Vol.2, No.7, 676-681 (2010)
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
The association of circulating interleukin-18 with fasting
insulin and weight loss in obese children
Tim K. Tso1*, Wen-Nan Huang2, Chen-Kang Chang3
1Department of Food Science, National Chiayi University, 300 University Road, Chia-Yi, Taiwan, China;
*Corresponding Author: timtso@mail.ncyu.edu.tw
2Department of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan, China
3Sport Science Research Center, National Taiwan Sport University, Taichung, Taiwan, China
Received 20 February 2010; revised 23 March 2010; accepted 25 March 2010.
Obesity is an independent risk factor for de-
veloping cardiovascular disease and increases
insulin resistance in children. Interleukin (IL)-18
is a novel pro-inflammatory cytokine with po-
tential atherogenetic properties. This study ai-
med to identify circulating levels of IL-18 in
obese children and examine the effects of com-
bined nutritional education-physical activity co-
urse on circulating IL-18. Plasma IL-18, body
mass index (BMI), fasting glucose and insulin,
homeostasis model assessment insulin resis-
tance (HOMA IR), lipid profile, uric acid, high-
sensitive C-reactive protein (hs-CRP), and ho-
mocysteine were determined in 70 obese chil-
dren aged 10-12 years before and after attend-
ing a 13-week weight reduction program, which
included physical activities and nutritional edu-
cation. Twenty-five age-matched non-obese ch-
ildren served as controls. At baseline, obese
children had significantly higher levels of BMI,
fasting insulin, HOMA IR, triglyceride (TG), uric
acid, hs-CRP, and IL-18 but lower high-density
lipoprotein-cholesterol (HDL-C) than non-obese
children. Plasma IL-18 levels in obese children
decreased significantly after the weight reduc-
tion program. At baseline, plasma IL-18 lev els in
obese children positively correlated with BMI,
HOMA IR, insulin and TG but negatively corre-
lated with HDL-C. There was a significant rela-
tionship between plasma IL-18 and BMI change s.
Moreover, fasting insulin was responsible for
IL-18 variability in obese children. These find-
ings suggest that elevated plasma IL-18 levels
in obese children are partly associated with pa-
rameters of obesity and insulin resistance, and
are significa ntly affec ted by modest weight loss.
Keywords: Body Mass Index; Children; Insulin;
Interleukin; Obesity; Weight Loss
The increasing prevalence of childhood obesity has sig-
nificant medical and economical consequences. Obesity
in the youth increases the risk for cardiovascular com-
plications [1]. While mechanisms responsible for the
increased prevalence of childhood obesity and associated
chronic diseases have not been completely elucidated, its
prevention and treatment play an important role in re-
ducing cardiovascular risk. Weight loss induces decreased
lipid profiles [2], insulin resistance [3], and chronic in-
flammatory markers [4] in obese children.
Differential low-grade inflammation is associated with
obesity in the youth and some patterns of immune acti-
vation are related to insulin resistance [5]. Interleukin
(IL)-18 is a novel pro-inflammatory T helper-1 cytokine
produced by various cell types, including Kupffer cells,
activated macrophages, keratinocytes, intestinal epithe-
lial cells, osteoblasts, and adrenal cortex cells [6]. Re-
cent reports indicate that IL-18 concentrations may be
linked to type 2 diabetes mellitus [7,8], metabolic syn-
drome [9], hyperhomocysteinemia [7,10], obesity [11,12]
and insulin resistance [12]. Weight loss and exercise train-
ing are reported to reduce IL-18 in obese adults [11,13-15].
However, the association of IL-18 with childhood obe-
sity has not been completely established.
The purpose of the present study was to identify cir-
culating levels of IL-18 in obese children and examine
the effects of weight reduction on circulating IL-18.
T. K. Tso et al. / HEALTH 2 (2010) 676-681
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
2.1. Subjects
Seventy 4th-to-6th grade obese Chinese children (37 boys
and 33 girls) aged 10-12 years from the local elementary
schools were evaluated for plasma IL-18 levels and its
relationship to fasting insulin and weight loss before and
after completing a 13-week weight reduction program.
Obesity was based on the ideal body weight (IBW) cri-
teria and the study children were defined as obese if their
body weight was greater than 120% of IBW within age-
and gender-specific categories [16]. Twenty-five height-
and age-matched children (13 boys and 12 girls) with
body weight less than 110% of IBW from the same
schools served as non-obese controls.
All of the children had similar lifestyles with no pre-
vious physical training program or dietary consults. The
ethical committee of the National Taiwan Sport Univer-
sity (Taichung, Taiwan) approved the study and the par-
ents of all participating children provided written in-
formed consent.
2.2. Research Design
The 70 obese children participated in a 13-week weight
reduction program consisting of nutritional education
and physical exercise programs. Both programs were
directed and supervised by dieticians, nutritionists, phy-
sicians, physical education instructors, and coaches.
Both the children and their parents attended the first six
lectures of the nutrition intervention program (45 min-
utes per lecture, two lectures per week), and the children
continued the lectures thereafter.
The nutrition intervention program was taught by
school dieticians and was devoted primarily to nutri-
tional education. It included six topics: 1) introduction to
the food pyramid, food categories, food and beverage
choices; 2) introduction to nutrients and recommended
daily nutrient intake; 3) understanding food preparation,
balanced diet, eating habits, and over-eating control; 4)
learning about dietary recall, food records, and food
frequency questionnaire; 5) learning about simple con-
cepts of the food exchange list and practice of calorie
calculation; and 6) application and practice of nutrition
knowledge by playing games and giving tests.
Regarding physical activity intervention, all obese
children were instructed to participate in physical active-
ity three times per week (45 minutes per exercise session)
during the study period supervised by professional youth
coaches at the elementary schools. The physical active-
ties throughout this exercise intervention varied in inten-
sity and duration, but were similar to the type of exercise
that elementary school children regularly performed.
2.3. Experimental Approaches
Blood specimens before (baseline) and after (week 13)
the 13-week weight reduction program were collected in
the morning after an overnight fast and centrifuged im-
mediately to obtain serum or plasma aliquots that were
either used immediately or frozen at -80oC until the re-
quired assay.
Fasting glucose concentration was determined using
an enzymatic colorimetric method (Sigma Chemical
Company, St. Louis, MO, USA), while quantitative
measurement of fasting insulin concentrations was con-
ducted using an Abbott IMx Insulin Kit based on a mi-
cro-particle enzyme immuno-assay (MEIA) (Abbott
Laboratories, Dainabot, Tokyo, Japan). HOMA IR was
calculated according to the formulas in the HOMA
model [17]. Enzymatic methods were used to determine
plasma concentrations of total cholesterol (Beckman TC
Reagent) and TG (Beckman TG Reagent). Magne-
sium-dextran sulfate precipitation reagent was used to
separate HDL-C, which was then assessed enzymatically.
Low-density lipoprotein-cholesterol (LDL-C) was de-
termined using the Friedewald equation [18].
Plasma homocysteine levels were measured using
high-performance liquid chromatography with fluores-
cence detection. Quantitative determination of plasma
hs-CRP was assessed by particle-enhanced immuno-
nephelometry using a high sensitivity CRP immuno-
nephelometric assay kit (Dade Behring, Marburg, Ger-
many). Plasma IL-18 levels were assessed by enzyme-
linked immunosorbent assay (ELISA) using a Human
IL-18 ELISA kit (Medical & Biological Laboratories Co.,
LTD., Nagoya, Japan) based on the manufacturer’s in-
structions and analyzed with a Dynex MRX II mi-
cro-plate reader (DYNEX Technologies, Inc., Chantilly,
VA, USA) at a wavelength of 450 nm. This commercial
kit was used for detecting only bioactive IL-18, not the
immature pro-IL-18, as has been widely used. The intra-
and inter-assay coefficients of variation for IL-18 meas-
urements were 7.26% and 7.53%, respectively.
2.4. Statistical Analysis
Tested variables for comparison of means were ex-
pressed as mean ± standard error of mean (SEM). The
distribution of tested variables was examined graphically
for normality. An independent sample t test or Mann-
Whitney U test was used to examine mean differences
between the obese and the non-obese children. Paired t
test was used to compare values obtained before and
after attending the 13-week weight reduction program in
all obese children. Analysis of variance (ANOVA) was
used to compare values obtained from obese children
stratified by BMI and fasting insulin levels. Pearson’s
correlation or Spearman correlation analysis was used to
T. K. Tso et al. / HEALTH 2 (2010) 676-681
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
examine the relationships between IL-18 and tested
variables. A stepwise multiple regression analysis was
then performed to determine independent variables for
plasma levels of IL-18. A p value < 0.05 was considered
statistically significant. All statistical analyses were per-
formed using the Statistical Package of Social Sciences
(SPSS) 10.0 for Windows (SPSS Inc., Chicago, IL,
The 70 obese children (37 boys and 33 girls) had an av-
erage age of 11 years. All completed the weight reduc-
tion program without any reported discomfort or com-
plaints. About 67% (47/70) of them lost weight (mean:
1.69 ± 0.31 kg, range: 0.2-11 kg) and 87% (61/70) had
reduced BMI (mean: –1.26 ± 0.13 kg/m2, range:
0.04-5.62 kg/m2). In addition to reducing BMI (mean:
27.47 ± 0.38 vs. 26.59 ± 0.40 kg/m2, p < 0.001), the
weight reduction program also reduced plasma levels of
uric acid (mean: 6.16 ± 0.16 vs. 5.76 ± 0.15 mg/dL, p =
0.005), homocysteine (mean: 11.48 ± 0.32 vs. 10.06 ±
0.28 μmol/L, p < 0.001), hs-CRP (mean: 1.18 ± 0.02 vs.
1.01 ± 0.02 mg/L, p < 0.001), and IL-18 (mean: 161.44
± 4.03 vs. 132.57 ± 1.48 pg/mL, p < 0.001 ) without
significant changes in lipid profile or insulin resistance.
There were no gender or age differences for weight loss
and BMI reduction (data not shown).
The comparisons of test variables for the 70 obese and
25 non-obese children were shown in Table 1. Com-
pared to non-obese children, obese children had lower
HDL-C but higher levels of fasting insulin, HOMA-IR,
TG, uric acid, hs-CRP, and IL-18. The plasma IL-18 lev-
els of obese children by BMI and fasting insulin tertiles
at baseline, and the effects of weight reduction were
shown in Table 2. There was an increase in plasma
IL-18 levels in obese children with higher BMI and
fasting insulin. Obese children with fasting insulin in the
middle and top tertiles had significantly higher plasma
IL-18 levels than those in the bottom tertile. In addition,
plasma IL-18 levels of obese children decreased signifi-
cantly after the weight reduction program.
Table 3 showed the association of plasma IL-18 levels
with anthropometric measures and metabolic variables in
obese children at baseline. Plasma IL-18 levels in obese
children at baseline positively correlated with BMI, in-
sulin, HOMA-IR, and TG but negatively correlated with
HDL-C. Moreover, there was a significant relationship
between plasma IL-18 and BMI changes (r = 0.352, p =
0.004) but no significant correlations between plasma
IL-18 changes and those of other tested variables after
the weight reduction program (data not shown).
Moreover, stepwise multiple regression analysis was
performed with plasma IL-18 as dependent variable and
independent variables that included weight, BMI, fasting
insulin, fasting glucose, total cholesterol, TG, LDL-C,
HDL-C, uric acid, homocysteine, and hs-CRP. The re-
sults showed that fasting insulin was responsible for
plasma IL-18 variability in obese children (Table 4).
The present study investigated circulating levels of
IL-18 in 70 obese children and evaluated the beneficial
effects of combined nutritional education-physical activ-
ity intervention. The major finding was that obese chil-
dren have increased plasma IL-18 level, which is associ-
ated with BMI and markers of insulin resistance, and is
improved with only modest weight loss even without
improvement in insulin resistance.
Table 1. Characteristics of the study childrena.
children (n = 25)
Obese children
(n = 70)
Gender (boy/girl) 13/12 37/33
Height (cm) 147 ± 1 149 ± 1
Weight (kg) 43 ± 1 61 ± 1*
BMI (kg/m2) 20.02 ± 0.12 27.47 ± 0.38*
Glucose (mmol/L) 4.26 ± 0.07 4.28 ± 0.06
Insulin (μU/mL) 6.51 ± 0.33 20.28 ± 1.57*
HOMA IR 1.24 ± 0.07 3.91 ± 0.34*
TC (mmol/L) 4.16 ± 0.13 4.17 ± 0.09
TG (mmol/L) 0.65 ± 0.04 0.88 ± 0.05*
LDL-C (mmol/L) 2.38 ± 0.10 2.63 ± 0.08
HDL-C (mmol/L) 1.48 ± 0.05 1.14 ± 0.02*
Uric acid (mg/dL) 4.86 ± 0.25 6.16 ± 0.16*
Homocysteine (μmol/L) 10.88 ± 0.46 11.48 ± 0.32
hs-CRP (mg/L) 0.62 ± 0.06 1.18 ± 0.02*
IL-18 (pg/mL) 95 ± 4 161 ± 4*
Abbreviations: BMI, body mass index; HOMA IR, homeostasis model
assessment insulin resistance; TC, total cholesterol; TG, triglycerides;
LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density
lipoprotein cholesterol; hs-CRP, high sensitive C-relative protein; IL,
aValues are expressed as mean ± standard error of mean.
*p < 0.05 compared with non-obese children.
T. K. Tso et al. / HEALTH 2 (2010) 676-681
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
Table 2. Plasma concentrations of IL-18 (pg/mL) by body
mass index and fasting insulin tertiles at baseline, and effect of
weight reduction in obese childrena.
Mean ± SEM (95% CI) Pb
Body mass index
(kg/m2) tertiles
< 25.6 157 ± 7 (141-172)
25.6-28.4 173 ± 7 (159-187)
> 28.4 172 ± 6 (159-185)
Fasting insulin
(μU/mL) tertiles
< 14.8 151 ± 6 (138-163)
14.8-21.8 176 ± 9 (158-194)
> 21.8 176 ± 4 (168-184)
Weight reduction
Before 161 ± 4 (114-230)
After 133 ± 1 (117-158)
< 0.001
aValues are expressed as mean ± standard error of mean and 95% con-
fidence interval.
bStatistical significance (p < 0.05) of mean was determined by analysis
of variance for body mass index and fasting insulin tertiles, and by
paired t test for effect of weight reduction.
Childhood obesity is a great concern because it is as-
sociated with many risk factors for chronic diseases later
in life. Weight and BMI during childhood have been
correlated positively with fasting insulin, blood pressure,
and lipids in young adulthood [19]. BMI at age 13 years
is highly correlated with that at age 22 years [20]. In
addition, subjects with higher BMI as children show
higher total cholesterol and LDL-C and insulin resis-
tance in young adulthood [20]. The present study has
found that obese children have cardiovascular risk pro-
file in terms of lower HDL-C but higher levels of fasting
insulin, HOMA-IR, TG, uric acid, hs-CRP, and IL-18
than non-obese children. After a 13-week combined nu-
tritional education-physical activity program, 67% of
obese children had lower body weight with an average
weight reduction of 1.69 kg but range that varied from
0.2 to 11 kg. Even though weight loss was limited, the
weight reduction program not only reduced BMI but also
Tabl e 3. Correlation coefficients of IL-18 with anthropometric
measures and metabolic variables in obese children at baseline.
Obese children
r P
BMI 0.378 0.002*
Glucose –0.183 0.142
Insulin 0.323 0.008*
HOMA IR 0.248 0.044*
TC 0.125 0.316
TG 0.293 0.017*
LDL-C 0.156 0.210
HDL-C –0.291 0.018*
Uric acid 0.199 0.109
Homocysteine –0.022 0.858
hs-CRP 0.111 0.374
Abbreviations: BMI, body mass index; HOMA IR, homeostasis model
assessment insulin resistance; TC, total cholesterol; TG, triglycerides;
LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density
lipoprotein cholesterol; hs-CRP, high sensitive C-relative protein; IL,
*p < 0.05 indicated the statistical significance.
Table 4. Stepwise multiple regression analysis in obese chil-
dren at baselinea.
Beta t value P value
R2 = 0.143 Adjusted R2 = 0.115
F = 5.243
Fasting insulin0.287 2.394 0.008
aStepwise multiple regression analysis with plasma IL-18 as dependent
variable, while independent variables included weight, BMI, fasting
insulin, fasting glucose, total cholesterol, triglyceride, LDL-C, HDL-C,
uric acid, homocysteine, and hs-CRP.
lowered plasma IL-18 levels as well as other cardiovas-
cular risk factors, such as uric acid, homocysteine, and
Very few studies show an association between IL-18
and obesity in the youth, and obese children with meta-
bolic syndrome have significantly higher IL-18 [21].
IL-18 levels are associated with BMI and waist circum-
ference, fasting insulin, and HOMA-IR in adolescents
[5]. In the present study, obese children have signifi-
T. K. Tso et al. / HEALTH 2 (2010) 676-681
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
cantly higher IL-18 and such an elevation correlates with
cardiovascular risk factors such as BMI, HOMA-IR,
fasting insulin, TG, and HDL-C (inversely). In addition,
fasting insulin explains IL-18 variability in obese chil-
There are no reports that show the effects of weight
loss on plasma IL-18 in obese children, but an elevation
of plasma IL-18 in obese adults can be influenced by
interventions related to weight control. Plasma IL-18
decreases significantly after a 12-month weight loss pro-
gram with energy restrictions in obese women [11]. A
15-week hypo-caloric diet and daily exercise program
reduces body weight, plasma IL-18, and increases insu-
lin sensitivity in obese adults [22], while massive weight
loss induced by gastric bypass reduces plasma IL-18
[14]. A multi-disciplinary weight reduction program
emphasizing lifestyle changes is associated with reduced
IL-18 in obese pre-menopausal women [23]. An 8-week
exercise training also reduces adipose tissue IL-18
mRNA content in obese adults [15]. In the present study,
a 13-week combined nutritional education-physical ac-
tivity program has reduced plasma IL-18 without sig-
nificant changes in insulin sensitivity in obese children.
After the weight reduction program, 87% of obese chil-
dren in the present study have shown reduced BMI, but
only 41% show decreased HOMA IR and about 43% of
BMI-reduced obese children show decreased HOMA IR.
Taken together, a decrease in plasma IL-18 caused by the
weight reduction program in obese children is at least, in
part, due to changes of BMI per se, regardless of the
status of insulin resistance.
Systemic inflammation has been demonstrated in
overweight children as indicated by elevated CRP levels
[24]. It has also been shown that obese children have
higher hs-CRP levels than non-obese children [4,25] and
weight loss is associated with a significant decrease in
hs-CRP levels [4]. Homocysteine concentration is sig-
nificantly higher in hyper-insulinemic obese children
than in the normo-insulinemic obese children [25]. Ho-
mocysteine levels are significantly lower after a 12-week
weight loss program with dietary advice and light exer-
cise in obese middle-aged women with high homocys-
teine levels at baseline [26]. In the present study, plasma
levels of hs-CRP and homocysteine in obese children
have decreased significantly after the weight reduction
program. However, there is no relationship among
hs-CRP, homocysteine, and IL-18 before and after the
weight reduction program. The mechanism associated
with elevated circulating IL-18 and the effect of weight
loss on IL-18 in obese children seems to be independent
from other cardiovascular risk factors, such as CRP and
homocysteine, and warrants further elucidation.
The strength of the present study includes the effects
of the combined nutritional education-physical activity
intervention on obesity-related and/or obesity-indepen-
dent parameters in obese children, particularly IL-18,
which has been better studied in obese adults. However,
there are some weakness and limitations. Individual or
synergistic effects of nutritional education and exercise
on weight changes are not distinguished. In addition,
there is no full quantification of the interventions ac-
complished by the subjects due to lack of dietary records,
calorie counts, and estimates of physical activity inten-
sity. Thus, the cause and effect in the relationship be-
tween weight loss and improvements of tested variables
remain to be elucidated.
In conclusion, there are elevated circulating IL-18
levels in obese children. Modest weight loss through
weight reduction intervention has the beneficial effect of
reducing IL-18.
This study was supported by a research grant from the National Sci-
ence Council of Taiwan (NSC 95-2413-H-415-015). The authors wish
to thank Ms Zih-Chun Lin for her technical assistance.
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