Insulin Resistance, Childhood Obesity
MAKALE #1673 © Yazan Prof.Dr.Mehmet Emre ATABEK | Yayın Ekim 2008 | 3,347 Okuyucu
Evidence for Association Between Insulin Resistance and
Premature Carotid Atherosclerosis in Childhood Obesity
MEHMET EMRE ATABEK, OZGUR PIRGON, AND ALI SAMI KIVRAK
Selcuk University, Faculty of Medicine, 42080 Konya, Turkey
ABSTRACT:
The present study was undertaken to determine the
presence and predictors of the subclinical atherosclerosis in obese
children. Fifty obese children [mean age: 11.7
2.5 y, mean body
mass index (BMI): 28.2
4.0 kg/m2] and 50 age- and sex-matched
healthy nonobese controls (mean age: 11.4
3.73 y, mean BMI:
17.6
3.0 kg/m2) were enrolled in the present study. Oral glucose
tolerance test was performed to all obese subjects. Common carotid
artery intima-media thickness (IMT) was measured by highresolution
B-mode ultrasonography. Carotid artery IMT was significantly
increased (0.0476
0.007 versus 0.033 0.011 cm; p
0.001) in the obese group. There were significant relations between
carotid artery IMT and insulin sensitivity indexes derived from fasting
samples (fasting glucose to insulin ratio (FGIR;
p 0.004, r –0.404),
quantitative insulin-sensitivity check index (QUICK-I;
p 0.002, r
–0.401) and homeostasis model assessment of insulin resistance
(HOMA-IR;
p 0.034, r 0.300) in the obese group. In a
multivariate regression model, QUICK-I emerged as independent
correlates for mean IMT in obese children with the total variance
explained being 20.7% (
–0.58, p 0.001). We concluded that
insulin resistance is an independent risk factor for increased carotid
artery IMT in obese children.
(Pediatr Res 61: 345–349, 2007)
A
lthough the clinical complications of atherosclerosis such
as coronary artery disease and stroke usually occur in
middle and late age, autopsy studies have shown that the
atherosclerotic process in the vascular wall begins in childhood
and is accelerated in the presence of risk factors (1,2).
Clustering of cardiovascular risk factors is seen in children
and adolescents with the highest degree of insulin resistance
suggesting that adult cardiovascular disease is more likely to
develop in these young people (3,4). Type 2 diabetes mellitus
and metabolic syndrome prevalences among obese adolescents
are quite high in the urban area of Konya, central
Anatolia. In our previous study, we found that the prevalence
of metabolic syndrome was 27.2% with a significantly higher
rate among obese adolescents aged 12–18 y (37.6%) than
among obese children aged 7–11 y (20%) (5).
Increased common carotid artery IMT is significantly related
to known cardiovascular risk factors and to carotid
plaque, a more advanced atherosclerotic lesion (6). Measuring
carotid artery IMT with ultrasonography correlates well with
pathologic measurements and is reproducible. Increased carotid
artery IMT is correlated with cardiovascular risk factors
and the severity of coronary atherosclerosis and predicts cardiovascular
events in population groups (7,8). Carotid artery
IMT as a marker of early atherosclerosis has been studied
using vascular ultrasonography in children with familial hypercholesterolemia
(9), diabetes (10,11), hypertension (12),
and childhood obesity (13,14). In a recent study, Zhu
et al.
found a significant thickening of the intima-media layer in
the carotid artery of obese Chinese school children, compared
with nonobese controls (15). However, they have not
extensively investigated the predictors of increased carotid
artery IMT.
Although insulin resistance is a major risk factor for cardiovascular
events, only one study has been conducted for a
relation between insulin sensitivity indexes and carotid artery
IMT in obese children (16). In the present study, we investigated
the relationships between carotid artery IMT and insulin
sensitivity indices based on fasting samples and OGTT in
children with obesity.
METHODS
Subjects.
Fifty children (25 girls and 25 boys, mean age: 11.7 2.5 y,
mean body mass index (BMI): 28.2
4.0) were recruited from obese children
who attended the outpatient clinic of Pediatric Endocrinology Unit of Selcuk
University Hospital in Konya, Turkey. Control subjects (25 girls and 25 boys,
mean age: 11.4
3.73, mean BMI: 17.6 3.0) were enrolled the study
through nonobese healthy children who attended the hospital for minor illness
such as common cold, conjunctivitis, short stature, and constipation. After
managed in the primary care setting, we collected the blood samples of the
control group at the time of the control examination. Obese children were
included if they were 8–18 y age with BMI 95th percentile for age and
gender based on the standards of the Centers for Disease Control and
Prevention. Children were excluded if they had prior major illness including
type 1 or type 2 diabetes, took medications, or had a condition known to
influence body composition, insulin action, or insulin secretion (
e.g. glucocorticoid
therapy, hypothyroidism, Cushing’s disease). All subjects were in good
health and had normal thyroid function. The study was approved by the local
ethics committee of the University of Selcuk. Signed informed consent was
obtained for each subject over 12 y of age, and informed parental consent was
also obtained for all children regardless of age (Fig. 1).
Each child underwent a complete physical examination, including anthropometric
measures. Height and weight were measured in postabsorptive
conditions and with an empty bladder. Height was measured to the nearest 0.5
cm on a standard height board, and weight was determined to the nearest 0.1
kg on a standard physician’s beam scale with the subject dressed only in light
underwear and no shoes. The BMI was calculated as weight (in kilograms)
divided by height (in meters) squared. The degree of obesity was quantified
Received September 7, 2006; accepted October 24, 2006.
Correspondence: Mehmet Emre Atabek, M.D., Selcuk Universitesi Meram Tip Fakultesi,
Cocuk Sagligi ve Hastaliklari, 42080 Konya, Turkey; e-mail: meatabek@hotmail.com
DOI: 10.1203/pdr.0b013e318030d206
Abbreviations: BMI-SDS,
body mass index–standard deviation score;
FGIR,
fasting glucose-to-insulin ratio; HOMA-IR, homeostasis model assessment
of insulin resistance;
IMT, intima-media thickness; ISI, insulin
sensitivity index;
OGTT, Oral glucose tolerance test; QUICK-I, quantitative
insulin-sensitivity check index
0031-3998/07/6103-0345
PEDIATRIC RESEARCH Vol. 61, No. 3, 2007
Copyright © 2007 International Pediatric Research Foundation, Inc.
Printed in U.S.A.
345
using Cole’s least mean-square method, which normalizes BMI-skewed
distribution and expresses BMI as an SD score (BMI-SDS). This measure
gives age- and sex-specific estimates of the distribution median, the coefficient
of variation and the degree of skewness by a maximum-likelihood fitting
technique (17). Blood pressure was measured with a standard mercury
sphygmomanometer after the subjects had rested at least 10 min. Systolic
blood pressure (systolic BP) was recorded at the appearance of sounds, and
the diastolic blood pressure (diastolic BP) was recorded at the disappearance
of sounds.
Blood samples and OGTT.
The studies were performed in the morning
between 0730 and 0930 h after the children had fasted overnight. After a 3-d,
high-carbohydrate diet (300 g/d) and an overnight fast, a standard OGTT
(1.75 g/kg or a maximum of 75 g of glucose) was performed for all subjects
except for control group because of the ethical reasons. Venous blood samples
were obtained at 0, 30, 60, 90, and 120 min to measure plasma glucose and
insulin levels in the morning by venipuncture after an overnight fasting. After
clotting, the serum was separated and immediately explored for analyses.
Glucose was determined by the glucose oxidase method. Plasma concentrations
of total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides
were measured using a routine enzymatic methods with Olympus 2700
Analyzer (Olympus Diagnostica GmbH, Hamburg, Germany). Insulin levels
were measured by an Immulite immunoassay (Diagnostic Products, Los
Angeles, CA). Fasting total homocysteine concentrations were determined in
EDTA plasma with competitive immunoassay. Samples were separated from
the cells, and matched samples were spiked with total homocysteine and then
assayed by Immulite 2000 Analyzer (Diagnostic Products). Results were expressed
as micromoles per liter. Normal concentrations were 5 and 15
M (18).
Insulin indexes derived from fasting blood samples and OGTT.
The
HOMA-IR, QUICK-I, and FGIR were derived as estimates of insulin resistance.
FGIR was calculated as fasting insulin concentration (
U/mL)/fasting
glucose concentration (mg/dL). HOMA-IR was calculated as fasting insulin
concentration (
U/mL) fasting glucose concentration (mmol/L)/22.5 (19).
QUICK-I was calculated as 1/[(log fasting insulin concentration (
U/mL)
log fasting glucose concentration (mg/dL)] (20).
The total plasma glucose response and insulin secretion were evaluated
from the area under the response curve (AUC) estimated by the trapezoid rule.
The insulin sensitivity index (ISI) proposed by Matsuda and De-Fronzowas
calculated as follows: ISI-composite
10.000/square root of [(mean plasma
insulin
mean plasma glucose during OGTT) (fasting plasma glucose
fasting plasma insulin)] (21).
Ultrasound imaging.
The same sonographer, who was blinded to the
participant’s laboratory values and risk factor levels, did all examinations.
Scans were obtained at rest; the subjects were laid quietly for 10 min before
the first scan. High-resolution B-mode ultrasonography of the right common
carotid artery was performed with a LOGIQ 9 (GE Healthcare, Milwaukee,
WI) with a linear 10-MHz linear transducer. The participants were examined
in the supine position with the head turned slightly to the left. Longitudinal
images of the common carotid artery were obtained by combined B-mode and
color Doppler ultrasound examinations. The IMT of the common carotid
artery far wall was measured with the electronic calipers of the machines, as
described by Pignoli
et al. (22). On a longitudinal, two-dimensional ultrasound
image of the carotid artery, the posterior (far) wall of the carotid artery
was displayed as two bright white lines separated by a hypoechogenic space.
The distance between the leading edge of the first bright line of the far wall
and the leading edge of the second bright line indicated the carotid artery
IMT. The carotid artery IMT was measured during end diastole. The carotid
artery IMT measurements were performed on-line. The mean carotid artery
IMT was calculated for each children as the average of three consecutive
measurements of maximum far wall thickness obtained from the common
carotid artery, 20 mm below the carotid bulb. The coefficients of variation of
the measurements were less than 3%.
Statistical methods.
Data were expressed as mean SD. The Kolmogorov–
Smirnov test was applied separately for boys and girls to check the normality
of the variables. Differences in the means of variables were tested using both
parametric and nonparametric tests depending on the distribution of the
variables. Any variables that were not normally distributed were logtransformed
before data analysis. Statistical correlation was assessed using the
Pearson test (
r). Separate relationships between IMT and insulin sensitivity
indices (HOMA-IR, FGIR, QUICK-I, and ISI) were also examined after
adjustment for age, sex, BMI, BMI-SDS, systolic and diastolic blood pressure,
total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, and
total homocysteine using general linear regression models (backward analysis).
Statistical significance was taken as
p 0.05. All statistical analysis was
performed using the Statistical Package for Social Sciences (SPSS/Windows
version 11·0, SPSS Inc., Chicago, IL).
RESULTS
The characteristics of the study population are shown in
Table 1. Both the obesity group and control group showed no
significant difference in terms of gender composition, age, and
body height. Subjects in the obese group had a significantly
higher body weight, BMI, BMI-SDS and blood pressure. Total
cholesterol, LDL cholesterol, and triglyceride levels were
significantly elevated in obese children, whereas HDL was
only slightly lower than the controls. The carotid artery IMT
of obese children and controls ranged from 0.04 to 0.06 cm
and 0.02 to 0.05 cm, respectively. The obese group had
significantly higher carotid artery IMT than the controls
(0.0476
0.007 versus 0.033 0.011 cm; p 0.001). The
values of total homocysteine in obese group, which were all
within normal ranges, were slightly higher than those in
controls, but not significantly so (
p 0.053).
Table 2 shows the correlations between carotid artery IMT
and other measurements in obese children. When IMT was
considered as a continuous variable in the whole population of
obese children, it was found to be positively correlated in
Figure 1.
Relationship between carotid artery IMT and insulin sensitivity indexes. FGIR: r –0.404, p 0.004; HOMA-IR: r 0.3, p 0.034; QUICK-I:
r
–0.421, p 0.002).
346
ATABEK ET AL.
univariate analysis with fasting insulin level (
r 0.315, p
0.026), HOMA-IR (
r 0.300, p 0.034) and negatively
correlated with FGIR (
r –0.404, p 0.004), QUICK-I (r
–0.421,
p 0.002), but there was no association with weight
(
r 0.202, p 0.159), height (r 0.174, p 0.227), BMI
(
r 0.205, p 0.153), BMI-SDS (r 0.2, p 0.893),
systolic (
r 0.172, p 0.233) and diastolic blood pressure
(
r 0.052, p 0.718), total cholesterol (r 0.085, p
0.558), triglycerides (
r 0.076, p 0.600), LDL cholesterol
(
r 0.002, p 0.988), total homocysteine (r 0.105, p
0.469), fasting glucose level (
r 0.167, p 0.247),
AUC
glucose (r 0.04, p 0.782), AUCinsulin (r 0.029,
p
0.843) and ISI (r – 0.252, p 0.078). There were no
significant relationships between carotid artery IMT and
clinical and laboratory parameters in controls (data not
shown).
In the regression analysis, QUICK-I was negatively correlated
with increased IMT (
–0.58, p 0.001) even after
adjusting for age, sex, BMI, BMI-SDS, systolic/diastolic
blood pressure, total cholesterol, triglycerides, LDL cholesterol,
HDL cholesterol, and total homocysteine as co-factors
with the total variance explained being 20.7% (Table 3).
HOMA-IR, FGIR, and ISI were not significantly correlated
with IMT after adjusting for atherosclerotic risk factors.
DISCUSSION
In this study, we demonstrated the effect of insulin resistance
on carotid IMT in obese children. There has been
considerable interest in the insulin resistance and cardiovascular
disease. Central obesity and the attendant insulin resistance/
hyperinsulinemia occurring in childhood are the driving
force of the multiple metabolic syndrome X, insulin resistance
syndrome, or the “deadly quartet” (23). Therefore, we decided
to measure the IMT of common carotid artery in obese
children, since an increased IMT is known to be a parameter
of atherosclerotic changes and to be detected without obvious
abnormalities of the classic vascular risk factors. In the present
study, the number of risk factors identified in obese children
was associated with increased carotid artery IMT.
Autopsy studies in adolescents and young adults document
that atherosclerosis begins in adolescence and that the traditional
risk factors are associated with its development (24).
Studies on early atherosclerotic changes in children have
mainly focused on dyslipidemia, hypertension, obesity, and
diabetes as risk factors but not on insulin resistance or importance
of the insulin sensitivity indexes. The central role of
insulin in the background of the clustering of some cardiovascular
risk factors was first suggested by the reports on endogenous
hyperinsulinemia and insulin resistance in essential
hypertension (25). However, obese children exhibit glucose
intolerance, which is strongly associated with evidence of both
insulin resistance and impaired insulin secretion (26). Insulin-
Table 3.
Variable independently associated, in an age-, sex-, and
other risk factor-adjusted backward multiple linear regression
analysis, with the dependent variable carotid artery IMT in
obese children
Carotid artery IMT
r
2 p
QUICK-I 0.207 –0.58 0.001
AUC
insulin –0.29 0.057
Table 1.
Characteristics of the study population
Children
with obesity
Control
children
p
value
Number of subjects (f/m) 50 (25/25) 50 (25/25) —
Age (y) 11.7
2.5 11.4 3.73 0.721
Weight (kg) 64.1
21.6 38.4 14.8 0.001
Height (cm) 148.8
16.1 143.8 19.8 0.174
BMI (kg/m
2) 28.2 4.0 17.6 3.0 0.001
BMI-SDS 2.03
0.34 0.42 0.4 0.001
Systolic blood pressure
(mm Hg)
120.8
17.6 106.1 11.8 0.001
Diastolic blood pressure
(mm Hg)
79.3
11.8 66.4 9.0 0.001
Lipids
Total cholesterol (mg/dL)† 180.2
27.6 154.3 26.3 0.001
Triglycerides (mg/dL)‡* 133.6
84.1 81.2 31.7 0.001
LDL cholesterol (mg/dL)† 109.6
29.3 92.5 24.3 0.002
HDL cholesterol (mg/dL)† 47.3
13.5 48.5 10.2 0.626
Total homocysteine (
mol/L) 9.8 3.9 8.3 3.6 0.053
Carotid artery IMT (cm) 0.0476
0.007 0.033 0.011 0.001
Fasting glucose level
(mg/dL)§
97.5
8.5 88.9 8.7 0.001
Fasting insulin level
(
U/mL)¶*
16.0
11.0 5.8 4.6 0.001
FGIR 9.6
7.8 32.5 46.3 0.001
HOMA-IR 3.92
3.0 1.32 0.95 0.001
QUICK-I 0.32
0.03 0.39 0.08 0.001
OGTT derived indexes
AUC
glucose (mg/dL 120 min) 11754 1431 — —
AUC
insulin (U/mL 120 min) 6504 2689 — —
ISI 4.35
2.52 — —
Data are given as mean
SD.
† To convert to mmol/L, multiply by 0.0259.
‡ To convert to mmol/L, multiply by 0.0113.
§ To convert to mmol/L, divide by 18.
¶ To convert to pmol/L, multiply by 6.945.
* Statistical analysis was undertaken on log-transformed variables.
Table 2.
Relationship between carotid artery intima media
thickness, insulin sensitivity indexes, and the other cardiovascular
risk factors in obese children
Variables
r p
Weight 0.159 0.202
Height 0.227 0.174
BMI-SDS 0.20 0.893
Systolic blood pressure 0.172 0.233
Diastolic blood pressure 0.052 0.718
Total cholesterol 0.085 0.558
Triglycerides 0.076 0.600
LDL cholesterol 0.002 0.988
HDL cholesterol –0.120 0.405
Total homocysteine 0.105 0.469
Fasting glucose level 0.167 0.247
Fasting insulin level 0.315 0.026
FGIR –0.404 0.004
HOMA-IR 0.300 0.034
QUICK-I –0.421 0.002
AUC
glucose 0.04 0.782
AUC
insulin 0.029 0.843
ISI –0.252 0.078
INSULIN RESISTANCE AND C-IMT
347
resistant individuals who can compensate by hyperinsulinemia
may escape diabetes, but are still prone to other complications,
such as early atherosclerosis, progression of obesity (especially
central type), acanthosis nigricans, increased skin tags,
hypertension, dyslipidemia, hypercoagulation, polycystic
ovary syndrome, fatty liver infiltration, focal segmental glomerulosclerosis,
as well as increased cancer rate (27). However,
few research reports have studied the relations between
carotid artery IMT and insulin resistance indexes.
In the present study, fasting glucose was not associated with
carotid artery IMT, although fasting insulin was significantly
associated with carotid artery IMT in children with obesity.
Therefore, these data supported the idea that insulin resistance
may have a role in the development of early structural atherosclerotic
vascular changes in children with obesity. The ISI
and AUC
insulin, derived from the OGTT appear to be useful
outcome measures for clinical trials in obese children and
adolescents in terms of improving insulin sensitivity and
glucose tolerance (28). We did not find a relation between
insulin sensitivity indexes (ISI and AUC) derived from OGTT
measurements and carotid artery IMT in obese children. Balletshore
et al.
(16) have also reported that glucose-clamp
assessed insulin sensitivity was not correlated with IMT.
However, in the present study, conducted in a group of obese
children, we showed that insulin sensitivity indexes derived
from fasting samples and elevated basal insulin levels were
significantly associated with increased carotid artery IMT. We
found FGIR and QUICK-I are more significantly related with
carotid artery IMT than HOMA-IR.
Carotid artery IMT is affected by many factors including
serum lipids. Autopsy studies in children have also shown a
significant relationship between serum cholesterol concentration
and early atherosclerotic lesions (1,2). Increased carotid
artery IMT has previously been demonstrated in children with
familial hypercholesterolemia. Case-control studies of children
and young adults demonstrate that familial hypercholesterolemia
and borderline hypertension are associated with
greater IMT (11–13). In the present study, serum lipid levels
in obese children were significantly higher than those of
healthy subjects. However, we did not find a significant
relationship between carotid artery IMT and serum lipids. The
reason for this negative result might be owing to fact that our
subjects had not very high lipid levels as did in familial
hypercholesterolemia. Although, reduction in BMI slows the
yearly rate of increase in carotid-wall thickness (29), the
thickness of the arterial wall increasing with proportional to
BMI is still a matter of debate. In the present study, we also
did not find a significant relationship between anthropometric
data and carotid artery IMT. The number of subjects is
relatively small which might explain these non significant
results.
Retrospective and prospective studies have demonstrated
that hyperhomocysteinemia is the other risk factor for premature
cardiovascular disease independent of other classic risk
factors, such as smoking, hypercholesterolemia, arterial hypertension,
and diabetes (30 –33). Elevated plasma homocysteine
has been shown to be a significant risk factor for higher
carotid artery IMT (34). However, the other studies from
Davis
et al. (35) and Mahoney et al. (36), in the same cohort,
did not find plasma homocysteine as a risk factor. These
observations suggest that elevated homocysteine levels and
lipids may not affect carotid artery IMT at a younger age. In
the present study, we demonstrated that homocysteine levels
in obese children were slightly higher than healthy subjects
and also homocysteine levels was significantly associated with
basal insulin levels (data not shown), although we were unable
to show a relationship between fasting plasma homocysteine
levels and carotid artery IMT. Our data support that plasma
homocysteine levels might be a characteristic for early atherosclerosis
in obese children.
Childhood obesity seems to contribute to the development
and progression of early atherosclerosis, particularly in combination
with insulin resistance. Our observations suggest that
high insulin levels may have an important role in the pathogenesis
of early atherosclerosis. According to our findings, the
insulin indices derived from basal samples seem to be more
useful for assessing subclinical atherosclerosis than indices
obtained from OGTT, FSIVGTT, and clamp studies none of
which are feasible in the pediatric age group.
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