The association of circulating interleukin-18 with fasting insulin and weight loss in obese children

doi:10.4236/health.2010.27102

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Vol.2, No.7, 676-681 (2010)

doi:10.4236/health.2010.27102

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.

ABSTRACT

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

1. INTRODUCTION

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

677

2. MATERIALS AND METHODS

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

678

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,

USA).

3. RESULTS

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).

4. DISCUSSION

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.

Non-obese

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,

interleukin.

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

679

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)

0.169

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)

0.008

Weight reduction

program

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,

interleukin.

*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

hs-CRP.

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

680

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-

dren.

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.

5. ACKNOWLEDGEMENTS

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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