| Abstract |
It has long been demonstrated that dyslipidaemia, hypertension,
hyperinsulinaemia and central obesity tend to co‐exist in certain individuals. This
co‐occurrence had been considered accidental though, as these conditions are
all very common in adults. In 1988 it was first proposed that this risk factor
clustering had a common underlying process, namely insulin resistance. The
concept of a unique pathophysiological condition characterised by
dyslipidaemia, obesity, hypertension and insulin resistance had a tremendous
appeal and changed the way of studying and understanding cardiovascular
diseases. Several terms have been used to describe this condition, among them
“syndrome X”, “insulin resistance syndrome”, “deadly quartet”, “multiple
metabolic syndrome”, “ dysmetabolic syndrome” and ,lastly, just “metabolic
syndrome”. In the present study we preferred the term “multiple metabolic
syndrome” (MMetSyn) feeling that it fits better to a condition of multiple
abnormalities and is less confusing with other paediatric disorders.
MMetSyn consists of abnormal glucose metabolism, dyslipidaemia, hypertension
and obesity and several measures of these abnormalities have been used for its
diagnosis. While a substantial debate exists over what other abnormalities
should be included in the MMetSyn and which are the best measures of them,
several definitions for its diagnosis have been proposed. The World Health
Organisation (WHO) first developed its definition in 1998, US National
Cholesterol Education Program III (NCEP III) followed in 2001 (with a most
recent update in 2005) and most recently the International Diabetes
Foundation (IDF) published its own proposal in 2005, with the NCEP III definition
being the most widely used. According to the NCEP III definition the MMetSyn is
present when 3 or more of the following 5 criteria are met: fasting glucose &γτ 100
mg/dL, blood pressure (BP) ΄&γτ 130/85 mm Hg, triglycerides (TG) ΄&γτ 150 mg/dL,
high‐density lipoprotein cholesterol (HDL‐C)΄&λλτ΄΄ 50 mg/dL (women) and &λλλλτ 40
mg/dL (men) and waist circumference (WC)΄&γγγτ΄΄ 102 cm (men) and&γγγγγγγγγγτ΄΄ 88cm
Insulin resistance is considered by many investigators the main
pathophysiologic event leading to the rest of the abnormalities of the
MMetSyn, whereas others regard dysfunctional energy storage to be the
fundamental issue. The former pathophysiologic explanation of events implies a
disruption of intracellular insulin signalling resulting in promotion of the
mitogenic and pro‐inflammatory effects of insulin, in detriment of its metabolic
and anabolic effects. According to the supporters of the latter pathophysiologic
theory, obesity is the key abnormality, which causes excess lipid accumulation.
When the capacity of adipose tissue to store triglycerides and free fatty acids is
exceeded, lipid infiltration of liver and muscles occurs, which further causes
insulin resistance and the rest of the metabolic abnormalities of MMetSyn.
Several theories have been developed concerning the aetiology of MMetSyn.
According to the encocrine theory the MMetSyn has a central neuroendocrine
origin and is a consequence of stress of contemporary way of life, which causes
overproduction of cortisol and suppression of growth and sex hormones. The
immunologic theory presumes that the MMetSyn is the result of chronic
inflammation and it is the inflammatory mediators that cause insulin resistance
and dyslipidaemia. This theory is supported by the elevated levels of c‐reactive
protein (CRP) and pro‐inflammatory cytokines, such as interleukin‐6 (IL‐6) and
tumor necrosis factor‐alpha (TNF‐α) that are found in many individuals with
MMetSyn phenotype. A different aspect is given by theories supporting the
foetal origin of MMetSyn, which are based on epidemiological studies relating
MMetSyn with a history of intrauterine growth retardation and subsequent
rapid, catch‐up growth. According to this view IUGR, a result of genetically
determined dysfunction of insulin or insulin‐like growth factor‐I (IGF‐I)
receptors, leads to pancreatic hypoplasia and reduced capacity of insulin
production. Intrauterine stress causes further endocrine abnormalities, which
promote insulin resistance. Thus, these babies are unable to adapt to the
affluent nutritional environment after birth. All theories for the origins of
MMetSyn incorporate the recent knowledge on the endocrine properties of
adipose tissue and imply a genetic background, which remains to be defined.
A relatively high prevalence of MMetSyn is a worldwide phenomenon. This
prevalence appears to be increasing because of a parallel rise in the prevalence
of obesity, which have reached epidemic dimensions in several countries even
among the younger ages. The available evidence indicates that in most
countries between 20% and 30% of the adult population can be characterised
as having the MMetSyn, with small differences between USA, Europe, Japan
and India. Even in developing countries of Latin America and Asia the
prevalence of the MMetSyn is increasing. Race and gender differences have
been reported with higher rates among white men and women of black or
Hispanic origin. Extreme rates reaching 50% of the adult population have also
been reported in certain populations, such as native Americans and inhabitants
of Australia and New Zeeland of Pacific origin.
During the last 2‐3 years some investigators have questioned the clinical utility
of the MMetSyn. The claim is made that the primary clinical focus should
remain on the individual metabolic risk factors and that aggregating them into
a syndrome adds little to clinical management. In spite of these concerns it
seems that clustering of risk factors is a real and relatively common
phenomenon and increasing rates among children and adolescents call for
greater emphasis on early recognition and prevention.
Longitudinal studies have shown that obesity tends to persist over time. The
probability of childhood obesity persisting into adulthood is estimated to
increase from approximately 20% at 4 years of age to approximately 80% by
adolescence. This persistence over time is also true for the rest of the
cardiovascular risk factors and data mainly derived from the Bogalusa Heart
Study showed that the clustering of risk factors, which constitute the
dysmetabolic syndrome tracks also strongly from childhood to young
adulthood. The follow‐up examination of individuals who were recruited as
children and adolescents found the majority of subjects who were initially in
the highest quartile of the multiple risk index to remain there 8 years later. The
alarming increase of type 2 diabetes (T2D) among children and adolescents
during the last decade suggests that MMetSyn can occur very early in life, in its
full‐blown expression.
Epidemiology
Childhood,
Adolescence
In the face of the increasing rates of childhood obesity a simple method to
identify subjects at risk for co‐morbidity among obese children would be
extremely useful. While numerous epidemiological studies of the last decade
suggest increasing rates of MMetSyn phenotype among obese children and
adolescents, its definition in growing individuals is rather difficult. Many
investigators have proposed definitions of MMetSyn for children and
adolescents by modifications of the adults’ criteria, however there is no general
agreement yet. Central more than overall obesity has been found to be
associated with the cluster of abnormalities of MMetSyn in children and waist
circumference (WC) as an indicator of intra‐abdominal fat accumulation has
been proved a better predictor of cardiovascular risk factors than body mass
index (BMI) in younger ages. However, there is no agreement on which WC cutoff
points could divide children and adolescents at risk for the development of
MMetSyn. The diversity in populations, settings and methodology used in
different studies has led to diverse conclusions and proposals. Some authors
have suggested the 90th age‐ and gender‐ specific WC percentile as a diagnostic
cut‐off for MMetSyn in childhood whereas others the 75th. Moreover there is
not much information about the association of diet and fitness with the
MMetSyn phenotype at the younger ages.
In this study we investigated the clinical relevance of WC in identifying
adolescents with MMetSyn phenotype and adverse dietary and fitness patterns,
within a school‐based healthy population of adolescents who participated in a
program of assessment of cardiovascular risk factors and multidisciplinary
intervention involving schoolchildren in the island of Crete. For this purpose, we
divided in quartiles for WC the original cohort and compared the subjects of the
extreme quartiles for the presence of cardiovascular risk factors, their
clustering, insulin resistance and body fitness.
The study participants are part of a cohort of schoolchildren who participated in
a broader program of assessment of cardiovascular risk factors among
schoolchildren, which started in 1992 under the responsibility of the
Department of Social Medicine, Division of Preventive Medicine and Nutrition of
the School of Medicine of the University of Crete and included 1046 firstgraders,
aged 5.5‐6.5 years old, attending 40 randomly selected primary schools
PRESENT
STUDY
Introduction
Purpose
Population
in three different prefectures of the island of Crete. The original cohort was
divided in intervention (602 subjects) and control (444 subjects) groups and
representative samples of both groups were re‐evaluated during 1994‐1995 at
age 8.5‐9.5 years (461 children), during 1997‐1998 at age 11.5‐12.5 years (831
children) and during 2001‐2002 at age 14.5‐15.5 years (634 children). The
program had the approval of the Institutional Ethics Committee of the University
of Crete and the Greek Ministry of Education. The families participated in the
study were contacted by informative letters about the study purposes and
procedures together with consent forms sent at least 2 weeks before the
examination dates. For all study participants signed consent forms by parents or
guardians were obtained. Verbal assent from children was also necessary for
participation. The examinations took place in schools between 8.30 am and
13.00 pm and the children were evaluated in a 12‐hour fasting state, with
clinical examination and measurement of blood pressure, anthropometric
values, blood sampling, fitness tests and questionnaires.
The population of the present study was part of the original cohort and included
adolescents who took part in both the 1997‐1998 and the 2001‐2002
examinations, had blood tests available, belonged in extreme quartiles (&γγτ75th
and ΄&λλλλλτ25th) of WC measurements at 12‐year‐old examination and remained in
the same quartiles at 15‐year‐old re‐evaluation. The record of each study
participant included anthropometric measurements, physical examination
findings, including Tanner stage, blood glucose, lipids and insulin levels and
calculation of homeostatic model assessment index (HOMA‐IR) and dietary data.
The records of the 15‐year‐old examination were used in the present analysis.
Body weight and height were measured with subjects being without shoes, on
underwear and WC was measured at the umbilical level. BMI was calculated as
weight in kilograms divided by the square of height in meters. Blood pressure
(BP) was measured with the use of mercury sphygmomanometers and
appropriate size cuffs, with children in the sitting position and the average of
three measurements was recorded and included in the analysis. Blood samples
were maintained in ice‐containing tank packs until their transfer to the
Nutritional Research Laboratory of the Department of Social Medicine,
University of Crete, where blood glucose, triglycerides (TG), total cholesterol
(TC), high‐density lipoprotein cholesterol (HDL‐C), low‐density lipoprotein
Methods
cholesterol (LDL‐C) and insulin were measured. HOMA‐IR was calculated with the
previously reported equation (fasting insulin x fasting glucose)/22.5.
Cardiorespiratory fitness was estimated according to children’s performance on
the Endurance 20 m shuttle Run Test (ERT). Dietary data were assessed by
questionnaires regarding weekly food frequency consumption and 24h recall
technique of last weekday. The foods were coded and analysed using the
University of Crete’s computerised “Greek Diet” food database.
Metabolic syndrome was defined as ΄&γγγγγγτ 3 of the criteria proposed for the diagnosis
of MMetSyn in children and adolescents by modification of the most recently
proposed criteria for the diagnosis of MMetSyn in adults by NCEP, ATP III. Insulin
resistance was assessed by fasting hyperinsulinaemia and high HOMA‐IR.
Adequate cardiorespiratory fitness was defined as ERT ΄&γγτ50th percentile for age
and gender.
Data were analysed with the SPSS statistical software package SPSS 14.0.
Statistical differences in numerical values between the two groups of WC were
assessed with Student t test and the chi square test was used to compare
proportions. Risk estimation for adolescents in the highest WC quartile was
assessed by logistic regression analysis and determination of odds ratio for each
risk factor and age, gender and original categorization in intervention and control
groups, as covariates. P values ΄&λτ 0.05 were considered statistically significant.
According to the inclusion criteria, 207 adolescents were selected, 105 of which
belonged in the highest WC quartile (΄&γτ75th percentile) and 102 in the lowest
(΄&λτ25th percentile) WC quartile. The two groups did not differ in age or gender
distribution. Adolescents with WC ΄&γτ75th percentile presented with significantly
higher fasting insulin (17±0.9 vs 9.1±1.0 μIU/mL), triglycerides (78.0±3.4 vs
62.3±3.3 mg/dL), LDL‐cholesterol (106.8±2.8 vs 96.1±2.8 mg/dL), homeostasis
model assessment index (HOMA‐IR) (3.29±1.8 vs 1.81+0.2), systolic blood
pressure (125.6±1.1 vs 116.0±1.1 mm Hg ), and diastolic blood pressure
(78.0±0.9 vs 71.5±0.9 mm Hg) and significantly lower HDL‐cholesterol (46.2±1.2
vs 53.4±1.1 mg/dL) and physical fitness as compared to their peers with WC
΄&λτ25th percentlile. Clustering of 3 CVD factors pointing to a full MMetSyn
phenotype was found for 13.5% of the 15‐year‐olds with WC ΄&γγγγγγγγτ75th percentile,
whereas most students with WC΄&λλτ΄΄ 25th percentile had no risk factors at all.
Among the criteria of MMetSyn, the risk was highest for hypertriglyceridaemia
Results
(odds ratio 6.12, p= 0.006) and high blood pressure (odds ratio 4.05, p= 0,001).
Although the risk for increased fasting blood glucose was not high, adolescents
with WC&γγγγτ 75th percentile had considerably higher risk for elevated fasting insulin
levels and high HOMA‐IR. The possibility of adequate cardiorespiratory fitness
(ERT ΄&γτ 50th percentile) was only 0.15. The analysis of dietary data revealed
significantly higher daily energy intake by the adolescents in the lowest quartile of
WC and no significant differences between the two groups in macronutrients,
fiber, calcium and iron intake.
In this study we demonstrated that WC, a simple anthropometric measurement
very easily available in clinical practice, can effectively identify adolescents with
increased possibility for clustering of cardiovascular risk factors. Moreover a
considerable proportion of adolescents with WC ΄&γτ 75th percentile for age and
gender has already the characteristics of the full‐blown expression of the
MMetSyn. WC has been successfully tested as such a tool in a number of studies
in children, most of which were either curried out in clinical settings or included
paediatric populations of wide age arrays. We have tested WC in a more
homogeneous, school‐based population of adolescents who have nearly
completed their pubertal development, and our findings suggest that WC should
be included in the diagnostic criteria of MMetSyn in young age. However, the WC
cut‐off which could better identify subjects at risk at the younger ages should be
further investigated.
The prevalence of MMetSyn among the adolescent participants of our study with
WC > 75th percentile was within the lower rates of MetS that have been reported
for overweight/obese children and adolescents, in accordance with results from
analogous studies in European countries. Higher rates of MMetSyn among
general populations of overweight/obese children and adolescents, ranging from
20‐50% have been reported mostly in the USA. These extreme rates have recently
been questioned and concerns were raised whether they reflect reality or express
a statistical overestimation, explained by the different criteria of MMetSyn used,
the wide age range and the different ethnicities of participants.
In accordance with previous studies, our results confirm that high fasting glucose
levels is the least common component of MMetSyn in children and adolescents.
Discussion
Other indexes of impaired glucose metabolism such as fasting insulin or HOMA‐IR
reflect better the status of insulin resistance, which characterizes the MMetSyn
phenotype, in younger ages. The broad use of these important indexes however is
limited by the scarcity of data for childhood. The significantly lower performance
of adolescents with WC΄&γτ 75th percentile on the ERT cardiorespiratory fitness test
reflects reduced physical activity levels, which is in agreement with other studies.
In the analysis of dietary data we found that children with WC ΄&γτ 75th percentile
are surprisingly presented with lower daily energy consumption. Because only a
self‐reported recall technique was used for dietary assessment we cannot exclude
underreporting, which is a common problem of this method of dietary recording.
In conclusion, the results of this study suggest that WC ΄&γτ 75th percentile for age
and gender can successfully identify less active adolescents with increased
cardiovascular risk and MMetSyn phenotype. However normative reference WC
data need to be collected. Fasting insulin and HOMA‐IR are better indexes of
insulin resistance than fasting glucose in the younger ages and should probably be
included in the diagnostic criteria of MetS in children and adolescents. More
objective methods than self‐reporting are necessary for evaluating the association
of MMetSyn phenotype and dietary data in young ages.
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