Adolesc Med 17 (2006) 565–587

Supersize Teens:
The Metabolic Syndrome
Rollyn M. Ornstein, MD*, Marc S. Jacobson, MD
Division of Adolescent Medicine, Schneider Children’s Hospital, 410 Lakeville Road,
Suite 108, New Hyde Park, NY 11040, USA

Atherosclerotic cardiovascular disease (ASCVD) is the number one cause

of death in adults in westernized societies [1]. It is accepted that obesity plays
a central role in the pathophysiology and natural history of ASCVD, as well
as of type 2 diabetes mellitus (DM), another known risk factor in the devel-
opment of ASCVD. Furthermore, it has long been recognized that specific
metabolic symptoms often cluster in individuals and collectively convey
increased cardiovascular risk [2]. The metabolic syndrome (MS), initially
referred to as syndrome X or insulin resistance syndrome, was first
described by Reaven [3] in 1988 as a connection between resistance to insu-
lin-stimulated glucose uptake and hypertension, dyslipidemia, type 2 DM,
and ASCVD. Studies within the last decade demonstrate that the process
of atherosclerosis begins in early childhood and is strongly associated
with various risk factors, including body mass index (BMI), blood pressure
(BP), and serum lipids [4–6]. Obesity is a common cause of insulin resistance
in children and adolescents [7] and is correlated with various cardiovascular
risk factors [2,4]. Additionally, the incidence of type 2 DM has been increas-
ing at an alarming rate in children and adolescents [8–10]. Because it is clear
that the MS exists in adults, and many of the variables appear to be present
in childhood, it appears reasonable to accept the existence of the MS in chil-
dren and adolescents. This statement carries important implications for rec-
ognizing the children who are at risk, performing appropriate screening, and
treating, if not preventing, the medical complications of the MS.

* Corresponding author.
E-mail address: rornstei@nshs.edu (R.M. Ornstein).

1547-3368/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.admecli.2006.06.018 adolescent.theclinics.com
566 ORNSTEIN & JACOBSON

Overview of the metabolic syndrome

The metabolic syndrome in adults
As mentioned earlier, the clustering of certain cardiovascular risk factors
has long been recognized and has come to be known as the MS. Fig. 1 de-
picts in general terms the relationship of the clinical features that compose
the MS and result in increased ASCVD risk. The figure is not meant accu-
rately to reflect the percentage of subjects with one of the clinical features
who also have another, but to provide the clinician with a frame of reference
for understanding this complex syndrome. Only recently, two clinical defini-
tions of the MS have been accepted by consensus for adults: the World
Health Organization (WHO) criteria [11] and the Third Report of the
National Cholesterol Education Program’s (NCEP) Adult Treatment Panel
(ATP III) (Table 1) [12]. The WHO definition is based on disease processes,
whereas the ATP III is more risk factor–based. In late 2005, a scientific
statement was issued by the American Heart Association (AHA) and Na-
tional Heart, Lung, and Blood Institute, recognizing the burgeoning prob-
lem of the MS. Changes to the ATP III criteria were proposed in an
effort to detect greater numbers of patients who would later develop type
2 DM (see Table 1) [13].
Several epidemiologic studies have sought to determine the prevalence
and characteristics of the MS in various adult populations [14–20]. Despite
the differences in the definitions, results appear to be consistent across pop-
ulations. Two independent studies [15,20] reported that the sex- and age-
adjusted prevalence of the MS in United States adults, using ATP III
criteria, was 23.7% and 24%, respectively. According to the results of a large
family study of type 2 DM in Finland and Sweden, the prevalence of the MS

Insulin resistance Obesity

Carbohydrate intolerance

MS

Vascular Damage
Dyslipidemia/Hypertension

Fig. 1. Relationship of the features of the metabolic syndrome.

 THE METABOLIC SYNDROME 567

Table 1
Clinical definitions of the metabolic syndrome in adults
WHO criteria [11] ATP III criteria [12]
IFG and/or IGT and/or insulin resistance Any three of the following:
and two or more of the following:
WHR O0.90 (men), O0.85 (women) or Fasting blood glucose R110 mg/dL
BMI R30 kg/m2 Modification: R100 mg/dLa
TG R1.7 mmol/L (150 mg/dL) WC R102 cm (men), R88 cm (women)
or HDL-cholesterol !0.90 mmol/L Modification: see belowa
(35 mg/dL) (men), !1.0 mmol/L
(39 mg/dL) (women)
BP R160/90 mm Hg (or treated TG R150 mg/dL
hypertension) Modifieddconsidered abnormal if
treateda
Microalbuminuria HDL-cholesterol !40 mg/dL (men), !50
mg/dL (women)
Modifieddconsidered abnormal if
treateda
BP R130/85 mm Hg (or treated
hypertension)
Abbreviations: HDL, high-density lipoprotein; IFG, impaired fasting glucose; IGT, im-
paired glucose tolerance; TG, triglycerides; WC, waist circumference; WHR, waist-to-hip ratio.
a
In 2005, an expert panel of the American Heart Association and National Heart, Lung,
and Blood Institute concluded that the fasting glucose threshold should be lowered to 100
mg/dL, in accordance with the American Diabetes Association’s reduction of the levels required
to be considered impaired. Additionally, it allowed for adjustment of waist circumference values
to lower thresholds in individuals or ethnic groups that are prone to insulin resistance and sug-
gested that TG, HDL-cholesterol, and blood pressure values be considered abnormal if a person
is on drug treatment for these risk factors [13].

was 15% in men and 10% in women with normal glucose tolerance, and
64% in men and 42% in women with impaired glucose tolerance (IGT)
[14]. These studies have confirmed the role that the MS plays in conveying
risk for type 2 DM [16,17] and ASCVD [14,18], as well as for mortality as-
sociated with these diseases.
Because obesity is a common and easily recognizable concomitant of the
MS that has become epidemic in children and adolescents [21], there has
been recent attention directed toward the study of the MS in this
population.

Prevalence of the metabolic syndrome in children and adolescents

Numerous large population studies have demonstrated the prevalence of
the MS in childhood. In general, the prevalences are low when compared
with those of adults (3% to 4%). This finding is not surprising, because,
in adult studies, the prevalence increases dramatically with age (eg, 6.7%
among 20- to 29-year-olds versus 43.5% among those aged 60 to 69 years)
[15]. The Bogalusa Heart Study, a population-based longitudinal study of
568 ORNSTEIN & JACOBSON

risk factors for cardiovascular disease in black and white children, defined
the MS as having four features to a degree greater than or equal to the
75th percentile for age and gender, based on population data from the study
itself [22]. Included in the definition were BMI, mean arterial BP, triglycer-
ides (TG) to high-density lipoprotein (HDL)–cholesterol ratio, and fasting
insulin. Using this definition, the investigators found a prevalence of 4.8%
in white and 3.7% in black children (aged 5 to 11 years) and 3.0% and
2.7% in white and black adolescents, respectively [23]. The Cardiovascular
Risk in Young Finns Study, a large multicenter study of the risk factors for
coronary heart disease and their determinants in children, adolescents, and
young adults, found a comparable 4% prevalence of the MS using the pa-
rameters of low HDL-cholesterol, high TG, and high systolic BP [24]. Of
note, these studies were published before the ATP III and WHO definitions.
The prevalence of the MS was more recently determined in 2430 United
States adolescents who took part in the third National Health and Nutrition
Examination Survey (NHANES III, 1988–1994) [25]. These investigators
used a definition of the MS similar to that of the ATP III, with adaptations
based on pediatric reference data where available. The prevalence of the MS
overall was 4.2%, with that of males significantly higher at 6.1%, versus
2.1% in females. This study also found that 28.7% of adolescents who
are considered overweight (BMI R95th percentile) met criteria for the
MS. In this representative sample of adolescents, 41% had at least one
risk factor, with 14.2% having at least two. High TG and low HDL-choles-
terol were the most commonly encountered abnormalities in this study. By
comparison, high fasting glucose was the least prevalent at 1.5%. Another
group used the NHANES III data to determine the prevalence of the MS
in 12- to 19-year-olds, using somewhat less stringent pediatric cut-off points
for each risk factor, in an effort to be more analogous to ATP III. They dis-
covered a higher prevalence of 9.2%, with a rate of 31.2% in those subjects
who were classified as overweight [26]. It is of interest that the NHANES III
data may underestimate the current prevalence of the MS, as childhood
overweight continues to rise [21].
Weiss and colleagues [27] investigated the effect of variable degrees of
obesity on the prevalence of the MS among adolescents, using modified
APT III and WHO criteria. They found that the overall prevalence of the
MS was 38.7% in moderately obese patients (BMI z-score 2.0 to 2.5) and
nearly 50% in severely obese patients (BMI z-score O2.5). No overweight
patients (BMI 85th to 97th percentile) or nonobese patients (BMI !85th
percentile) met criteria for the MS. Of note, each individual risk factor
was exacerbated by an increasing level of obesity. Most recently, a school-
based, cross-sectional study of a predominantly biracial teenage cohort
compared prevalences of the MS, using both ATP III and WHO guidelines.
The investigators found that the ATP III–defined prevalence was 4.2%, the
WHO-defined prevalence was 8.4%, and the rates were 19.5% and 38.9%,
respectively, for those who were obese [28].
 THE METABOLIC SYNDROME 569

Role of ethnicity in the prevalence of the metabolic syndrome

Ethnicity appears to play a role in the rates and manifestations of the MS
in children and adolescents. Certain ethnic groups, for instance, Hispanics,
blacks, Native Americans, and Asian Americans, appear to be especially
prone to both insulin resistance and obesity. In the adult NHANES III
study, Mexican Americans had the highest age-adjusted prevalence
(31.9%), with blacks having the lowest rates (21.6%) [15]. Likewise, in the
first adolescent NHANES III study, the prevalences were higher among
Mexican Americans (5.6%) and whites (4.8%) than among blacks (2.0%)
[25]. The prevalence of overweight in Hispanic youth has doubled in the
past decade, with a rate of 21.8% most recently noted [29]. Based on this
statistic, Cruz and colleagues [30] investigated the prevalence of the MS in
a sample of overweight Hispanic children, aged 8 to 13 years, based on mod-
ified ATP III criteria. They found that 30% of their subjects, who had a fam-
ily history of type 2 DM, had the MS. Additionally, approximately 90% of
the study participants had at least one abnormality of the MS.
Interestingly, it is known that black children have a similarly high prev-
alence of obesity (23.6%) to Mexican Americans [21,29]. They also have sig-
nificantly higher fasting insulin levels than white children prepubertally,
before the onset of overweight [31]. Insulin hypersecretion persists into ad-
olescence as the more significant insulin abnormality in blacks [32]. Yet the
rates of the MS in black youth are lower when the same ATP III criteria are
used [22,23,25]. As in adults, black youth have lower TG and higher HDL-
cholesterol levels, but higher BP, when compared with white children [23].
Although Weiss and colleagues [27] originally found lower prevalence of
the MS in their black subjects, when they reanalyzed the data using lipid
threshold levels specific to blacks, the prevalence and the effect of obesity
were similar to those in the white and Hispanic subjects. Thus, it may be
prudent to consider the use of criteria specific for race and ethnicity when
evaluating for the MS.

Pathophysiology of the metabolic syndromedinsulin resistance and obesity

Although there appears to be some agreement on the definition of the MS
in adults, debate still exists as to whether insulin resistance or obesity is the
central underlying cause of the syndrome. Insulin resistance may be defined
as a diminished biologic response to a normal concentration of circulating
insulin. Obesity is key in the development of insulin resistance, and risk
for insulin resistance is accentuated with increasing obesity [33]. Several
mechanisms are cited as contributory. For example, adipocytes release
free fatty acids (FFAs), high circulating levels of which cause ‘‘lipotoxicity.’’
This state induces insulin resistance in liver and muscle [34]. Additionally,
adipose tissue secretes the hormone adiponectin, which augments insulin
sensitivity. Levels of adiponectin are decreased in obese individuals [35].
570 ORNSTEIN & JACOBSON

Adipocytes also secrete cytokines that promote insulin resistance and are
associated with the MS (eg, tumor necrosis factor–alpha and interleukin-6)
[33].
Insulin is the main hormonal signal for energy storage in adipocytes. Hy-
persecretion of insulin by the pancreas is known to contribute to weight gain
in certain circumstances (eg, in infants of diabetic mothers and initiation of
insulin therapy in diabetes). Because insulin resistance and hypersecretion
tend to coexist, it may be difficult to delineate their respective roles in the
origins of obesity. Even so, insulin resistance appears to encourage weight
gain in adults, as well as in children, especially in the abdominal area.
This effect may be due to selective insulin sensitivity of adipose tissue con-
current with resistance in skeletal muscle and hepatic tissue. Another expla-
nation is the ‘‘thrifty phenotype’’ hypothesis, whereby human metabolism is
programmed to build greater nutrient stores during periods of abundance to
survive times of deprivation [33]. It is not clear whether insulin hypersecre-
tion leads to insulin resistance, or whether the opposite is true. One study of
obese children demonstrated that postprandial hyperinsulinemia occurred
several years before insulin resistance [36].
In adults, it is widely accepted that both insulin resistance and obesity are
the fundamental abnormalities in the MS and contribute to the other risk
factors [37–39], although the original description of the syndrome did not
include obesity as an essential characteristic [3]. Studies in children provide
a unique opportunity to determine causative factors, because the evolution
of the MS may be examined prospectively. The Cardiovascular Risk in
Young Finns Study was one of the first to investigate the childhood predic-
tors of the MS. The investigators found higher baseline fasting insulin levels
in those subjects who manifested hypertriglyceridemia 6 years later, as well
as clustering of the other features of the syndrome. This finding was inde-
pendent of obesity, indicating that insulin resistance precedes the develop-
ment of the MS in childhood and adolescence [24]. Similarly, in Pima
Indian children, a population prone to obesity and type 2 DM, early hyper-
insulinemia predicted increased rate of weight gain and obesity over approx-
imately 9 years, independent of baseline BMI [40]. A cross-sectional study of
357 children likewise concluded that there is an early association of insulin
resistance, as determined by the euglycemic insulin clamp, with the other
risk factors for the MS, independent of BMI. The clustering of risk factors
was seen in children with the highest degree of insulin resistance [41].
Investigators from the Bogalusa Heart Study examined the relative influ-
ences of childhood adiposity and insulin on the risk for developing MS in
adulthood in subjects aged 8 to 17 years at baseline, followed for 11.6 years.
They discovered that a high childhood BMI was a significant predictor of
clustering of all four features of the MS in adulthood. Although this was
also true for hyperinsulinemia, the association disappeared after adjusting
for BMI [42]. They also found that offspring of parents who had ASCVD
(and who were therefore considered at risk for ASCVD) acquired excess
 THE METABOLIC SYNDROME 571

body fatness starting in childhood, then exhibited hyperinsulinemia as

young adults [43].
Although these last two studies suggest that childhood obesity may play
the more causative role in the development of the MS, they do not explain
why childhood obesity does not universally lead to the MS. As mentioned
earlier, the NHANES III data demonstrated that 30% of overweight chil-
dren develop the MS, whereas 70% do not [25]. Insulin sensitivity was
62% lower in overweight subjects who had the MS than in those overweight
children who did not manifest the MS in a study of Hispanic children with
a family history of type 2 DM, after controlling for body composition. Fur-
thermore, insulin sensitivity, independent of fat mass, was positively corre-
lated with HDL-cholesterol and negatively correlated with TG and BP; this
relationship was not observed for total fat mass [30]. These findings support
the hypothesis that insulin resistance is the mediator by which adiposity
affects serum lipids and BP and plays a central role in the MS.

Waist circumference/Central adiposity

Central adiposity may in fact be a better clinical indicator of metabolic
risk than BMI alone [44–47]. Measurement of waist circumference (WC),
as opposed to other anthropometric variables such as waist-to-hip ratio
(WHR), may serve as a useful clinical tool in identifying patients at risk.
Many studies in children and adolescents have supported this theory [48–53].
Most recently, a 10-year longitudinal cohort study of black and white girls
(the National Heart, Lung, and Blood Institute Growth and Health Study)
found that early obesity, and most notably central adiposity, is a significant
predictor for the development of the MS during adolescence [54]. In fact, the
prevalence of the MS in girls who had persistently increased central adiposity
was 12.1%, compared with 3% for the whole study population. A high tracking
coefficient existed for WC; approximately 72% of girls had increased central
adiposity at baseline and 10 years later. These findings underscore the theory
that WC is a key predictor of the metabolic repercussions of obesity.
In adults, WC, rather than WHR, is well correlated with visceral adipose
tissue [46,55]. Furthermore, visceral fat accumulation is associated with in-
sulin resistance and dyslipidemia [45,47], as well as with ASCVD in adult
women [56]. One theory behind these findings is that intra-abdominal adipo-
cytes are more lipolytically active, which may serve to inhibit insulin clear-
ance and promote insulin resistance [34]. As in adults, visceral fat accretion,
in contrast to subcutaneous abdominal fat, may contribute more signifi-
cantly to the pathophysiology of the MS in childhood [57]. In pubertal girls,
WC has been shown to be a good estimate of the amount of truncal fat,
as quantified by MRI [58]. Weiss and colleagues [59] showed that, in obese
children and adolescents who had prediabetes, intramyocellular and intra-
abdominal fat accumulation, as determined by MRI, was strongly associ-
ated with the development of severe peripheral insulin resistance. Similarly,
572 ORNSTEIN & JACOBSON

Cruz and colleagues [60] demonstrated that, in overweight Hispanic youth

with a family history of type 2 DM, both visceral fat and total fat signifi-
cantly influenced the differences seen in insulin sensitivity.
Therefore, data indicate that obesity and, possibly more importantly,
central adiposity, together with increased susceptibility to insulin resistance,
may promote the development of the MS in childhood and adolescence.
Furthermore, it is possible that, among overweight children, insulin resis-
tance makes a more significant contribution to the development of the
MS during childhood than overall obesity.

Impaired glucose tolerance and type 2 diabetes mellitus in children

and adolescents
As mentioned in the introduction, it was discovered in the mid-1990s that
the incidence of type 2 DM in adolescents was increasing concomitantly
with the national obesity epidemic [8–10]. In 2000, the American Diabetes
Association published a consensus position paper on the subject, which
mentioned that between 8% and 45% of newly diagnosed cases of diabetes
in children are non–immune-mediated [61]. The cause of discrepancy in re-
corded rates is most likely the variability among different racial and ethnic
populations, with Native Americans, Hispanics, African Americans, and
South Asians reportedly having higher prevalences than white youth [62].
It is known in adults that impaired fasting glucose or IGT is a transitional
stage in the pathophysiologic process of the development of type 2 DM
[63,64]. This process is likely to be similar in children and adolescents. Ad-
ditionally, insulin resistance and deterioration of insulin secretion portend
the development of type 2 DM [65–67].
It is still debated whether insulin resistance or impaired insulin secretion
is the primary abnormality in type 2 DM in adults. In children and adoles-
cents, deficient insulin action appears to be the fundamental defect, which is
later coupled with failure of pancreatic b-cells in the progression to frank
diabetes [61]. Abnormal fasting glucose is not common in children and ad-
olescents, with a prevalence of 1.5% to 1.8%, and of only 2.5% to 2.6% in
overweight youth [25,68]. However, IGT after provocation with glucose is
common among overweight children and adolescents, seen in approximately
a quarter of the subjects studied by Sinha and colleagues [69]. Furthermore,
4% of this sample had asymptomatic type 2 DM. Insulin resistance ap-
peared to be the best predictor of IGT, after controlling for BMI. Another
study found the prevalence of IGT to be 28% in a sample of overweight La-
tino children with a family history of type 2 DM. This finding was indepen-
dent of degree of obesity, in contrast to the former study [70]. The children
who had IGT also demonstrated deficient b-cell function related to age. An-
other study of obese youth who had IGT revealed decreased insulin
sensitivity, in addition to b-cell dysfunction. These investigators also showed
 THE METABOLIC SYNDROME 573

that those subjects who had IGT had a greater visceral-to-subcutaneous fat
ratio, as determined by MRI, and suggested that the progression to IGT is
determined by this pattern of fat partitioning [59]. In a study of 710 obese
European children, the prevalence of IGT was found to be 4.5%. Both in-
sulin resistance and impaired insulin secretion contributed to the hypergly-
cemia, and the level of obesity was associated with other cardiovascular risk
factors, independent of insulin resistance [71].

Effects of puberty
Onset of puberty, with its accompanying insulin resistance and resultant
hyperinsulinemia [72,73], plays a role in the development of both IGT and
type 2 DM. It is thus not surprising that most adolescents present with type
2 DM at midpuberty, when the homeostasis of compensatory hyperinsuline-
mia with normal glucose tolerance is exhausted, and insulin hyposecretion
with IGT ensues [61]. Adolescents who have type 2 DM are almost always
obese, with mean BMI in one clinical series ranging from 26 to 38 kg/m2.
They also tend to have elevated BP and hypertriglyceridemia [62], thereby
demonstrating the clustering of cardiovascular risk factors seen in the MS
and perhaps making this the extreme end of the MS spectrum.
Investigators from the Bogalusa Heart Study compared offspring of
parents who did and did not have type 2 DM and found that the former
demonstrated significant excess body fat beginning in childhood and an
escalating risk factor profile as they progressed through adolescence
into young adulthood [74]. Because it is known that type 2 DM has
strong genetic and familial determinants, these results may have important
implications for screening and prevention in such children.

Hypertension and the metabolic syndrome

Essential hypertension is multifactorial, involving the interplay of ge-
netic, physiologic, and biochemical systems derangements. The prevalence
in children and adolescents is increasing, along with the obesity epidemic.
In children and adolescents, there appear to be several possible pathogenic
mechanisms involved, including disturbances in autonomic function, insulin
resistance, and abnormalities of vascular structure and function. Hyperten-
sion associated with obesity is probably due to a combination of these
factors [75].
Insulin increases both renal sodium retention and free water clearance.
Additionally, insulin resistance is associated with increased activity of the
sympathetic nervous system, as well as stimulation of growth of vascular
smooth muscle. Although insulin levels have been found to be significantly
higher in patients who have essential hypertension, obesity is certainly a con-
founding factor [75]. A study by Cheng and colleagues [76] found a common
genetic link between BP and insulin sensitivity on the same region of
574 ORNSTEIN & JACOBSON

chromosome 7q. This finding actually supports the possibility of a genetic

cause for the MS. Investigators from the Bogalusa Heart Study observed
clustering of cardiovascular risk factors, including elevated systolic and di-
astolic BP measurements in overweight children and adolescents, even at
a young age [77]. Similarly, Maffeis and colleagues [49] conducted a cross-
sectional study in prepubertal children and discovered that WC was most
significantly associated with systolic and diastolic BP, and that children
with a WC greater than the 90th percentile were more likely to have multiple
cardiovascular risk factors. In a study by Sinaiko and colleagues [41], after
adjusting for BMI, BP was not associated with insulin sensitivity as mea-
sured by the euglycemic insulin clamp. However, they did note a significant
clustering of the other risk factors, which were also related to BP. These au-
thors concluded that the common mediator was body fatness, not insulin re-
sistance, in young persons who had features of the MS. In a study of black
and white children, insulin sensitivity, independent of body composition,
was negatively associated with BP early in life [78].

Dyslipidemia and the metabolic syndrome

Abnormalities of serum lipids are a central feature of the MS. They re-
flect acquired defects in the metabolism of carbohydrates and fats, as well
as lifestyle variations in diet and physical activity leading to energy imbal-
ance. Many serum lipid abnormalities are seen, including elevated total
and low-density lipoprotein (LDL)–cholesterol, small, dense LDL particles,
and lipoprotein B and E isoforms disturbances. Two in particular are of pri-
mary concern: hypertriglyceridemia and low HDL-cholesterol [79].
Hypertriglyceridemia results when energy intake is in excess of energy ex-
penditure, when excess saturated fat content of the diet leads to excess very-
low-density lipoprotein (VLDL) production, or when capillary endothelium
in the vascular beds of the muscle or adipose tissue is depleted of lipoprotein
lipase. These conditions may all coexist in a given individual. When any of
these situations is present, excess serum VLDL is manifest as fasting and
postprandial hypertriglyceridemia [79].
Low levels of HDL-cholesterol are often associated with hypertriglyceri-
demia because the TG-rich lipoproteins, VLDL and chylomicrons, are the
recipients in the enzyme-mediated transfer of cholesterol from HDL particles
by means of the enzyme Cholesterol Ester Transfer Protein. This transfer is
the rate-limiting step in reverse cholesterol transport of tissue cholesterol to
the liver for excretion by means of bile acids. Therefore, the level of HDL-
cholesterol is an antirisk factor for ASCVD. Low level of HDL-cholesterol
may result from genetic defects or be acquired by lifestyle [79].
Dyslipidemia has been linked to obesity as well as insulin resistance. In
a study of insulin resistance and lipids, an ‘‘atherogenic’’ lipid profile
(high LDL-cholesterol and TG with low HDL-cholesterol) was observed
 THE METABOLIC SYNDROME 575

in the obese, euglycemic adolescents when compared with lean adolescents.

Additionally, there was a correlation between dyslipidemia and degree of in-
sulin resistance [80]. Researchers from the Bogalusa Heart Study also noted
that overweight children were more likely than their lean peers to have ele-
vated total cholesterol, LDL-cholesterol, and TG, as well as hyperinsuline-
mia [77]. In a recent longitudinal study of black and white girls, baseline TG
level was predictive of future MS in the white girls only [54].
Insulin resistance may cause abnormalities in lipid metabolism in a few
ways. First, hyperinsulinemia augments hepatic VLDL synthesis, thereby
contributing to increased TG and LDL-cholesterol levels. Resistance to in-
sulin’s action on lipoprotein lipase in peripheral tissues has a similar effect.
Second, insulin resistance increases the rate of apolipoprotein A1/HDL-
cholesterol degradation more quickly than it is synthesized, resulting in
lower levels of HDL-cholesterol [81]. Furthermore, it has been demon-
strated that hyperinsulinemia in children leads to impaired suppression of
total body lipid oxidation and plasma FFA concentration [7].

Menstrual abnormalities associated with the metabolic syndrome

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder, affect-
ing 5% to 10% of women of reproductive age [82]. The characteristic
features of this syndrome include hyperandrogenemia, with resultant
hirsutism and acne, and oligomenorrhea or amenorrhea, with anovulatory
cycles and infertility. PCOS appears to start in the perimenarcheal period
and thus is now recognized as a significant cause of menstrual disturbances
in adolescents, especially when accompanied by clinical signs of androgen
excess. PCOS is often described as an abnormal and exaggerated pubertal
response in four developmental areas: maturation in the pattern of lutein-
izing hormone (LH) secretion, increase in adrenal androgen production,
increase in body mass, and beginning of an adult pattern of insulin
resistance [83].
Although insulin resistance is not one of the diagnostic criteria for PCOS,
it has been accepted as a common feature of the disorder for more than 20
years. It appears paradoxical that women with PCOS should exhibit insulin
resistance in relation to carbohydrate metabolism yet demonstrate effects of
ovarian hyperresponsiveness to insulin; this is why it is termed selective in-
sulin resistance [84]. Early research suggested that hyperandrogenemia led
to hyperinsulinemia, because androgens may produce mild insulin resis-
tance. However, it is currently recognized that insulin resistance quite prob-
ably plays an early and central role in the pathogenesis of ovarian and
reproductive dysfunction in PCOS. The compensatory hyperinsulinemia
increases ovarian androgen production, decreases hepatic sex hormone–
binding globulin production, and may also directly enhance pituitary LH
secretion [82,83].
576 ORNSTEIN & JACOBSON

It is notable that insulin resistance in PCOS can be independent of

obesity, which is a feature of the syndrome in only approximately 50% of
women [85]. Nevertheless, PCOS is certainly a risk factor for the early devel-
opment of type 2 DM and its associated ASCVD, independent of obesity.
One large prevalence study found that approximately 40% of women who
had PCOS had IGT, including 7.5% who had type 2 DM [82]. Therefore,
adolescent females who present with the features of PCOS, irrespective of
weight status, represent a specific subpopulation that warrants investigation
into the presence of features of the MS.

Definition of the metabolic syndrome in children and adolescents

Because we know that several of the risk factors seen in the MS track into
adulthood, it appears appropriate to include these same features when de-
veloping a working definition in children. One major difference between
adults and children, as mentioned earlier, is that the prevalence of fasting
hyperglycemia is low in children, whereas IGT is more common. It may
therefore be reasonable to use the latter as a component of the definition
as opposed to the former. Additionally, it is not universally accepted to
use the WC over the BMI as a measure of obesity. Recent studies have
adopted the ATP III definition, using pediatric thresholds for certain com-
ponents [25–28,30]. However, even these studies exhibit discrepancies
among their definitions. One problem of defining the MS in children is
that the lipid threshold values have not been modified by NCEP since
1991 [86]. Recently, a set of WC percentiles for African American, European
American, and Mexican American children have been developed, based on
NHANES III data [87]. However, these have not yet been applied in epide-
miologic studies. Additionally, it is not clear whether threshold values for
each risk factor should be specific for ethnicity and gender, as has been sug-
gested for adults. Nevertheless, a proposed definition of the MS in children
and adolescents, based on ATP III criteria, is presented in Table 2. The 90th
(or 10th) percentile was used as a cut-off to be consistent with ATP III.
However, it could be argued that using the 75th (or 25th) percentile as
a threshold would detect more at-risk patients at a time when prevention
might be more feasible.

Screening and treatment for the metabolic syndrome in childhood

and adolescents
Approaches to screening
Although the overall prevalence of the MS in children and adolescents is
low compared with that of adults, it is clear that overweight youth represent
a population at risk [25–27,30]. Therefore, although screening all children
may not be appropriate, it appears essential to screen overweight youth,
 THE METABOLIC SYNDROME 577

Table 2
Proposed defining criteria and cut-off values for the various feature of the metabolic syndrome
in children and adults
Features of MS Age (y) Males Females
a
High glucose
Fasting d R100 mg/dL R100 mg/dL
2-h post–standard OGTT d R140 mg/dL R140 mg/dL
Systolic BP, mm Hgb 8 112 111
12 120 119
15 127 123
17 132 125
Adultf R130 R130
Diastolic BP, mm Hgb 8 73 72
12 76 76
15 79 79
17 82 80
Adult R85 R85
Triglycerides, mg/dLc 12–19 135 170
16–19 165 168
Adult R150 R150
HDL-cholesterol, mg/dLd 6–8 37 37
9–11 39 38
12–15 35 36
16–19 33 37
Adult %40 R50
Waist circumference, cme 8 71.2 70.5
12 84.8 82.7
15 95 91.9
17 101.8 98
Adult R102 R88
Abbreviation: OGTT, oral glucose tolerance test.
a
Data are based on the American Diabetes Association recommendations; same for chil-
dren and adults [108].
b
Data are from the National High Blood Pressure Education Program Working Group on
High Blood Pressure in Children and Adolescents [90]. Data are values for the 90th percentile,
assuming a height percentile of 50. Data are available for ages 1 to 17 years.
c
Data are from NHANES III [108]. Values are 90th percentile for age and gender. There
are also separate values for non-Hispanic white, non-Hispanic black, and Mexican American
children and adolescents. Data are available from ages 4 to 19 years.
d
Data are from NHANES III [109]. Values are 10th percentile for age and gender. There
are also separate values for non-Hispanic white, non-Hispanic black, and Mexican American
children and adolescents. Data are available from ages 4 to 19 years.
e
Data are from NHANES III [87]. Values are 90th percentile for age and gender of total
population. There are also separate values for European American, African American, and
Mexican American children and adolescents. Data are available for ages 2 to 18 years. WC
was measured with a tape measure just above the uppermost lateral border of the right ilium,
at the end of normal expiration, and recorded to the nearest millimeter.
f
Adult Treatment Panel definition of the MS in adults [12,13].
Adapted from Cruz ML, Goran MI. The metabolic syndrome in children and adolescents.
Curr Diabetes Reports 2004;4:53–62.
578 ORNSTEIN & JACOBSON

especially those belonging to minority groups considered at higher risk.

Additionally, family history is important: One study concluded that insulin
resistance and obesity may be the earliest signs of the MS in children who
have at least one parent with the MS [88]. Currently, pediatric guidelines
recommend screening for obesity [89], type 2 DM [61], hypertension [90],
and dyslipidemias [2,86,91–93] in those children considered at risk; however,
these each fall under different pediatric subspecialties. Adoption of a screen
for the MS could unify these recommendations and facilitate strategies for
identifying and treating overweight youth. The features outlined in Table
2 could serve as a possible screen for those children with a BMI greater
than or equal to the 95th percentile.

Treatment strategies
The need to identify youth who are at risk for developing type 2 DM and
ASCVD and to implement treatment to prevent these diseases is the impetus
for defining the MS at all. Two statements from the AHA on cardiovascular
health and prevention of disease in childhood provide clear synopses for
health professionals of assessment and intervention in all areas of the MS,
as well as physical activity and smoking [92,93]. Therapeutic lifestyle change
(TLC) remains the primary therapy for treatment of the MS in both adults
and children. This strategy attempts to target the underlying problem (ie, in-
sulin resistance), which, when improved, can influence the improvement of
other cardiovascular risk factors.

Diet and exercise

TLC focuses on healthy eating, reduction in sedentary activities, and in-
crease in regular physical activity. Healthy eating refers to making choices
about food types and amounts that promote optimum energy balance.
For an adolescent, optimum energy balance needs to vary considerably de-
pending on stage of growth and hence sexual maturity. Finding and achiev-
ing this balance in the context of risk for, or existing, MS is difficult under
the best of circumstances and is complicated by the toxic food and lifestyle
environment in which teens are currently immersed.
Step one is a thorough nutritional assessment, best performed by a regis-
tered dietitian experienced in working with adolescents [94]. This assessment
may include a direct measurement of resting energy expenditure by means of
a metabolic cart. Once the nutrition assessment is completed, diet change
can begin. The emphasis should be on reducing saturated fat and simple car-
bohydrates in the diet. Methods for implementing appropriate diet modifi-
cations were recently reviewed in detail in this journal [94].
One simple measure that may have a great effect on reducing rates of
childhood overweight and obesity is to curtail the consumption of sugary,
carbonated beverages. A school-based educational program in the United
Kingdom was found to be effective in this regard [95]. Interestingly, the
 THE METABOLIC SYNDROME 579

Coronary Artery Risk Development in Young Adults study discovered that

increased dairy consumption was inversely associated with all components
of the MS. This finding may be explained by changes in dietary patterns
(eg, low glycemic index) associated with dairy intake [96].
Physical activity recommendations for adolescents were also recently re-
viewed in this journal [97]. To explain briefly, energy expenditure may best
be thought of as consisting of time spent in (1) sedentary, (2) mild or mod-
erately active, or (3) vigorous activities. Strategies are necessary for all three
types of exercise. For example, it is useful to assess the time spent watching
television, because reduction of this time is one of the best documented ways
to reduce BMI in children [98]. Increasing the time spent in daily activities in
the mild-to-moderate range, such as walking, yoga, stretching, biking, and
chores, should not be forgotten as an important part of therapy. Vigorous
activity like competitive or noncompetitive intramural sports may be impor-
tant for some teenagers and unrealistic for others. An ongoing repeat assess-
ment is necessary to tailor the program to the individual and family. Current
recommendations are that all adolescents trying to maintain weight partic-
ipate in 30 minutes of vigorous activity on most days of the week, and those
trying to lose weight participate in 1 hour daily [93,99]. An 8-month longi-
tudinal study showed that physical training, particularly of the high-inten-
sity type, had a beneficial effect on several of the components of the MS
in obese adolescents [100].
Some studies in severely obese adults who underwent bariatric surgery
have shown high cure rates for the MS, as well as significant prevention
of the progression from IGT to type 2 DM [101,102]. Although this is not
a widely accepted procedure in obese adolescents, multidisciplinary pro-
grams have embarked on it in adolescents who have either a BMI of at least
40 kg/m2 and serious obesity-related comorbidities (eg, obstructive sleep ap-
nea, type 2 DM) or a BMI greater than 50 kg/m2 and less severe comorbid-
ities [103]. Therefore, this may serve as a therapeutic modality for those at
greatest risk and for whom other weight loss and lifestyle intervention
efforts have failed.

Metformin and other insulin-lowering modalities

Studies have been conducted in high-risk (BMI O30 kg/m2), insulin-resis-
tant adolescents using metformin (Glucophage), a biguanide drug that acts
as an insulin sensitizer as well as an antihyperglycemic. The exact mecha-
nism of action of metformin is unknown. One 6-month randomized, dou-
ble-blind, placebo-controlled longitudinal study specifically did not restrict
caloric intake and found significant improvements in glucose tolerance
and fasting insulin, as well as a small but statistically significant reduction
in BMI standard deviation score [104]. Another 8-week randomized, dou-
ble-blind, placebo-controlled trial, in which all subjects were placed on a hy-
pocaloric diet, observed that the metformin group had significantly greater
weight loss, greater decrease in body fat, greater improvement in
580 ORNSTEIN & JACOBSON

hyperinsulinemia, and enhanced insulin sensitivity compared with the pla-

cebo group. These findings were accompanied by significant reductions in
plasma cholesterol, TG, and FFAs in the metformin group only [105]. Sub-
jects in both studies tolerated the metformin well, with only some of them
experiencing the transient gastrointestinal side effects that are typical of
the drug. These two studies suggest that metformin could serve as a benefi-
cial adjunct to the standard treatment of TLC.
Thiazolidinediones are drugs that reduce insulin resistance and are much
stronger insulin sensitizers than metformin. In one study of high-risk His-
panic adult women, troglitazone improved insulin resistance and delayed
or prevented progression to type 2 DM [67]. Clinical trials in the pediatric
population for metformin, as well as thiazolidinediones, are ongoing. How-
ever, these medications are not currently approved for the treatment of the
MS without type 2 DM in children and adolescents.

Lipid-lowering agents
Treatment of dyslipidemia is achieved primarily through TLC and weight
control. When this fails, particularly in the older adolescent and young adult,
pharmacotherapy may be considered. Lipid-lowering agents (Table 3) are
currently only US Food and Drug Administration (FDA)–approved for het-
erozygous familial hypercholesterolemia [106,107]. No agents are currently
approved for the abnormal lipid manifestations of the MS, so only off-label
use is available. The agents most appropriate for hypertriglyceridemia and
low HDL-cholesterol are niacin (best given in the extended-release prepara-
tion Niaspan) and the fibric acid derivatives, gemfibrozil and fenofibrate.
Niacin may aggravate hyperglycemia, so it must be used with caution in
type 2 DM and possibly MS. Fibrates may be a better choice; however,
they interact with many antihypertensives (eg, diuretics, angiotensin convert-
ing enzyme [ACE] inhibitors, and b-blockers), so caution is also required with
their use [79]. Statins may be indicated when LDL-cholesterol remains greater

Table 3
Lipid-lowering agents
Drug class Examples Action Side effects Dosage
Niaspan Lowers VLDL Flushing 500–1000 mg
synthesis [ AST & ALT daily
Hyperglycemia
Fibrate Gemfibrozil Lowers VLDL Dyspepsia Varies with
Fenofibrate synthesis Constipation preparation
Myositis
Anemia
Statin Lovastatin Inhibits hepatic Myalgia 10–80 mg daily
Atorvastatin cholesterol synthesis Myositis
Pravastatin [ AST & ALT
Simvastatin
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
 THE METABOLIC SYNDROME 581

than 160 mg/dL despite other treatments, and when other risk factors are
present as well [92,93].

Antihypertensives
Although weight control through dietary modification and regular phys-
ical activity can make pharmacotherapy for obesity-related hypertension
unnecessary, there are circumstances where medications are indicated.
Because the long-term outcomes of untreated hypertension and the long-
term effects of antihypertensives on growth and development are unknown,
a clear indication for starting therapy should be identified before prescribing
medication. Indications include inadequate response to TLC, evidence of
target-organ damage (left ventricular hypertrophy being the chief manifesta-
tion in children and adolescents), and symptomatic hypertension [90].
Recent clinical trials have broadened the number of drugs that have FDA
labeling for pediatric dosages. Pharmacotherapy should be initiated with
a single drug, usually at the discretion of an experienced clinician. Recom-
mended classes include ACE inhibitors, angiotensin-receptor blockers,
b-blockers, calcium channel blockers, and diuretics. The goal for treatment
is reduction of BP to less than the 95th percentile, unless comorbid condi-
tions are present, in which case the BP should be lowered to less than the
90th percentile. Children and adolescents who have the MS represent
a group for whom ‘‘step-down’’ therapy may be considered. In this ap-
proach, a gradual decrease in the medication after a prolonged course of sat-
isfactory BP control may be attempted, with the ultimate goal of complete
discontinuation of the drug. This strategy may work in conjunction with
continual and successful TLC [90].

Summary
The MS represents a constellation of risk factors, including obesity, dys-
lipidemia, fasting hyperglycemia or IGT, and hypertension, that predispose
to ASCVD and type 2 DM. The prevalence in children and adolescents is
low, at about 4% of the general population. However, in those who are
overweight, these rates are much higher at 30% or greater, with many
more having at least one of the features. Ethnicity appears to affect the ob-
served rates of the MS in various adolescent populations. Insulin resistance
and obesity underlie the pathophysiology of the MS, each most likely con-
tributing both individually and synergistically. Because obesity has become
epidemic in children and adolescents, and diagnosis of type 2 DM is on the
rise, it is clear that interventions need to be made early, in an effort to pre-
vent the morbidity and mortality associated with the MS. The most effective
treatment for the MS in most adolescents is TLC. When this is insufficient,
an insulin-sensitizing medication, such as metformin, may be a useful ad-
junct. In addition, antihypertensives and lipid-lowering modalities may be
necessary in certain cases.
582 ORNSTEIN & JACOBSON

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