of Endocrinology, B-265, The Children’s Hospital, 1056 E. 19th Avenue, Denver, Colorado 80218.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
It has been demonstrated that conditions accompanied by insulin resistance, including obesity, polycystic ovary syndrome, and non-insulin-dependent diabetes mellitus, are associated with decreased IGFBP-I levels (11, 12). In children, serum IGFBP-I levels have been found to correlate inversely with pubertal stage (13), a relationship previously explained by the increasing insulin levels that accompany puberty (14). Insulin levels are high during puberty in response to the physiological decrease in insulin sensitivity that occurs during this time (15, 16). Consequently, puberty provides a model for comparing the relationship of IGFBP-I to both insulin levels and measures of insulin sensitivity. In this study, we examined these relationships in a large group of pubertal boys and girls. In addition, we analyzed the impact of other variables, such as gender, body fatness, and IGF-I levels on IGFBP-I concentrations.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The study population consisted of 104 healthy, nondiabetic
children, ranging in age from 9.8–14.6 yr. These subjects are
described in a previous study examining insulin sensitivity during
puberty (16). Pubertal development was assessed by the criteria of
Marshall and Tanner according to pubic hair and breast or genital
development (17). The characteristics of the subjects are shown in
Table 1
. Forty-nine of the boys were
Caucasian, two African-American, and two Hispanic. Forty-nine of the
girls were Caucasian, one African-American, and one Hispanic. The study
protocol was approved by the Colorado Multiple Institutional Review
Board, and informed consent was obtained from the participating
subjects and their parents.
|
Insulin sensitivity index (Si) was calculated from a frequently sampled iv glucose tolerance test using Bergman’s modified minimal model (18, 19). All subjects were admitted to the Pediatric General Clinical Research Center at The Children’s Hospital in Denver after a 10-h overnight fast. An iv catheter was inserted into each arm. After 30 min, baseline blood samples, including measurements of IGFBP-I and insulin levels, were drawn. At zero time, 25% dextrose (0.3 g/kg) was infused over 60 sec. Twenty minutes after the dextrose infusion, a bolus of tolbutamide (300 mg/1.73 m2) was infused over 60 sec. Additional blood samples were drawn from the contralateral arm at 2, 4, 8, 19, 22, 25, 30, 35, 40, 50, 70, 90, and 180 min. Each sample was placed in a chilled heparinized tube for the measurement of glucose and insulin.
Anthropometric measurements
Height and weight were measured with subjects barefoot and wearing a hospital gown. Height was measured with a Harpendon stadiometer. Body mass index (BMI) was calculated (weight in kilograms divided by the square of the height in meters) (20).
Underwater weighing
Each subject underwent a hydrostatic determination of body density, which allows for the calculation of percentage of body fat. This procedure was described previously (16). Percent body fat was estimated from body density using a modified Siri equation as described by Lohman (21). This modified equation takes into account gender and age differences in the density of fat free mass.
Assays
Immediately after collection, plasma glucose measurements were
made by the glucose oxidase method (model 2300 STAT Glucose Analyzer,
Yellow Springs Instrument Co., Yellow Springs, OH). Insulin was
determined by a double antibody RIA technique (22). The intra- and
interassay coefficients of variation for insulin were between
5.8–6.4% and 5.4–5.8%, respectively. IGFBP-I levels were assessed
by a coated tube immunoradiometric assay provided by Diagnostic Systems
Laboratory (Webster, TX). Serum was appropriately diluted to measure
within the linear range of the assay, which is between 0.15–20 ng/mL.
Thirteen of the 104 subjects had IGFBP-I values lower than the
sensitivity of the assay of 0.15. For statistical analysis, these
values were considered to be 0.075. Intra- and interassay variation was
5%. Serum IGF-I levels were also measured by a double antibody RIA
technique (125I RIA Kit, INCSTAR Corp., Stillwater, MN),
with intra- and interassay coefficients of variation of 9.6% and
7.7%, respectively. Serum estradiol and testosterone concentrations
were also determined using RIA kits (Coat-A-Count Estradiol and
Coat-A-Count Total Testosterone, Diagnostic Products Corp., Los
Angeles, CA). The sensitivity of the assay for estradiol was 29 pmol/L
and for testosterone 0.21 nmol/L.
Calculations
All Si determinations were calculated from glucose and insulin data from the frequently sampled iv glucose tolerance test by the Bergman modified minimal model program (18). In this method, mathematical models of glucose and insulin kinetics are implemented on the computer and are used to analyze the plasma glucose and insulin dynamics following iv glucose and tolbutamide injection.
Statistical analysis
All statistical analyses were performed using the Statistical Analysis Software (SAS) system (Cary, NC). All correlations reported are Pearson’s linear correlation coefficients. Paired t tests were used to assess reliability. A one-way ANOVA was used to compare the mean levels of various body fat measurements and IGFBP-I levels. In evaluating the combined effects of gender and Tanner stage on IGFBP-I levels and insulin sensitivity, a two-factor ANOVA was used. A stepwise multiple regression analysis was used to investigate independent predictors of IGFBP-I.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
In all subjects, IGFBP-I levels ranged from <0.15 to 52.5 ng/mL
with a mean value of 9.9 ± 1.0. The mean IGFBP-I level in boys
(12.6 ± 1.6) was significantly higher than that in girls
(7.0 ± 1.2; P < 0.01). When Tanner stage was
taken into consideration, IGFBP-I levels were significantly higher in
Tanner stage 2 children (11.7 ± 1.6) than in Tanner stage 3
children (7.6 ± 1.1; P < 0.08). IGFBP-I levels
of Tanner stage 3 girls (4.6 ± 1.3) were significantly lower than
those of both Tanner stage 2 boys (13.5 ± 2.5; P
< 0.002) and Tanner stage 3 boys (11.3 ± 1.7; P
< 0.03), but not significantly different than Tanner stage 2 girls
(9.5 ± 1.9) (Table 2).
|
The mean fasting insulin level in boys (65.1 pmol/L ± 7.1)
was not significantly different than the mean fasting insulin level in
girls (68.9 ± 4.3). Additionally, there were no differences in
fasting insulin levels between Tanner stages (Table 2
). There were,
however, significant differences in insulin sensitivities. The mean Si
in boys (1.28 ± 0.09 x 10-4
min-1/pmol/L) was higher than that in girls (1.00 ±
0.07, P < 0.01). When Tanner stage was taken into
consideration, Si was significantly lower in Tanner stage 3 girls
(0.83 ± 0.09) compared with that of Tanner stage 2 girls
(1.16 ± 0.09, P < 0.05), Tanner stage 2 boys
(1.26 ± 0.13, P < 0.005), and Tanner stage 3
boys (1.32 ± 0.12, P < 0.005) (Table 2). The
Si’s of the latter three groups were not significantly different from
each other.
IGF-I measurements
The mean IGF-I level in girls (33.8 ± 1.2 nmol/L) was
significantly higher than that in boys (29 ± 1.1 nmol/L,
P < 0.005). IGF-I levels were also higher in Tanner 3
children (36.8 ± 1.1) than in Tanner 2 children (26.8 ±
.85, P < 0.0001). Tanner stage 3 girls had higher
IGF-I levels (39.3 ± 1.4 nmol/L) than Tanner stage 2 girls
(28.1 ± 1.1 nmol/L, P < 0.0001), Tanner stage 2
boys (25.8 ± 1.2 nmol/L, P < 0.0001), and Tanner
stage 3 boys (33.7 ± 1.5 nmol/L, P < 0.006).
Additionally, Tanner stage 3 boys had higher IGF-I levels than Tanner
stage 2 boys and girls (P < 0.01) (Table 2).
Body fatness measurements
Table 3 shows the mean BMI, percent
body fat, and total fat mass for the subjects divided according to
gender and Tanner stage. When looking at Tanner stages combined, there
were no gender differences between any of these variables. However,
Tanner stage 2 girls had a significantly lower BMI and fat mass than
Tanner 2 boys and Tanner 3 girls (P < 0.05). Tanner
stage 3 boys had a lower BMI, percent body fat, and fat mass than
Tanner stage 2 boys (P < 0.05). Tanner stage 3 boys
also had a lower percent body fat than Tanner 3 girls
(P < 0.05) (Table 3).
|
There was a strong positive correlation between IGFBP-I levels and
Si (r = 0.65, P < 0.0001) (Fig. 1), whereas the correlation between
IGFBP-I and fasting insulin levels was lower (r = -0.38,
P < 0.0001). An inverse relationship was also found
between IGFBP-I levels and all measures of body fatness (BMI, r =
-0.46, P < 0.0001; fat mass, r = -0.44,
P < 0.0001; percent body fat, r = -0.41,
P < 0.0002) (Fig. 2). In
girls, IGFBP-I levels were also inversely correlated to IGF-I levels
(r = -0.41, P < 0.003) (Fig. 3). IGFBP-I levels were not related to
either testosterone or estrogen levels. A stepwise multiple regression
analysis was constructed considering the variables gender, Tanner
stage, insulin sensitivity, body fatness, levels of IGF-I, fasting
insulin, and sex steroids. Two-way interactions of these variables were
also analyzed. When all subjects were considered, IGFBP-I levels were
best predicted by insulin sensitivity (P < 0.0001) and
IGF-I levels (P < 0.015) (for the overall model,
r2 = 0.45, P < 0.0001).
|
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Although insulin directly inhibits IGFBP-I production, IGFBP-I levels are suppressed in insulin-resistant subjects. This suggests that resistance to insulin-mediated glucose disposal is accompanied by the preservation of hepatic insulin sensitivity in regards to IGFBP-I production. Given that insulin itself directly inhibits IGFBP-I, it is interesting that IGFBP-I levels are more strongly related to measures of insulin sensitivity than to insulin levels themselves. This may be secondary to the rapid oscillatory nature of insulin secretion, and C-peptide levels may have a stronger correlation to IGFBP-I levels (25). Additionally, it may be that portal insulin concentration is the primary regulator of IGFBP-I production (25). Peripheral insulin reflects but does not necessarily predict portal insulin concentrations. Consequently, the strong relationship found between IGFBP-I and insulin sensitivity probably reflects the insulin dependence of both variables.
IGFBP-I is thought to decrease the action of IGF-I by inhibiting its binding to cell membranes (10). Although most studies suggest that IGFBP-I’s primary role is to regulate the metabolic actions of free IGF-I, there is evidence that it may also regulate the mitogenic effects of IGF-I. Cox et al. (26) demonstrated that coadministration of recombinant human IGFBP-I (rhIGFBP-I) with rhIGF-I to hypophysectomized rats resulted in inhibition of the growth-promoting effects of rhIGF-I. Additionally, IGFBP-I has been postulated to play a role in the linear growth retardation seen in children with chronic renal failure. In these children, IGFBP-I levels and serum IGF-binding activity have been shown to be elevated in comparison with controls (27). Consequently, it is interesting to speculate, as others have, that there is a relationship between IGFBP-I levels and growth in obese children. It is well known that obese children have accelerated growth rates and high serum IGF-I concentrations despite diminished GH secretion; however, the mechanisms underlying these altered relationships remain unclear (28). It is possible that insulin-mediated suppression of IGFBP-I in obese children may increase free IGF-I levels and thus contribute to the enhanced growth observed. The same mechanism may operate in pubertal children, where insulin resistance and growth occur simultaneously.
Gender differences in IGFBP-I levels were demonstrated, with boys having significantly higher levels than girls. Other studies of children, to our knowledge, have not shown these gender differences. Holly et al. (14) measured IGFBP-I levels during fasting in prepubertal and pubertal children and only found a tendency for prepubertal boys to have higher peak IGFBP-I levels than prepubertal girls. In a larger study, Juul et al. (29) measured IGFBP-I levels in 907 children and found no gender differences. Adult studies have shown that women have higher IGFBP-I levels than men (30). The mechanism underlying these gender differences found in adults have not been elucidated; however, it has been suggested that estrogen may increase IGFBP-I concentrations (31, 32). In our study, boys had higher levels of IGFBP-I, and this may be explained by the observation that boys had higher insulin sensitivities than girls. Gender differences in IGF-I levels could also contribute to the observed differences in IGFBP-I. Boys had lower IGF-I levels than girls, and IGFBP-I levels in girls were found to be inversely correlated to IGF-I. Because we studied children in early puberty, possible estrogen effects would not necessarily be manifested, because levels in girls have not reached adult values.
In the present study, IGFBP-I levels were also found to have a strong univariate inverse correlation with body fatness. This is most likely explained by the effect of body fatness on insulin sensitivity. In a previous study, we showed that insulin sensitivity in early pubertal children was most strongly related to body fatness (16). Additionally, the univariate relationship between IGFBP-I and body fatness in the present study does not persist when subjected to a multiple model that includes insulin sensitivity. This suggests that body fatness is not independently associated with IGFBP-I.
In conclusion, IGFBP-I levels in pubertal children show gender differences opposite those observed in adults. Boys had significantly higher IGFBP-I levels than girls, and this seems to be secondary to gender differences in insulin sensitivity. Additionally, insulin, IGF-I and body fatness are inversely related to IGFBP-I levels. The strongest relationship, however, was between insulin sensitivity and IGFBP-I. This suggests that the insulin resistance occurring during puberty, especially in obese children, does not extend to resistance of IGFBP-I suppression. It is interesting to speculate that insulin-mediated suppression of IGFBP-I levels may increase free IGF-I, and thus enhance its mitogenic actions. This, consequently, could contribute to the enhanced growth observed in obese as well as pubertal children.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received August 5, 1997.
Accepted February 17, 1998.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
ez L, Potau N, Zampolli M, Riqué
S, Saenger P, Carrascosa A. 1997 Hyperinsulinemia and decreased
insulin-like growth factor-binding protein-1 are common features in
prepubertal and pubertal girls with a history of premature pubarche. J Clin Endocrinol Metab. 82:2283–2288.This article has been cited by other articles:
 |
|
 |
|
  A. L. Carrel, R. R. Clark, S. Peterson, J. Eickhoff, and D. B. Allen School-Based Fitness Changes Are Lost During the Summer Vacation Arch Pediatr Adolesc Med, June 1, 2007; 161(6): 561 - 564. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Shimizu, B. R Beckman, A. Hara, and W. W Dickhoff Measurement of circulating salmon IGF binding protein-1: assay development, response to feeding ration and temperature, and relation to growth parameters J. Endocrinol., January 1, 2006; 188(1): 101 - 110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Carrel, R. R. Clark, S. E. Peterson, B. A. Nemeth, J. Sullivan, and D. B. Allen Improvement of Fitness, Body Composition, and Insulin Sensitivity in Overweight Children in a School-Based Exercise Program: A Randomized, Controlled Study Arch Pediatr Adolesc Med, October 1, 2005; 159(10): 963 - 968. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. F. Liew, S. D. Wise, K. P. Yeo, and K. O. Lee Insulin-Like Growth Factor Binding Protein-1 Is Independently Affected by Ethnicity, Insulin Sensitivity, and Leptin in Healthy, Glucose-Tolerant Young Men J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1483 - 1488. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, A. D. Rogol, J. C. Lovejoy, M. Sheffield-Moore, N. Mauras, and C. Y. Bowers Endocrine Control of Body Composition in Infancy, Childhood, and Puberty Endocr. Rev., February 1, 2005; 26(1): 114 - 146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Wolk, S. C. Larsson, B. Vessby, A. Wolk, and K. Brismar Metabolic, Anthropometric, and Nutritional Factors as Predictors of Circulating Insulin-Like Growth Factor Binding Protein-1 Levels in Middle-Aged and Elderly Men J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1879 - 1884. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.-L. Tsou, Y.-D. Jiang, C.-C. Chang, J.-N. Wei, F.-C. Sung, C.-C. Lin, C.-C. Chiang, T.-Y. Tai, and L.-M. Chuang Sex-Related Differences Between Adiponectin and Insulin Resistance in Schoolchildren Diabetes Care, February 1, 2004; 27(2): 308 - 313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Denburg, M. E. Silfen, A. M. Manibo, D. Chin, L. S. Levine, M. Ferin, D. J. McMahon, C. Go, and S. E. Oberfield Insulin Sensitivity and the Insulin-Like Growth Factor System in Prepubertal Boys with Premature Adrenarche J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5604 - 5609. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Moran, D. R. Jacobs Jr., J. Steinberger, P. Cohen, C.-P. Hong, R. Prineas, and A. R. Sinaiko Association between the Insulin Resistance of Puberty and the Insulin-Like Growth Factor-I/Growth Hormone Axis J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4817 - 4820. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. K. Hansen, J. O. L. Jorgensen, and J. S. Christiansen Body Composition and Circulating Levels of Insulin, Insulin-Like Growth Factor-Binding Protein-1 and Growth Hormone (GH)-Binding Protein Affect the Pharmacokinetics of GH in Adults Independently of Age J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2185 - 2193. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E Charmandari, C G D Brook, and P C Hindmarsh Why is management of patients with classical congenital adrenal hyperplasia more difficult at puberty? Arch. Dis. Child., April 1, 2002; 86(4): 266 - 269. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Silfen, A. M. Manibo, M. Ferin, D. J. McMahon, L. S. Levine, and S. E. Oberfield Elevated Free IGF-I Levels in Prepubertal Hispanic Girls with Premature Adrenarche: Relationship with Hyperandrogenism and Insulin Sensitivity J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 398 - 403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Charmandari, P. C. Hindmarsh, A. Johnston, and C. G. D. Brook Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency: Alterations in Cortisol Pharmacokinetics at Puberty J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2701 - 2708. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Poretsky, N. A. Cataldo, Z. Rosenwaks, and L. C. Giudice The Insulin-Related Ovarian Regulatory System in Health and Disease Endocr. Rev., August 1, 1999; 20(4): 535 - 582. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. E. Schoen, C. M. Tangen, L. H. Kuller, G. L. Burke, M. Cushman, R. P. Tracy, A. Dobs, and P. J. Savage Increased Blood Glucose and Insulin, Body Size, and Incident Colorectal Cancer J Natl Cancer Inst, July 7, 1999; 91(13): 1147 - 1154. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
