REVIEW ARTICLES

Metabolic syndrome revisited

Hermes Florez1,2,3 and Ron Goldberg1
University of Miami Miller School of Medicine;
2
Miami Veterans Affairs Medical, Miami, FL, USA;
3
University of Zulia School of Medicine, Maracaibo, Venezuela
(hflorez@med.miami.edu; rgoldber@med.miami.edu)
1

Abstract
The metabolic syndrome is a cluster of metabolic abnormalities associated with increased
risk for cardiovascular disease and type 2
diabetes. The most commonly used criteria to
define the metabolic syndrome include the presence of abdominal obesity, high blood pressure,
elevated fasting plasma glucose and dyslipidemia
(high triglyceride and/or decreased HDL cholesterol). There is great variation in the prevalence
of the metabolic syndrome worldwide, with
increasing trends related to the epidemic of obesity in most countries. Insulin resistance and a
state of chronic inflammation are also underlying
factors contributing to this syndrome. C-reactive
protein is an emerging biomarker that may be
useful for risk stratification. The presence of the
metabolic syndrome identifies those with higher
long-term cardiovascular risk and thus calls for
intensified lifestyle therapy weight loss,
increased physical activity and antiatherogenic
diet. In some patients, pharmacologic interventions may be indicated for the management of
specific components of this syndrome, mostly
depending upon the severity of the abnormality.
Further studies are needed to define treatment
algorithms for patients diagnosed with the metabolic syndrome based on a particular combination of its components.
Key words:
Metabolic syndrome, cardiovascular disease, diabetes,
insulin resistance, obesity, inflammation, mortality

Historical background to definition of the

metabolic syndrome
Investigators in the late 1980s, studying the relationships between dyslipidemia, obesity, insulin
resistance, glucose intolerance and the procoagulant state, independently recognized that these
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factors were associated with one another as well

as with cardiovascular disease (CVD) [15]. This
cluster of CVD risk factors began to be referred
to as a syndrome using several different names:
the metabolic syndrome [68], the insulin resistance syndrome [9], or syndrome X [3]. As evidence accumulated to indicate that these risk
factors played an important role in the development of CVD, the need to enhance awareness of
them among health professionals increased.
Accordingly the term metabolic syndrome was
formally adopted first by the World Health Organization (WHO) in 1999 [10] and soon after by
the National Cholesterol Education Program
(NCEP)/Adult Treatment Panel III (ATP III) in
2001 [11] and then by others to describe a cluster of metabolic factors associated with increased
risk of type 2 diabetes and CVD [12, 13].

Diagnostic criteria
The most commonly used diagnostic criteria
have been those of the WHO definition [10] and
the NCEP/ATP III definition [11], which was
updated in 2005 [13]. Recently the International
Diabetes Federation (IDF) published its definition of the metabolic syndrome (Table I) [14].
The latter two definitions are the more easily
applicable tools to assess the metabolic syndrome
in clinical practice.
It has been speculated that the predictive value
of the NCEP and WHO definitions may depend
on the prevalence of the core metabolic components (dyslipidemia, hypertension, obesity and
glycemia) in the population under investigation
[15]. Thus the usefulness of the NCEP vs. WHO
criteria with a differing emphasis on the components of the metabolic syndrome may vary
according to the background population to
which they are being applied. Prevalence estimates for the NCEP/ATP III definition of the
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Table I: Criteria for clinical diagnosis of the metabolic syndrome.
Clinical measurea

WHOb (1999) [10]

ATP III (2005) [13]

IDFc (2005) [14]

Abdominal obesity

WHR >0.90 (M)

Waist 102 cm (Asians 90 cm)(M) Waist 94 cm (Asians 90 cm)

WHR >0.85 (F)

or BMI <30 kg/m2

Waist 88 cm (Asians 80 cm) (F) Waist 80 cm (Asians 80 cm) (F)

Elevated blood pressure

140/90 mmHg
or specific medication

130 mmHg systolic

85 mmHg diastolic
or specific medication in patients
with hypertension

Elevated fasting blood glucose

IGT, IFG, T2DM

100 mg/dl (5.6 mmol/l), diabetes 100 mg/dl (5.6 mmol/l)
or lowered insulin sensitivityd or specific medication
or diabetes (IGT also accepted)

Elevated triglyceride

150 mg/dl (1.7 mmol/l)

Reduced HDL cholesterol

<35 mg/dl (0.9 mmol/l) (M) <40 mg/dl (1.03 mmol/l) (M)
<39 mg/dl (1.0 mmol/l) (F) <50 mg/dl (1.29 mmol/l) (F)
or specific medication

(M)

150 mg/dl (1.7 mmol/l)

or specific medication

130 mmHg systolic

85 diastolic
or specific medication in patients
with hypertension

150 mg/dl (1.7 mmol/l)

or specific medication
<40 mg/dl (1.03 mmol/l) (M)
<50 mg/dl (1.29 mmol/l) (F)
or specific medication

WHR, Waist-hip ratio; M, male; F, female; IGT, impaired glucose tolerance; IFG, impaired fasting glucose; T2DM, type 2 diabetes.
a
3 of 5 constitute diagnosis of the metabolic syndrome.
b
WHO definition: hyperglycemia (type 2 diabetes, IGT, IFG) or insulin resistance plus two other criteria (obesity, dyslipidemia, hypertension, microalbuminuria [albumin excretion 20 g/min or albumin:creatinine ratio 30 mg/g]).
c
IDF definition: abdominal obesity (ethnicity specific) plus two other criteria.
d
Top quartile of fasting insulin in non-diabetic population.

metabolic syndrome have been reported for several countries (Fig. 1) [1631]. These differ with
respect to the sample selection, the year in which
they were conducted, the precise definition used,
and the age and sex structure of the population.
There is a wide variation of prevalence by gender
and race/ethnicity [22].
Two more criteria sets for the diagnosis of the
metabolic syndrome have been suggested by the
American Association of Clinical Endocrinologists [32] and by the European Group for the
Study of Insulin Resistance [33]. The key differences from the NCEP and IDF criteria are that
both of these criteria sets are totally founded
on insulin resistance and exclude patients
with diabetes.
The IDF clinical definition requires abdominal obesity for metabolic syndrome diagnosis, as
a good surrogate for the more cumbersome measurement of insulin resistance and to reduce the
amount of laboratory testing necessary for identification. When abdominal obesity is present,
two additional factors originally listed in the
NCEP definition and now somewhat modified
are sufficient for diagnosis. The IDF emphasized
the presence of ethnic and national differences in
the abdominal obesity threshold [14, 34]. Recent
analyses in the US population (19992002)
showed that the IDF definition leads to a higher
prevalence estimate of the metabolic syndrome
(39%) than that based on the updated NCEP
definition (34.5%) [25], particularly in Mexican
American men.
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Underlying mechanisms: insulin resistance

and obesity
The predominant underlying risk factors for the
metabolic syndrome are thought to be insulin
resistance [3, 35, 36] and abdominal obesity [13,
3739]. Reaven [3] postulated that insulin resistance and its compensatory hyperinsulinemia
predispose patients to hypertension, hyperlipidemia and type 2 diabetes and are thus the underlying cause of much CVD. This constellation of
interrelated metabolic risk factors appears to
promote the development of atherosclerotic
CVD (Fig. 2). Although obesity was not included
in Reavens primary list of disorders caused by
insulin resistance, he acknowledged that it, too,
was correlated with insulin resistance or hyperinsulinemia, and that the obvious treatment for
what he termed syndrome X was weight maintenance (or weight loss) and physical activity. A
state of mild chronic inflammation has also been
related to features of the metabolic syndrome,
particularly obesity and insulin resistance [40],
as discussed below.
Insulin resistance

The metabolic syndrome is associated with

insulin resistance but is not a consequence of
insulin resistance alone nor of the lack of insulin
action alone [41]. Three mechanisms have been
proposed to explain how insulin resistance might
generate other features of the metabolic synVolume 18, Number 5, 2006

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Mexico (19971999)
Saudi Arabia (19952000)
Women
Men

Iran (19992001)
Turkey (2000)
USA (19992002)
Venezuela (19992001)
Portugal (2000)
USA (19881994)
Oman (2001)
Greece (2003)
Spain (20002003)
Italy (2000)
South Korea (1998)
India (2003)
Australia (19992000)
France (1996)
0

10

20

30

40

50

60

Prevalence (%)
Fig. 1: Prevalence of the metabolic syndrome in several countries according to NCEP/ATP III criteria. Data from a recent analysis
of a national survey showed a prevalence of 34% in Mexico (personal communication from Simon Barquera, MD, PhD).

drome: the effects of mild to moderate hyperglycemia, the effects of compensatory hyperinsulinemia, and the effects of unbalanced pathways
of insulin action. In insulin resistance conditions, the ability of insulin to augment glucose
uptake and inhibit hepatic glucose production is
impaired. The resultant hyperglycemia presents
a stimulus to the -cells, which secrete large
amounts of insulin after meals. In individuals
in whom -cell dysfunction occurs, glucose
intolerance and type 2 diabetes may develop,
and the development of hyperglycemia is associated with an increasing prevalence of the metabolic syndrome.
The two major pathways for insulin signaling
are the phosphatidylinositol 3-kinase (PI3K) and
the mitogen-activated protein (MAP) kinase
pathways [42]. In the metabolic syndrome the
pathways leading to activation of PI3K are
impaired, whereas the MAP kinase pathway,
which mediates the mitogenic and proinflammatory responses of insulin signaling, may be overstimulated [43], leading to unbalanced combinations of both reduced as well as excessive
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activation of metabolic targets via these two

pathways of insulin action.

Although insulin-resistant individuals

need not be clinically obese, they
nevertheless commonly have an
abnormal fat distribution characterized
by predominant upper body
fat accompanied by an expanded
visceral fat depot

Obesity

During the last decade, newly discovered adipokinetic pathways have suggested novel pathophysiologic mechanisms linking increased adipose tissue mass with the development of insulin
resistance and other components of the metabolic syndrome [44]. In the Insulin Resistance
Atherosclerosis Study [45], the strongest predictor of the metabolic syndrome was waist circumference; thus, abdominal obesity may precede
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Underlying
factors

Metabolic
factors

Insulin
resistance

Dyslipidemia
Hypertriglyceridemia
Small, dense LDL

Inflammation
Abdominal
obesity

Clinical
outcomes

Cardiovascular
disease

Low HDL
Hypertension

Type 2
diabetes

Hyperglycemia
Hypercoagulability

Fig. 2: Metabolic syndrome pathways.

the development of components of the metabolic

syndrome. Likewise, in the San Antonio Heart
Study [46], one-third of subjects with both a
large waist circumference and high BMI developed the metabolic syndrome during the 8-year
follow-up. Adjusting for fasting insulin concentrations had only a minor effect on the predictive
value of the anthropometric indices.
It is recognized that some people who are not
obese or even overweight by traditional measures
are nevertheless insulin-resistant and have
abnormal levels of metabolic risk factors (normal weight, metabolically obese) [47]. This was
also observed in lean individuals with two
diabetic parents or one parent and a first- or
second-degree relative [48]. Although insulinresistant individuals need not be clinically obese,
they nevertheless commonly have an abnormal
fat distribution characterized by predominant
upper body fat which is accompanied by an
expanded visceral fat depot (or visceral adiposity) and which is associated with increased
release of non-esterified fatty acids from adipose
tissue [49, 50]; this contributes to ectopic lipid
accumulation in muscle and liver, which is
thought to predispose to insulin resistance [51]
and dyslipidemia [52]. The tendency to increase
visceral fat with only modest increases in subcutaneous fat and body weight is especially true in
populations from Asia [34]. This has led to the
recommendation in the IDF and the American
Heart Association update on the NCEP definition of the metabolic syndrome that cut-points
for increased waist circumference be set lower
for these populations. Therefore some investigators regard insulin resistance as a mediating factor in the metabolic syndrome, but not as the
primary cause, and consider dysfunctional
energy storage to be a fundamental step [41].
Abnormalities in the processing and storage of
fatty acids and triglycerides, the molecules that
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account for most of the bodys energy utilization

and storage, are observed when there is too
much triglyceride or body fat (i.e. obesity).
When the capacity of adipocytes to store triglyceride is exceeded, fat accumulates in hepatocytes, skeletal myocytes and other tissues. Excessive maldistribution of fat in visceral tissues
appears to be a marker or perhaps a determinant
of insulin resistance. Visceral adiposity correlates
well with insulin resistance and most features of
the metabolic syndrome.
The adipose tissue of obesity exhibits abnormalities in the production of adipokines, which
may separately affect insulin resistance and/or
modify the risk of atherosclerotic CVD. These
include increased production of inflammatory
cytokines [53, 54], plasminogen activator
inhibitor-1 [55] and other bioactive products
[44]; at the same time the potentially protective
adipokine, adiponectin, is reduced [56]. All of
these changes have been implicated in the genesis of metabolic risk factors. Indeed, as mentioned above, some individuals exhibit the metabolic syndrome with only a moderate degree of
total body obesity [47].

Inflammation and the metabolic syndrome

In recent years extensive studies have uncovered
the importance of systemic low-grade inflammation in the initiation and development of atherosclerosis as well as acute CVD events [5759].
Several cytokines and acute-phase reactants have
been shown to be associated with and predict
CVD, including C-reactive protein, interleukin 6
(IL-6), serum amyloid A, fibrinogen, white
blood cell count, D-dimer, plasminogen activator, tumor necrosis factor- (TNF), lipoprotein
phospholipase A2, interleukin-18, metalloproteinase PAPP-A and secretory non-pancreatic
phospholipase A2 type IIA [6062]. In addition,
systemic inflammation is also associated with
atherogenic changes in lipoprotein metabolism
including hypertriglyceridemia; elevated triglyceride-rich lipoprotein; small, dense LDL; and
decreased HDL cholesterol [63].
C-reactive protein correlates with the severity
of the metabolic syndrome [64] and, even
though several studies support the role of
inflammation in the development of the metabolic syndrome, the nature of the relationships
among these inflammatory markers, the presence of dyslipidemia and the degree of insulin
resistance remain unclear [6567].
There is evidence that obesity and chronic
subclinical inflammation may play intermediary
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roles in the pathogenesis of CVD and type 2 diabetes [68]. The levels of C-reactive protein and
IL-6 increase with the degree of adiposity and
may lead to higher insulin resistance and the risk
of developing type 2 diabetes [69]. To the extent
that elevated IL-6 and C-reactive protein levels
reflect adipocyte activation, the availability of
these markers represents an approach for early
identification of individuals at increased risk
of the metabolic syndrome, type 2 diabetes
and CVD.

The American Heart Association

recommends the use of C-reactive
protein as the best inflammatory marker
in the clinical assessment of CVD risk

Among a wide range of biomarkers, C-reactive

protein is considered to be the most applicable
for clinical use. In several studies, C-reactive
protein has actually predicted CVD better than
other inflammatory biomarkers including intercellular adhesion molecule-1 and vascular cell
adhesion molecule-1, TNF and IL-6, and independently of LDL cholesterol and other lipoprotein levels [61]. In the general population, the
level of C-reactive protein has been found to
consistently predict incident myocardial infarction, stroke, peripheral arterial disease, sudden
cardiac death, and recurrent ischemia and death
in patients with angina and acute coronary
symptoms [70]. The American Heart Association
recommendations state that, although inconclusive, evidence supports the use of C-reactive
protein as the best inflammatory marker in the
clinical assessment of CVD risk [60].

Association of the metabolic syndrome with

mortality and CVD
There is uncertainty about the clinical and public health importance of the metabolic syndrome
[71, 72]. A recent report summarizing its predictive value [73] concluded that the populationattributable risk (PAR) associated with the metabolic syndrome, based on the NCEP and WHO
definitions, is approximately 67% for all-cause
mortality and 1217% for CVD. A report from
the Framingham Heart Offspring Study [74]
recently showed that the PAR for the metabolic
syndrome as a predictor of CVD and coronary
heart disease was 34% and 29%, respectively, in
men and 16% and 8%, respectively, in women.
The metabolic syndrome components that conVolume 18, Number 5, 2006

tributed most to the cardiovascular outcomes

were elevated blood pressure and low HDL cholesterol, with PAR estimates of 33% and 25%,
respectively.
The metabolic syndrome varies in its predictive capacity for CVD by ethnicity, gender and
the presence or absence of hyperglycemia [75,
76]. In the Framingham Offspring database, the
metabolic syndrome accounted for approximately one-fourth of cardiovascular morbidity
[74]. In the Botnia study, subjects with the
metabolic syndrome had a threefold increased
risk of coronary heart disease and stroke, a fiveto sixfold increased risk of CVD death, and
increased all-cause mortality [77]. In Finnish
men, insulin resistance and the metabolic syndrome predicted coronary heart disease events
and both CVD and all-cause mortality [78]. The
risk of death from all causes and CVD increased
with growing numbers of abnormalities [79].
The presence of the metabolic syndrome identifies those with relatively high long-term risk of
CVD and thus calls for intensified lifestyle
therapy. It needs to be stressed that the metabolic syndrome itself is a relatively poor indicator
of absolute short-term risk [80], because it does
not contain key determinants of short-term risk
such as age, serum cholesterol, gender and
smoking status. A more accurate predictor of
short-term risk is Framingham scoring, which
includes all of the major risk factors.

Metabolic syndrome and diabetes

development
The metabolic syndrome not only accompanies
but also precedes and predicts type 2 diabetes
[81, 82]. The San Antonio Heart Study investigators compared OGTT results against the
NCEP and WHO criteria for the metabolic syndrome in predicting diabetes. Of the three,
impaired glucose tolerance on the OGTT was
the best with a predictive value of 43% vs. 31%
by the NCEP criteria and 30% by the modified
WHO criteria [83]. Furthermore, even in subjects with impaired glucose tolerance, the presence of the metabolic syndrome increased the
risk of progression of type 2 diabetes, although
further studies are needed to confirm this observation. Interestingly, in a study among nondiabetic American Indians, the homeostasis
model assessment for insulin resistance and the
metabolic syndrome at baseline were associated
with an increased risk of type 2 diabetes, but
CVD was not predicted independently of other
cardiovascular risk factors [84].
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In a recent review of prospective studies using
the NCEP and WHO definitions of the metabolic syndrome, Ford [73] found that the PAR
for type 2 diabetes was between 30% and 52%.

The primary goal of clinical management

in patients with the metabolic syndrome
is to reduce their long-term risk of CVD

In the Framingham cohort, the presence of the

metabolic syndrome at baseline was also found
to be a powerful predictor of new-onset diabetes.
Using the revised NCEP definition for the metabolic syndrome, the PAR for type 2 diabetes was
62% in men and 47% in women [74]. As
expected, elevated blood glucose (100 mg/dl)
was associated with the highest PAR of 62%
for type 2 diabetes, while the combination of
elevated blood glucose, abdominal obesity and
low HDL cholesterol was associated with a large
12-fold increased risk of incident type 2
diabetes. However, trait combinations that did
not include elevated blood glucose also imparted
an approximately fivefold increased risk of incident type 2 diabetes. This is consistent with the
concept that the metabolic syndrome trait combination reflects an underlying insulin resistance
pathophysiology.

Management of the metabolic syndrome

The primary goal of clinical management in
patients with the metabolic syndrome is to
reduce their long-term risk of CVD. The primary
emphasis should be on the modification of
underlying risk factors (obesity, physical inactivity and atherogenic diet) through lifestyle
changes. Not only do these interventions
improve individual metabolic syndrome components, but they have been shown to ameliorate
the underlying pathophysiologic determinants of
the syndrome, such as obesity, insulin resistance
and inflammation [13, 85]. No studies have
examined the value of tailoring the treatment
algorithm to the particular combination of criteria that resulted in the diagnosis of the metabolic
syndrome [72], nor whether the presence of the
metabolic syndrome justifies earlier application
of pharmacologic interventions for preclinical
abnormalities in syndrome components, e.g. prehypertension, prediabetes or suboptimal lipid
levels. Specific pharmacologic interventions may
be indicated for the management of clinically
significant components of the syndrome, e.g.
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hypertension, dyslipidemia, glucose intolerance

or the procoagulant state. It is unknown whether
insulin sensitizers, as an approach to the treatment of insulin resistance itself, or the use of
agents that lower C-reactive protein levels such as
statins, fibrates, nicotinic acid and thiazolidinediones would be of value in preventing CVD in
all or a subset of patients with the metabolic syndrome outside their current clinical indications.

Acknowledgments
Dr Florezs work is supported by grants from the
Department of Veterans Affairs MiamiGRECC
and CSP#465, Pan American Health Organization RC/RG-T/VEN/3201, and UMHumana
Health Service Research. Dr Goldbergs work is
supported by grants from the National Institutes
of Health NIDDK DK01 0500 and
2RO1HL36588-16.

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Volume 18, Number 5, 2006