Vol. 80, No.

1
Journal of Chnical Endocrinology and Metabolism Prrntrd rn U.S.A.
Copyright 0 1995 by The Endocrine Society

Gender and Tanner Stage Differences in Body

Composition and Insulin Sensitivity in Early Pubertal
Children*
SHARON H. TRAVERS, BARRETT W. JEFFERS, CLIFFORD A. BLOCH,
JAMES 0. HILL, AND ROBERT H. ECKEL
Divisions of Endocrinology and Biostatistics, Department of Pediatrics, The Children’s Hospital,
University of Colorado Health Sciences Center, Denver, Colorado 80218; and The Center for Human
Nutrition and Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine,
University of Colorado Health Sciences Center, Denver, Colorado 80262

ABSTRACT 0.006) in stage 3 girls compared to those in the other 3 groups. The
A cross-sectional analysis examining the impact of gender and best predictor of Si in all subjects was BMI (? = -0.63; P < 0.0001).
early pubertal stage on insulin sensitivity (Si) and body composition In a stepwise multiple regression analysis, Si was best predicted from
was carried out as part of a longitudinal study to determine how Si BMI, gender, and Tanner stage. According to this model, Si decreased
relates to body composition changes during puberty. The study pop- as BMI increased and was lower in girls and Tanner stage 3 children.
ulation consisted of 97 healthy children (age range, 9.7-14.5 yr; 28 In boys, Si was best predicted from total fat mass and Tanner stage.
Tanner stage 2 boys, 25 stage 3 boys, 22 Tanner stage 2 girls, and 22 In airls. Si correlated inverselv with BMI. parental obesity, and in-
stage 3 girls). Si was determined by the modified minimal model of sulin-like growth factor-I leveis. Neither testosterone nor-estradiol
Bergman. Body fatness was assessed by body mass index (BMI), levels were associated with Si. These results demonstrate that Si, like
skinfold thickness, hydrodensitometry, and bioelectrical impedance. body composition, has gender-dependent changes during puberty. It
Results showed that stage 3 girls and stage 2 boys had significantly is, thus, possible that these pubertal changes in Si relate to changes
more body fat than stage 2 girls and stage 3 boys. Si was significantly in body composition. (J Clin Endocrinol Metab 80: 172-178, 1995)
lower (P < 0.02) and insulin-like growth factor-I levels higher (P <

I? UBERTY is an important period for the development

obesity, as the presence of obesity during this time has
a very high likelihood of persisting into adulthood
of

(l-3). It
It has been demonstrated in several studies that puberty
is associated with decreased insulin sensitivity
sessed by either the glucose clamp technique or the minimal
when as-

has been reported that up to 80% of obese adolescents will model method (9-12). None of these studies, however, had
become obese adults (3). Furthermore, the severity of obesity a sufficient number of subjects to fully evaluate gender and
in adults is greater in those who were obese as adolescents Tanner stage differences within early puberty. Additionally,
(4). there has been no study to our knowledge that has looked at
In all children, regardless of whether obesity develops, the relationship between Si and actual body fat content or
significant changes in body composition occur during pu- body fat distribution in children.
berty. Both boys and girls increase their total fat mass during As part of a longitudinal study to determine how insulin
puberty. In girls, the percentage of body fat increases sensitivity relates to body composition changes during pu-
throughout puberty, whereas in boys, the percentage of body berty, in a cross-sectional analysis we examined the impact
fat decreases (5). Furthermore, these changes in percent body of gender and early pubertal stage (Tanner stage 2 and 3) on
fat are evident even in the earliest stages of puberty. The insulin sensitivity and body composition. As there are gen-
cause of the gender-dependent changes in body composition der-dependent differences in body composition changes
is for the most part unknown. during puberty, we speculated that there may be differences
Recently, metabolic predictors of weight gain in adults in insulin sensitivity between genders that may predict these
have been elucidated. These include a high respiratory quo- changes.
tient and enhanced insulin sensitivity (6-8). In both of these
situations, a metabolic environment exists that favors
carbohydrate oxidation, antilipolysis, and fat storage. Subjects and Methods
Subjects
Received April 25, 1994. Revision received September 9, 1994. Ac-
cepted September 21, 1994. The study population consisted of 97 healthy nondiabetic children,
Address all correspondence and requests for reprints to: Sharon H. ranging in age from 9.7-14.5 yr. There were no first degree relatives with
Travers, M.D., Division of Endocrinology, B-265, The Children’s Hos- type I &sul&-dependent diabetes mellitus. Pubertal hevelopment was
pital, 1056 East 19th Avenue, Denver, Colorado 80218. assessed bvi the criteria of Marshall and Tanner accordinn to pubic hair
* This work was supported in part by Grant MOI-RR-00069 from the and breast or genital development (13). The characterist&of tLe subjects
General Clinical Research Centers Program, National Center for are shown in Table 1. There were 53 boys and 44 girls. Of the boys,
Research Resources, NIH. pubertal development was Tanner stage 2 in 28 and stage 3 in 25. Of the

172

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 INSULIN
Table 1. Characteristics of 97 subjects
Boys
Tanner 2 Tanner 3 Tanner
No. 28 25 22
Age (yr) 12.7 k 0.9 13.2 k 0.7 11.4 i- 0.9
Ht (cm) 154.4 i- 6.1 163 -t 6.6 147 + 7.2
Wt (kg) 53.4 + 15.2 53.2 2 9.2 40 k 7.9
Values are the mean + SIX
girls, pubertal development was Tanner stage 2 in 22 and stage 3 in 22.
Forty-three of the boys were Caucasian, 2 were African-American, and
2 were Hispanic. Forty-three of the girls were Caucasian, and 1 was
African-American. None of the subjects was taking any medications
known to influence glucose metabolism. None of the subjects was taking
part in a physical fitness training program. The study protocol was
approved by the Colorado Multiple Institutional Review Board, and
informed consent was obtained from the participating subjects and their
parents.
Frequently sampled iu glucose tolerance test
The insulin sensitivity index (Si) was calculated from a frequently
sampled iv glucose tolerance test using Bergman’s modified minimal
model (14, 15). All subjects were admitted to the Pediatric General
Clinical Research Center at the Children’s Hospital (Denver, CO) after
a 10-h overnight fast. An iv catheter was inserted into each arm. After
30 min, 0 min blood samples were drawn. At zero time, 25% dextrose
(0.3 g/kg) was infused over 60 s. Twenty minutes after the dextrose
infusion, a bolus of tolbutamide (300 mg/1.73 m2) was infused over 60
s. 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 wear-
ing a hospital gown. Height was measured with a Harpendon stadi-
ometer. Parental heights and weights were obtained by direct measure-
ments in 88 individuals and by report in 76 individuals. Body mass index
(BMI) was calculated (weight in kilograms divided by the square of the
height in meters) (16). The percentage of ideal body weight (IBW) was
calculated in the children according to the height and weight standards
from the National Center for Health Statistics percentiles (17). This
provides for an evaluation of weight in relation to age, gender, and
height. For the parents, height and weight standards were taken from
the 1983 Metropolitan Life Insurance Company tables (18). Parental
obesity was defined as 120% or more over IBW.
Waist, umbilicus, and hip circumferences were measured in triplicate
by the same person to the nearest 1.0 mm. The waist measurement was
made with a cloth tape at the level of the greatest lateral indentation. The
hip circumference was defined at the level of the greater trochanter and
symphysis pubis.
Skinfold thickness measurements were made in triplicate on the
nondominant side of the body. Measurements were made to the nearest
0.1 mm with Lange skinfold calipers (Cambridge Scientific Industries,
Cambridge, MA) at the following sites: 1) triceps, halfway between the
acromion process and the olecranon process; and 2) subscapular, 20 mm
below the tip of the scapula, at an angle of 45” to the lateral side of the
body. The mean of the three measurements was used as the represen-
tative value for each site. The equations used for the prediction of percent
body fat were developed by Slaughter et nl. (19) and take into account
the effects of age and gender on body density.
Underwater weighing
Each subject underwent a hydrostatic determination of body density,
which allows for the calculation of percentage of body fat. Body weights
in air and underwater were measured to the nearest 25 g using Heath
platform and Chatillon spring scales (Kew Gardens, NY) respectively.
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SENSITIVITY IN PUBERTY 173
Residual lung volume was determined (simultaneously with underwa-
ter weighing) using a closed circuit, nitrogen dilution method. The
Girls nitrogen concentration during rebreathing was measured with a Med-
2 Tanner 3 Science 505-D Nitralizer (St. Louis, MO). The percent body fat was
estimated from body density using a modified Siri equation, as de-
22 scribed by Lehman (20). This modified equation takes into account
12.2 2 0.9 gender and age differences in the density of fat-free mass. Reproduc-
156 ? 7.2 ibility tests showed an average difference of 2-4% between measure-
54.2 i- 14.4 ments for the same subject.
Bioelectric impedance analysis (BIA)
Each subject also underwent BIA to estimate body composition. Re-
sistance and reactance were measured with the subject lying supine by
use of an impedance analyzer with two body surface electrodes and a
conduction current of less than 1 wamp and 50 kilohertz (model 410,
Biodynamics, Bellevue, WA). One surface electrode was placed on the
dorsal surface of the right hand, and one on the dorsal surface of the right
foot. The percent body fat and fat-free mass were calculated using the
prediction equations of Houtkooper cf nl. (21).
Assays
Immediately after collection, the heparinized blood samples were
centrifuged, and plasma glucose measurements were made by the glu-
cose oxidase method (model 2300 STAT Glucose Analyzer, Yellow
Springs Instrument Co., Yellow Springs, OH). Additional plasma was
stored at ~20 C until insulin assay. Insulin was determined by a double
antibody RIA technique (22). The intraassay coefficient of variation for
insulin was 5.8% at 287 pmol/L and 6.4% at 718 pmol/L. The interassay
coefficient of variation for insulin was 5.8% at 287 pmol/L and 5.4% at
718 pmol/L.
Serum insulin-like growth factor-I (IGF-I) levels were also measured
by a double antibody RIA technique ( i2sI RIA Kit, Incstar Corp., Still-
water, 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 Ange-
les, CA). The sensitivity of the assay for estradiol was 29 pmol/L, and
that for testosterone was 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 (14). 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 after
iv glucose and tolbutamide injections.
Statistical analysis
All statistical analyses were performed using the Statistical Analysis
Software (SAS) program (SAS Institute, Cary, NC). All correlations re-
ported are Pearson’s linear correlation coefficients. Paired t tests were
employed to assess the reliability of the three procedures used to mea-
sure percent body fat. A one-way analysis of variance with four groups
(Tanner stage 2 boys, Tanner stage 3 boys, Tanner stage 2 girls, and
Tanner stage 3 girls) was used to compare the mean levels of various
body fatness measurements and IGF-I levels, and to evaluate the com-
bined effect of gender and Tanner stage in relation to Si. An unpaired
t test was used to compare the mean Si values between boys and girls
and the mean testosterone levels (boys) and estradiol levels (girls) be-
tween Tanner stages 2 and 3. A stepwise multiple regression analysis
was performed to consider the relationship between Si and several
variables concurrently.
174 TRAVERS ET AL. JCE & M . 1995
Vol80 . No 1

Results (28.8 +- 1.1 nmol/L; P < O.OOOl), Tanner stage 2 boys

(25.2 t 1.3 nmol/L; P < O.OOOl), or Tanner stage 3
Body fatness measurements
boys (33.3 t- 1.3 nmol/L; P < 0.006). Additionally, Tanner
The correlations between the various techniques used to stage 2 girls had higher IGF-I levels than Tanner stage 2
assess body fatness are shown in Table 2. As shown, all boys (P < 0.05), and Tanner stage 3 boys had higher values
estimates of percent body fat, percent IBW, and BMI were than Tanner stage 2 boys (P < 0.0001).
highly correlated with one another. Testosterone levels in Tanner stage 3 boys (6.8 f 0.7
Table 3 shows the mean BMI, percent IBW, percent body nmol/L) were significantly higher than those in Tanner stage
fat, and total fat mass for the subjects divided according to 2 boys (2.3 +- 0.4 nmol/L; P < 0.0001). Likewise, estradiol
gender and Tanner stage. Underwater weighing estimated levels in Tanner stage 3 girls (110 i- 22 pmol/L) were sig-
significantly higher values of percent body fat than either nificantly higher than those in Tanner stage 2 girls (36.7 -+ 7.3
skinfold thickness or bioelectric impedance (P < 0.0001). pmol/L; P < 0.002).
Tanner stage 3 girls had significantly greater mean BMI,
percent IBW, percent body fat (by skinfold and BIA), and Prediction of insulin sensitivity
total fat mass than Tanner stage 2 girls (significant P values
for these and the following differences are shown in Table 3). The best predictor of insulin sensitivity in all subjects,
Tanner stage 3 girls also had greater mean percent IBW and using a univariate approach, was body fatness. All measures
percent body fat (by all techniques) than Tanner stage 3 boys. of body fatness were strongly inversely correlated with in-
For no measure of body fatness were Tanner stage 3 girls sulin sensitivity (Table 4) with BMI having the highest cor-
significantly different from Tanner stage 2 boys. Tanner stage relation when grouping boys and girls together (r = -0.63;
3 boys had significantly lower mean BMI, percent IBW, per- P < 0.0001; Fig. 2). When obese children (those with IBW
cent body fat (by all techniques), and total fat mass than >120%) were eliminated from this analysis, insulin sensi-
Tanner stage 2 boys and Tanner stage 3 girls (with the ex- tivity still had a strong negative correlation to BMI (r =
ception of BMI and fat mass). For no measure of body fatness -0.41; P < 0.0004). A stepwise multiple regression analysis
were Tanner stage 3 boys significantly different from Tanner was performed to consider the relationships between the
stage 2 girls. Tanner stage 2 boys had significantly greater following variables and insulin sensitivity: body fatness mea-
mean BMI, percent IBW, percent body fat (all techniques), surements, gender, Tanner stage, IGF-I, body fat distribution
and total fat mass than Tanner stage 3 boys and Tanner stage [waist to hip ratio (WHR) and umbilicus to hip ratio], and
2 girls (with the exception of BIA). Consequently, Tanner parental obesity (whether a subject had no, one, or two obese
stage 3 girls and Tanner stage 2 boys tended to be fatter than parents). Additionally, testosterone and estradiol levels were
Tanner stage 2 girls and Tanner stage 3 boys. considered when looking at boys and girls separately. Two-
way interactions of these variables were also analyzed. When
all subjects were considered, insulin sensitivity was best pre-
Si measurements
dicted from BMI (P < O.OOOl),gender (P < O.OOl),and Tanner
The mean Si in boys (1.28 + 0.08 X 1O-4 min/pmol.L) was stage (P < 0.03; for the overall model: r2 = 0.51; P < 0.0001).
higher than that in girls (1.03 2 0.07; P < 0.05). When Tanner According to this model, insulin sensitivity decreased as BMI
stage was taken into consideration, Si was significantly lower increased. Also according to this model, Si was higher in
in Tanner stage 3 girls (0.83 2 0.1) compared to that in Tanner Tanner stage 2 children and in boys. The impact of gender
stage 2 girls (1.23 2 0.1; P < 0.02), Tanner stage 2 boys (1.27 and Tanner stage on insulin sensitivity is illustrated in Fig.
+ 0.13; P < O.Ol), and Tanner stage 3 boys (1.3 2 0.12; P < 3. As shown, within Tanner stage 2 children, boys were more
0.007; Fig. 1). The Si values of the latter three groups were not insulin sensitive than girls for a given BMI (Fig. 3a; P < 0.04).
significantly different from each other. Within Tanner stage 3 children, although not statistically
significant, a trend was seen for boys to be more insulin
IGF-I, testosterone, and estradiol measurements sensitive (Fig. 3b). Body fat distribution, IGF-I levels, and
parental obesity did not add significantly to this model.
IGF-I levels were significantly higher in Tanner stage 3 When a stepwise multiple regression analysis was per-
girls (38.6 ? 1.4 nmol/L) than in Tanner stage 2 girls formed for boys only, insulin sensitivity was best predicted

Table 2. Correlations between measures of body fatness (n = 97)

% IBW 7c BF KJWY c/c BF (BIA)’ Fat ma&’

BF &)”
BMI 0.96 0.84 0.84 0.82 0.95
% IBW 0.84 0.83 0.79 0.89
% BF (UW) 0.87 0.85 0.91
% BF (SF) 0.85 0.84
% BF (BIA) 0.83
P < 0.0001 for all correlations.
a Percent body fat estimated from underwater weighing.
’ Percent body fat estimated from skinfolds.
’ Percent body fat estimated from bioelectric impedance.
’ Total fat mass estimated from underwater weighing.

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 INSULIN SENSITIVITY IN PUBERTY 175

Table 3. Body fatness in children by gender and Tanner stage Table 4. Correlations between body fatness and insulin
sensitivity
Boys Girls
Tanner 2 Tanner 3 Tanner 2 Tanner 3 r value
(n = 28) (n = 25) (n = 22) (n = 22) BMI -0.63
BMI 22.2 2 1.0 19.8 2 0.5” 18.2 + 0.6 22.0 + l.lb % IBW -0.61
% IBW 122 2 0.1 104 * 0.0” 103 * 0.0 117 + O.ld % BF (UW) -0.56
% BF NJWY 31.0 ? 1.9 24.3 ? 1.1’ 25.5 + 1.6 29.0 + 1.9 % BF (SF) -0.63
% BF (SF)’ 23.1 2 1.9 17.9 2 1.3” 19.8 + 1.0 24.0 + 1.28 % BF (BIA) -0.60
% BF (BIA)& 23.2 !I 1.7 17.6 ? l.Oa 18.1 ? 1.3 24.7 2 2.1b Fat Mass (kg) -0.61
Fat mass (kg)’ 17.8 2 1.8 13.2 2 0.9” 10.6 t 1.1 16.7 + 2.1b P < 0.0001 for all correlations. See Table 3 for abbreviations.
Values are the mean 2 SEM. 3
a P < 0.05, Tanner 3 boys vs. Tanner 2 boys. .
b P < 0.01, Tanner 3 girisvs. Tanner 2 girls.
‘P < 0.01, Tanner 3 boys vs. Tanner 2 boys. 0.8. .
d P < 0.05, Tanner 3 girls vs. Tanner 2 girls.
e Percent body fat estimated from underwater weighing.
f Percent body fat estimated from skinfolds.
g P < 0.07, Tanner 3 girls vs. Tanner 2 girls.
h Percent body fat estimated from bioelectric impedance.
i Total fat mass estimated from underwater weighing.

from total fat mass(P < 0.0001)and Tanner stage (P < 0.006)
(for the overall model: ? = 0.59; P < 0.0001). Again, insulin
sensitivity decreased as total fat mass and Tanner stage in-
creased. Testosterone, IGF-I, body fat distribution, and
parental obesity did not contribute to this model.
In girls, insulin sensitivity correlated inversely with BMI
(P < 0.0006), parental obesity (P < O.Ol), and IGF-I levels
(P < 0.02; for the overall model, ? = 0.57; P < 0.0001). The
relationship between BMI and insulin sensitivity changed
depending on whether the girls had parents who were obese
(Fig. 4). Girls who had no obese parents were more insulin
sensitive at lower body massindices.
Discussion
Significant changes in body composition are known to
occur during puberty in concert with changes in the hor-
monal environment. Gonadal steroids, GH, IGF-I, and insu-
lin levels all increasethroughout puberty at the sametime as
the percent body fat increasesin girls and decreasesin boys.
Total fat massincreasesin both sexes;however, becausethere
is a dramatic increase in fat-free massin boys, their fat mass
contributes proportionately lessto body weight. At the end
2.00 I
2h 1.50 I - -
-.--
Boys Stage 2 Boys Stage 3 Girls Stage 2
FIG. 1. Insulin sensitivity in 96 children divided according to gender
and Tanner stage. Data are expressed as the mean + SEM. a and b,
P < 0.007, girls stage 3 vs. boys stages 2 and 3; c, P < 0.02,girls stage
3 vs. girls stage 2.
rl
15 20 25 30 35
Body Mass Index (kg/m*)
FIG. 2. Insulin sensitivity vs. BMI in 96 children, boys and girls
combined (r = -0.63; P < 0.0001).
of pubertal development, boys have approximately 1.5 times
the fat-free massas girls and half the percent body fat (5). It
is also during puberty when gender differences in body fat
distribution become apparent. Girls emerge from puberty
with predominantly lower body (gluteal) fat and boys with
upper body (truncal) fat (23).
Although our current data are cross-sectional, the results
are consistent with these pubertal changes in body compo-
sition, as the Tanner stage 3 girls had greater body fat than
Tanner stage 2 girls, and Tanner stage 3 boys had lessbody
fat than Tanner stage 2 boys. It is interesting that the Tanner
stage 3 girls and Tanner stage 2 boys had mean values for
percent IBW of 117% and 122%, respectively. This may rep-
resent a bias in sampling, in that we happened to recruit
overweight children in those two groups. However, this may
also reflect the fact that IBW is calculated from age- and
sex-specific standards and does not take into account pu-
bertal stage. As girls are known to be fatter in Tanner stage
3 of puberty and boys fatter in Tanner stage 2 of puberty,
these subjects may have appropriate IBW values for their
respective pubertal stage.
Underwater weighing gave consistently higher estimates
of percent body fat than either skinfold thickness or BIA.
When adult constants are used for calculating body compo-
sition from body density, the percent body fat is invariably
overestimated in children (5). However, we employed age-
and sex-specific constants in our calculations, which adjust
for the chemical immaturity of fat-free massin children and,
thus, should not overestimate body fat (201. It should be
Girls Stage 3 noted, however, that these constants are age, not pubertal or
bone age, specific. As children enter puberty at different
chronological ages,and their development is more related to
their stage of puberty and skeletal maturation, constants
derived according to pubertal stage or bone age may make

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176 TRAVERS ET AL. JCE & M . 1995
Vol80 . No 1

A What causes the pubertal changes in body fat and body fat
3r -/ distribution? It seems reasonable to speculate that the hor-
monal environment unique to puberty somehow contributes.
GH is both an anabolic and lipolytic hormone; consequently,
elevated levels of GH in both sexes during puberty contribute
to increases in lean body mass (25). In boys, testosterone
promotes the growth of lean body mass as well. The trend to
upper body fat distribution in boys, however, cannot be
easily explained by GH or testosterone (26). In girls, it is
2-y q
likely that female sex steroid hormones are involved in fat
accumulation and especially fat distribution during puberty.
15 20 25 30 35 In a recent study of Tanner stage 2 girls and body fat dis-
Body Mass Index (kg/mz) tribution, those with a predominant lower body fat distri-
bution had higher free estradiol levels (27). Although ele-
vated GH levels in girls during puberty should restrict fat
B 3.00 -
accumulation, GH may be involved in protecting girls from
0
2 2.50
- l Girls
abdominal fat accumulation. Consequently, it appears that
z I..\> --3 Boys in both boys and girls, gonadal steroids and GH do not
E 2.00 t
completely explain the gender-specific changes in body
,P
composition.
Recently, enhanced insulin sensitivity has been shown to
predict weight gain in adults (8). In this situation, increased
glucose oxidation and antilipolysis both occur, thus favoring
carbohydrate oxidation and fat storage. It is our hypothesis
that insulin sensitivity may somehow relate to pubertal
10 15 20 25 30 35 changes in body composition. It is known that puberty is
Body Mass Index (kg/m’)
associated with a decrease in insulin sensitivity; however, the
exact cause is unclear. Some have attributed the decrease in
FIG. 3. A, Insulin sensitivity US.BMI in Tanner stage 2 boys andgirls. insulin sensitivity to the higher GH levels during puberty
For boys, indicated by dashed line, r = -0.82 and P < 0.001. For girls,
indicated by solid line, r = -0.43 and P < 0.05. The slopes of the lines
(10-12, 28). These studies showed a negative relationship
are significantly different (P < 0.04). B, Insulin sensitivity us. BMI in between insulin sensitivity and either IGF-I or mean GH
Tanner stage 3 boys and girls. For boys, r = -0.43 and P < 0.04. For level. These studies, however, did not attribute the pubertal
girls, r = -0.72 and P < 0.0002. The slopes of the lines were not decrease in insulin sensitivity to changes in body fatness,
significantly different.
with the reasoning that body mass indices did not differ
between the groups they studied. There is only one study, to
31 I
I - l 0 Obese Parent our knowledge, that has looked at differences in insulin
sensitivity between Tanner stages within puberty (12). They
also did not find differences in body mass indices between
Tanner stages; however, the number of subjects per group
studied were small, i.e. five boys and six girls in Tanner stage
2 and four boys and one girl in Tanner stage 3. In a larger
sample size, we found significant differences in body com-
position between Tanner stages 2 and 3 of puberty within
each gender. As mentioned previously, these differences
should be expected because the known changes in body
composition during puberty. Consequently, it is possible that
Body Mass Index (kg/m*) decreased insulin sensitivity during puberty may be in part
FIG. 4. Insulin sensitivity US.BMI in girls with no obese parents and related to increased body fatness, especially in girls. Our
girls with one or two obese parents. For girls with no obese parents, Tanner stage 3 girls had greater body fat and lower insulin
r = -0.66 and P < 0.02. For girls with one or two obese parents, r = sensitivity than Tanner stage 2 girls. Tanner 2 boys, however,
-0.71 and P < 0.0001. The slopes of the lines were marginally dif-
ferent (P < 0.09).
were fatter than Tanner 3 boys, but were not less insulin
sensitive. Consequently, as others have proposed, there are
more sense. Consequently, these constants may not be en- other factors determining insulin sensitivity during puberty.
tirely valid, especially in pubertal children. On the other We did not measure GH levels, so we do not know the
hand, skinfold thickness and BIA estimates are both known influence of GH on insulin sensitivity in our subjects. Other
to underestimate body fat in obese individuals (24). Even studies have used IGF-I levels to indicate GH secretion and
though this difference existed when estimating absolute per- have shown significant relationships with insulin sensitivity
cent body fat, all of the measures of body fatness were highly (10-12). We also showed that in girls, but not boys, IGF-I was
correlated with one another and will be adequate for eval- negatively correlated to insulin sensitivity. This is in agree-
uating longitudinal changes. ment with the findings of Cook et al. (12). The reason that

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 INSULIN SENSITMTY
insulin sensitivity was not associated with IGF-I levels in
boys may be because of the pubertal stages we studied. In
contrast to girls, in whom IGF-I levels are the highest early
in puberty, IGF-I levels in boys peak toward the end of
puberty; consequently, the relationship between IGF-I and Si
may not be evident until then. Can IGF-I levels be used,
however, to indicate the metabolic actions of GH? GH en-
hances lipolysis and has effects on carbohydrate metabolism
to cause insulin resistance (29). On the other hand, high IGF-I
levels, comparable to those achieved in puberty, have insu-
lin-like effects (30). Additionally, the production of IGF-I is
influenced not only by GH, but also by nutritional status. It
is widely known that obesity is associated with elevated
IGF-I levels (31). Consequently, one cannot assume that the
relationship between IGF-I and insulin sensitivity is due only
to GH.
Body fatness had the best overall correlation with insulin
sensitivity in both boys and girls. It was surprising to us that
of all the various measures of body fatness, BMI had the
strongest correlation to Si. This may be because BMI is a
relatively easy parameter to measure and is not subject to the
variability that more difficult techniques will have. Despite
the strong negative relationship between body fatness and
insulin sensitivity, there was significant variability in insulin
sensitivity in the nonobese children. With this variability, it
will be especially interesting to follow these nonobese chil-
dren longitudinally to determine whether their initial insulin
sensitivity relates to changes in their body composition. Like-
wise, there is very little variability in insulin sensitivity at
high BMI values. This suggests that being overweight takes
precedence, bringing insulin sensitivity to a minimum value,
and modifies the influence of other potential factors on in-
sulin sensitivity.
In the multiple regression analysis, insulin sensitivity was
best predicted by body fatness, gender, and Tanner stage.
When body fat is accounted for, boys tended to be more
insulin sensitive than girls, and Tanner stage 2 children
tended to be more insulin sensitive than Tanner stage 3
children. Additionally, boys and girls differed somewhat in
what factors determined their insulin sensitivity. In boys, fat
mass and Tanner stage were important predictors, whereas
in girls, parental obesity and IGF-I levels added to body
fatness as important predictors. Consequently, we demon-
strated that insulin sensitivity, like body composition, has
gender-dependent changes during puberty. It is thus possi-
ble that these pubertal changes in insulin sensitivity relate to
changes in body composition.
In our subjects, neither estrogen nor testosterone levels
were associated with insulin sensitivity. This may be because
we studied children early in puberty when sex hormones are
only beginning to rise; consequently, a relationship may be
seen later in puberty. However, it makes sense that sex ste-
roid hormones may not influence insulin sensitivity, because
these hormones remain increased into adult life, yet insulin
sensitivity returns to prepubertal values (15). Body fat dis-
tribution was not associated with insulin sensitivity when
total body fatness was accounted for. In adults, visceral fat
has a stronger relationship to insulin sensitivity than total
body fat (32). We used the WHR and umbilicus to hip ratio
to estimate body fat distribution in our subjects. Studies that
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IN PUBERTY
have used magnetic resonance imaging to assess visceral fat
in children have not found that WHR is a good indicator of
visceral fat (27). Consequently, it is possible that by using a
more accurate technique to assessvisceral fat, one would find
a relationship with insulin sensitivity.
In our study, children with obese parents were signifi-
cantly fatter than those with lean parents (data not shown).
It was interesting to us that in girls, insulin sensitivity was
related to parental obesity, even after body fatness was taken
into consideration. At lower BMI values, girls who had one
or two obese parents tended to be less insulin sensitive than
girls who had no obese parents. At higher BMI values, the
reverse was found, with girls having obese parents tending
to be more insulin sensitive. It is well known that the risk of
developing obesity is significantly higher in children who
have obese parents (33). Consequently, it will be interesting
to observe whether the greater insulin sensitivity of these
obese children of obese parents relates to future weight gain
over puberty.
In summary, we found that insulin sensitivity in early
pubertal children was primarily associated with body fat-
ness. In the nonobese children, there was significant vari-
ability in insulin sensitivity, suggesting that there are mul-
tiple factors that influence insulin sensitivity. In obese
children, however, insulin sensitivity was brought to a min-
imum value, with very little variability. This suggests that
body fat has such a strong influence on insulin sensitivity
that other potential factors are modified. Although our cur-
rent cross-sectional data do not allow for determination of
cause and effect, the longitudinal data collected in this cohort
will be important in determining whether insulin sensitivity
relates to future changes in body composition. It will also be
interesting to see whether the gender differences we found
in insulin sensitivity relate to gender-dependent changes in
body composition.
Acknowledgments
We thank Jamie Erskine for her assistance in the anthropometric
measurements, and Teresa Sharp, Tracy Horton, and Debbie Jacobson
for performing the underwater weight measurements. We also appre-
ciate the Children’s Hospital General Clinical Research Center staff for
their tremendous effort in helping to complete this project.
References
1. Dietz WH. 1981 Obesity in infants, children, and adolescents in the
United States. I. Identification, natural history, and aftereffects. Nutr
Res. 1:117-137.
2. Rosenbaum M, Leibel RL. 1988 Pathophysiology of childhood
obesity. Adv Pediatr. 35:73-138.
3. Lloyd JK, Wolff OH, Whelen WS. 1961 Childhood obesity. Br Med
J. 2:145-148.
4. Rimm IJ, Rimm AA. 1976 Association between juvenile onset obe-
sity and severe adult obesity in 73,532 women. Am J Public Health.
66:479-481.
5. Hergenroeder AC, Klish WJ. 1990 Body composition in adolescent
athletes. Pediatr Clin North Am. 37:1057-1080.
6. Zurlo F, Lillioja S, Esposito-Del Puente A, et al. 1990 Low ratio
of fat to carbohydrate oxidation as predictor of weight gain: study
of 25-h RQ. Am J Physiol. 259:E650-E657.
7. Kubota S, Tamai H, Ishimoto-Goto J, et al. 1993 Carbohydrate
178 TRAVISRS ET AL. JCE & M . 1995
Vol80. No 1

oxidation rates in patients with anorexia nervosa. Metabolism. 42: 21. Houtkooper LB, Going SB, Lohman TG, Roche AF, Van Loan M.
928-931. 1992 Bioelectrical impedance estimation of fat-free body mass in
8. Swinbum BA, Nyomba BL, Saad MF, et al. 1991 Insulin resistance children and youth: a cross-validation study. J Appl Physiol 72:
associated with lower rates of weight gain in Pima Indians. J Clin 366-373.
Invest. 88:168-173. 22. Desbuquois B, Aurbach GD. 1971 Use of polyethylene glycol to
9. Amiel SA, Sherwin RS, Simonson DC, Lauritano AA, Tamborlane separate free and antibody-bound peptide hormones in radioim-
WV. 1986 Impaired insulin action in puberty. A contributing factor munoassays. J Clin Endocrinol Metab. 33:732.
to poor glycemic control in adolescents with diabetes. N Engl J Med. 23. Mueller WH. 1982 The changes with age of the anatomical distri-
315:215-219. bution of fat. Sot Sci Med. 16:191-196.
10. Bloch CA, Clemons l’, Sperling MA. 1987 Puberty decreases insulin
24. Deurenberg P. 1992 Methods for determining fat mass and fat dis-
sensitivity. J Pediatr. 110:481-487.
tribution. Acta Pediatr. 383fSuppl):53-57.
11. Caprio S, Plewe G, Diamond MP, et al. 1989 Increased insulin
secretion in puberty: a compensatory response to reductions in in- 25. Tanner JM, Hughes PCR, Whitehouse RH. 1977 Comparative ra-
sulin sensitivity. J Pediatr. 114:963-967. pidity of response of height, limb muscle, and limb fat to treatment
12. Cook JS, Hoffman RP, Stene MA, Hansen JR. 1993 Effects of mat- with human growth hormone in patients with and without growth
urational stage on insulin sensitivity during puberty. J Clin Endo- hormone deficiency. Acta Endocrinol (Copenh). 84:681-696.
crinol Metab. 77:725-730. 26. Rosenbaum M, Gertner JM, Leibel RL. 1989 Effects of systemic
13. Tanner JM. 1962 Growth and adolescence, 2nd ed. Oxford: Black- growth hormone (GH) administration on regional adipose tissue
well. distribution and metabolism in GH-deficient children. J Clin Endo-
14. Bergman RN, Beard JC, Chen M. 1986 The minimal modeling crinol Metab. 69:1274-1281.
method. Assessment of insulin sensitivity and beta-cell function in 27. De Ridder CM, de Boer TW, Seidell JC, et al. 1992 Body fat dis-
viva In: Clarke WL, Larner J, Pohl SL, eds. Methods in diabetes tribution in pubertal girls quantified by magnetic resonance imag-
research. New York: Wiley and Sons; vol 2:16-34. ing. Int J Obes. 16:443-449.
15. Cutfield WS, Bergman RN, Menon RK, Sperling MA. 1990 The 28. Arslanian SA, Heil BV, Becker DJ, et al. 1991 Sexual dimorphism
modified minimal-model: application to measurement of insulin in insulin sensitivity in adolescents with insulin-dependent diabetes
sensitivitv in children. I Clin Endocrinol Metab. 70:1644-1650. mellitus. J Clin Endocrinol Metab. 72:920-926.
16. Roche AF, Siervogel RM, Chumlea WC, Webb P. 1981 Grading 29. Sherwin RS, Schulman GA, Hendler R, et al. 1983 Effects of growth
body fatness from limited anthropometric data. Am J Clin Nutr. hormone on oral glucose tolerance and circulating metabolic fuels
34:2831-2838. in man. Diabetologia. 24:155-161.
17. Hamill PV, Drizd TA, Johnson CL, Reed RB, Roche AF, Moore
30. Laager R, Ninnis R, Keller U. 1993 Comparison of the effects of
WM. 1979 Physical growth: National Center for Health Statistics
recombinant human insulin-like growth factor-l and insulin on glu-
percentiles. Am J Clin Nutr. 32:607-629.
18. Metropolitan Life Insurance Co. 1983 Height and weight tables. Stat cose and leucine kinetics in humans. J Clin Invest. 92:1903-1909.
Bull. 64:2. 31. Binet E, Sclumberger A, Chaussain JL. 1976 Serum somatomedin
19. Slaughter MH, Lohman TG, Boileau RA, et al. 1988 Skinfold equa- activity in obese children. Pediatr Adolesc Endocrinol. 1:153-156.
tions for estimation of body fatness in children and youth. Human 32. Kissebah A, Vydelingum N, Murray R, et al. 1982 Relation of body
Biol. 60:709-723. fat distribution to metabolic complications of obesity. J Clin Endo-
20. Lohman, TG. 1986 Applicability of body composition techniques crinol Metab. 54:254-260.
and constants for children and vouths. Exert Sport Sci Rev. 14: 33. Gam SM, Clark DC. 1976 Trends in fatness and the origins of
obesity. Pediatrics. 57:443-456.

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