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INTRODUCTION
The metabolic syndrome refers to the clustering of
cardiovascular risk factors that include diabetes, obesity,
dyslipidaemia and hypertension (1, 2). This clustering of risk
factors, which is not thought to be grouped by chance alone, is
frequently seen in everyday clinical practice. Approximately 1
adult in 4 or 5, depending on the country, has metabolic
syndrome. Incidence increases with age; it has been estimated
that in the category over 50 years of age, metabolic syndrome
affects more than 40% of the population in the United States and
nearly 30% in Europe (2, 3).
Metabolic syndrome has been widely accepted as a simple
clinical tool for earlier detection of type 2 diabetes and
cardiovascular disease (4, 5). It has been estimated that people with
the metabolic syndrome are at twice the risk of developing
cardiovascular disease compared with those without the syndrome,
and experience a five-fold increased risk of type 2 diabetes (1, 4).
However, due to unclear underlying pathophysiologic
processes leading to its development, and confusion between the
conceptual definitions, metabolic syndrome continues to be a
source of medical controversy.
Recently, the American Diabetes Association (ADA) and the
European Association for the Study of Diabetes (EASD) have
advised refocusing on the individual components of the
syndrome without regarding the syndrome as an identifiable
target. This statement was not accepted by the International
Diabetes Federation (IDF), which emphasized that regardless of
the uncertainties of definition and aetiology, it is advisable to
regard the metabolic syndrome as a whole (5, 6).
PATHOPHYSIOLOGY
The association of obesity and metabolic abnormalities with
poor cerebrovascular outcome had been recognized long before
the concept of the metabolic syndrome became popular.
However, it was in 1988 when Dr Gerald Reaven postulated “the
syndrome X“, which we now call the metabolic syndrome (7).
Reaven noticed that there were many people who at the same
time had glucose intolerance, hyperinsulinaemia, high
triglycerides (TG), low high-density lipoprotein (HDL)
cholesterol, and hypertension, all being factors leading to the
development of cardiovascular disease. He proposed insulin
resistance as the driving force of the syndrome, which has
enabled more insight into the condition (7, 8).
Over the past decades many other abnormalities, in
particular chronic pro-inflammatory and pro-thrombotic states,
JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2009, 60, Suppl 7, 19-24
www.jpp.krakow.pl
L. DUVNJAK, M. DUVNJAK
THE METABOLIC SYNDROME – AN ONGOING STORY
Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Zagreb, and University
Hospital “Sestre Milosrdnice”, Division of Gastroenterology and Hepatology, Zagreb, Croatia
The metabolic syndrome refers to the clustering of cardiovascular risk factors that include diabetes, obesity,
dyslipidaemia and hypertension. Due to various definitions and unexplained pathophysiology it is still a source of
medical controversy. Insulin resistance and visceral obesity have been recognized as the most important pathogenic
factors. Insulin resistance could be defined as the inability of insulin to produce its numerous actions, in spite of the
unimpaired secretion from the beta cells. Metabolic abnormalities result from the interaction between the effects of
insulin resistance located primarily in the muscle and adipose tissue and the adverse impact of the compensatory
hyperinsulinaemia on tissues that remain normally insulin-sensitive. The clinical heterogeneity of the syndrome can be
explained by its significant impact on glucose, fat and protein metabolism, cellular growth and differentiation, and
endothelial function. Visceral fat represents a metabolically active organ, strongly related to insulin sensitivity.
Moderating the secretion of adipocytokines like leptin, adiponectin, plasminogen activator inhibitor 1 (PAI-1), tumor
necrosis factor alfa (TNF-alfa), interleukin-6 (IL-6) and resistin, it is associated with the processes of inflammation,
endothelial dysfunction, hypertension and atherogenesis. In 2005, the International Diabetes Federation (IDF) has
proposed a new definition, based on clinical criteria and designed for global application in clinical practice. Visceral
obesity measured by waist circumference is an essential requirement for diagnosis; other variables include increased
triglyceride and decreased HDL levels, hypertension and glucose impairment. Whatever the uncertainties of definition
and etiology, metabolic syndrome represents a useful and simple clinical concept which allows earlier detection of type
2 diabetes and cardiovascular disease.
Key words: metabolic syndrome, insulin resistance, visceral obesity, type 2 diabetes, cardiovascular disease
were added to the syndrome, rendering the definition more
complex. The issue of abdominal obesity as the core of the
syndrome has gained more attention (9-11). It has been
recognised that metabolic abnormalities linked to insulin
resistance are usually found in patients with abdominal obesity
(12, 13). Although endocrine research had identified insulin
resistance and visceral obesity as important players in its
pathogenesis, they failed to present a unifying hypothesis (Fig.
1). From a practical point of view, it seems that there is no need
to dissociate the two conditions. Insulin resistance is considered
to be at the core of the syndrome, while central obesity is its
most prevalent clinical manifestation (14).
INSULIN RESISTANCE
Insulin resistance can be defined as the inability of insulin to
produce its numerous actions, in spite of the unimpaired
secretion from the beta cells (15-17). Insulin is the most potent
anabolic hormone in our body, which has a significant role in
glucose, fat and protein metabolism, but also influences cellular
growth and differentiation, as well as the endothelial function.
These numerous actions explain the clinical heterogeneity of the
metabolic syndrome (7).
Insulin elicits its various biological responses by binding to
a specific receptor (15, 16). The ability of insulin receptor to
autophosphorylate and phosphorylate intracellular substrates is
crucial for complex cellular responses to insulin (15-17). Insulin
binding to the alfa subunit of insulin receptor results in
conformational changes in the receptor, stimulation of the
tyrosine kinase activity intrinsic to the βsubunit which in turn
triggers the signalling cascades (Fig. 2).
Insulin receptor transphosphorylation of several substrates
including insulin receptor substrate (IRS) proteins 1-4 leads to
the activation of downstream signalling pathways which mediate
insulin actions. The four IRS proteins show tissue-specific
differences in mediating insulin action, with IRS-1 playing a
prominent role in the skeletal muscle and IRS-2 in the liver. Two
major signalling pathways activated by insulin binding to its
receptor are the phosphatidylinositol-3’-kinase (PI3K) pathway
and mitogenic, or mitogen-activated protein kinase (MAPK)
pathway.
PI3K pathway plays a crucial role in the metabolic actions of
insulin, glycogen, lipid and protein synthesis, vasodilatation and
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Figure 1. Pathophysiology of the
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Figure 2. Conditions associated with
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anti-inflammatory effects. This pathway has been demonstrated
to be upstream of glucose transporters (GLUT) 4 translocation,
by which insulin promotes glucose uptake by muscle and
adipose tissue. The activation of MAPK pathway is associated
with cell growth and proliferation, decrease in nitric oxide
production and procoagulant effects (17, 18).
Insulin resistance could be caused by various genetic and
acquired conditions. Except in a few rare cases involving
antibodies against insulin receptor or mutations in the insulin
receptor gene, insulin resistance of the metabolic syndrome
results from impairments in cellular events distal to the
interaction between insulin and its surface receptor (7, 8).
Metabolic abnormalities result from the interaction between the
effects of insulin resistance located primarily in the muscle and
adipose tissue and the adverse impact of the compensatory
hyperinsulinaemia on tissues that remain normally insulin
sensitive (15, 16).
VISCERAL ADIPOSITY
Although adiposity has been traditionally defined as an
increase in total body mass, visceral fat accumulation has been
found to correlate with a cluster of metabolic abnormalities
observed among the metabolic syndrome patients (19).
Waist circumference is accepted as an easily obtainable
indicator of visceral adiposity. The standard calls for
measurement at the high point of the iliac crest in the supine
position (19-22).
Visceral fat, in comparison with the subcutaneous tissue,
represents a metabolically active organ, strongly related to
insulin sensitivity (23). Adipocytes from visceral fat have a very
different histology and biology from subcutaneous fat.
Subcutaneous fat tissue, characterised by small, insulin-sensitive
adipocytes, is a storage fat depot, without vascular stroma and
cellular infiltration. Fat taken from visceral compartments and
composed of large, insulin resistant adipocytes, has a well-
developed vasculature with the infiltration of inflammatory
cells. Increased lypolisis in large insulin resistant adipocytes
leads to increased synthesis of very-low-density lipoprotein
(VLDL) and low-density lipoprotein (LDL) in the liver, driving
some of typical changes in the lipoprotein profile.
Inflammatory cells regulate adipocyte behaviour as a source
of hormones and cytokines, called adipokines, with
proinflammatory and proatherogenic effects. Circulating levels
of cytokines including resistin, leptin, TNFα, interleukin -6 (IL-
6), C-reactive protein, fibrinogen and plasminogen activator
inhibitor 1 (PAI-1) are generally increased in obese subjects and
in patients with diabetes (23-26). On the contrary, visceral
adiposity is a state with a relative deficiency of adiponectin, a
tissue-specific circulating hormone with insulin-sensitising and
anti-atherogenic properties. Adiponectin stimulates glucose use
and fatty acid oxidation in the muscle, enhances insulin
sensitivity in the liver, increases free fatty acid (FFA) oxidation,
reduces hepatic glucose output and inhibits monocyte adhesion
and macrophage transformation to foam cells within the vascular
wall (24-26).
DEFINITIONS
Throughout the years several classifications for the
metabolic syndrome have been proposed, emphasising insulin
resistance or visceral obesity. However, there are 3 main ones:
The World Health Organization (WHO) definition, the Adult
Treatment Panel III (ATPIII) Report and the International
Diabetes Federation (IDF) consensus on the metabolic syndrome
(Table 1).
According to the WHO definition from 1999, the syndrome
is present in a person with diabetes, impaired fasting glucose,
impaired glucose tolerance or insulin resistance harbouring at
least two of the following criteria: waist-to-hip ratio >0.90 in
men or >0.85 cm in women, serum triglyceride ≥150mg/dl or
HDL-C<35mg/dl in men and <39mg/dl in women, urinary
albumin excretion rate >20 mcg/min and blood pressure ≥140/90
mmHg (27).
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Table 1. Definitions of the Metabolic Syndrome
In 2001, the National Cholesterol Education Program - Adult
Treatment Panel (NCEP–ATPIII) defined the metabolic
syndrome as having at least three of the following abnormalities:
waist circumference >102 cm in men and >88 cm in women,
serum triglyceride ≥150mg/dl, HDL-C 40mg/dl in men and
<50mg/dl in women, BP≥130/85 mmHg and serum glucose
≥110mg/dl (28). This definition was slightly modified in 2005
(2, 14). That same year, the International Diabetes Federation
(IDF) proposed a new definition based on clinical criteria and
designed for global application in clinical practice. This
definition represents modifications of the WHO and ATP III
definitions and places greater emphasis on visceral obesity as the
core feature of the syndrome. Visceral obesity measured by waist
circumference is an essential requirement for the diagnosis,
while other variables employed by ATP III are slightly (Table 1).
IDF defined visceral obesity for different ethnic populations
based on waist circumference measurements obtained from
epidemiologic data of various ethnic populations (14).
CONDITIONS ASSOCIATED
WITH THE METABOLIC SYNDROME
Type 2 Diabetes
In insulin resistant state primary effects of insulin blood
glucose, i.e. decreased glucose hepatic production and
increased peripheral glucose uptake in the muscle, are
abolished. As long as the pancreatic beta cells are able to secrete
large amounts of insulin needed to prevent increases in plasma
glucose, normal glucose tolerance is maintained. In individuals
with abnormal beta cells due to both genetic and acquired
conditions, frank hyperglycaemia with relative insulin
deficiency will develop (8, 11, 16, 17). Although approximately
25% of insulin resistant patients have normal glucose tolerance
test, this condition significantly increases the risk of developing
type 2 diabetes (16).
Dyslipidaemia
Insulin resistant state is characterised by resistance to
insulin-inhibited lipolysis in the adipose tissue, leading to
overproduction of FFAs in the plasma and increased FFA uptake
by the liver.
FFA leads to increased liver concentrations of TG and
cholesterol esters (CE). High blood TG concentrations in the
form of VLDL induce cholesterol ester transfer protein (CETP)
activity, which promotes transfer of TG from VLDL to HDL and
a subsequent increase in HDL clearance and decreased HDL
concentrations. It also promotes the transfer of TG into LDL in
exchange for LDL cholesterol ester. The triglyceride-rich LDL
can undergo hydrolysis by hepatic lipase or lipoprotein lipase,
which leads to a small, dense, cholesterol-depleted LDL particle
(SD-LDL).
All three components of atherogenic dyslipidaemia are
individually associated with a cardiovascular risk (29, 39).
Hypertension
Insulin resistance and subsequent hyperinsulinaemia induce
blood pressure elevation by activating sympathetic nervous
system and renin-angiotensin-aldosterone system (RAAS)
resulting in sodium retention and volume expansion, and
endothelial and renal dysfunction (12, 16, 18). Hyperinsulinaemia
stimulates the activation of RAAS in blood vessels and the heart,
generating the production of angiotensin II and its pro-
atherogenic effects. At the same time, hyperinsulinaemia in
insulin resistant subjects stimulates the MAPK pathway, which
promotes vascular and cardiac injury (15, 16). The local RAAS in
the visceral adipose tissue exerts more powerful systemic effects
compared with the subcutaneous adipose tissue. Angiotensin II
acts through angiotensin 1 receptors, inhibiting vasodilatatory
effects of insulin on blood vessels and glucose uptake into the
skeletal muscle cells by blocking insulin action on
phosphatydilinositol-3 kinase and protein kinase beta through free
oxygen production (16, 18, 31). This leads to a decrease in nitric
oxide (NO) production in endothelial cells, vasoconstriction in
smooth muscle cells, and GLUT 4 inhibition in the skeletal
muscles. The second mechanism by which insulin resistance
contributes to hypertension includes angiotensin 1 receptor
overactivity, which further leads to vasoconstriction and volume
expansion (12, 17, 18).
Polycystic ovary syndrome (PCOS)
PCOS is the most common endocrine abnormality in
premenopausal women, characterised by oligo/anovulation,
clinical and/or biochemical hyperandrogenism and polycystic
ovarian morphology. Although the pathophysiology is not
completely understood, there is evidence that insulin resistance
and compensatory hyperinsulinaemia play a key role (8, 16, 32,
33). Hyperinsulinaemia acting on normally insulin sensitive
tissues augments androgen production. It has been proposed that
insulin acts directly and indirectly through the pituitary.
Insulin increases LH activity, stimulates ovarian receptors of
insulin and IgF, enhances the amplitude of serum LH pulses,
stimulates adrenal androgen production and suppresses hepatic
production of sex-hormone-binding globulin (SHBG), resulting
in increased testosterone (16, 17, 32-34).
Many studies have proven that women with PCOS are at an
increased risk for the development of type 2 diabetes,
dyslipidaemia, hypertension and cardiovascular disease (33-35).
The prevalence of the metabolic syndrome was found to be
nearly 2-fold higher in women with PCOS than in general
population, matched for age and BMI (34).
Non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) represents a
spectrum of several non-alcoholic-related steatotic liver
diseases, ranging from benign fatty liver to non-alcoholic
steatohepatitis (NASH), associated with cirrhosis and
hepatocellular carcinoma. Increased prevalence of obesity,
diabetes, hyperlipidaemia, and insulin resistance in patients
with NAFLD implicate a close link with the metabolic
syndrome (35, 36). Insulin resistance, present in 98% of
patients with NAFLD, leads to increased lipolysis and
circulating FFAs, decrease in insulin-mediated glucose
disposal, inhibition of glucose utilization and promotion of
gluconeogenesis (7, 8, 16). Elevated plasma glucose and
insulin concentrations promote de novo fatty acid synthesis
(lipogenesis) and impair β-oxidation, thereby contributing to
the development of hepatic steatosis. Decreased adiponectin
hinders FFAs oxidation contributing to fat accumulation in the
liver (8, 11, 17). However, the reason some patients with benign
disease develop the more aggressive form of NASH is unclear.
It seems reasonable that the development of NASH requires
additional pathophysiologic abnormalities. In the context of
multiple-hit hypothesis oxidative stress and various cytokines
like TNF-αhave been implicated in the progression of fatty
liver to NASH. TNF-α, synthesised by hepatocytes and
Kupffer, cells cause hepatocyte injury and inflammation,
leading to the activation of stellate cells and fibrosis (36, 37).
Various cytokines secreted by adipose tissue contribute to
22
insulin resistance in the muscle and liver (32-38). Recently it
has been postulated that the liver could be the primary source of
systemic insulin resistance. Insulin resistance caused by hepatic
activation of NF-κB promoting systemic inflammation and
insulin resistance in the skeletal muscle was documented in a
mice model (37, 38). Although there is no doubt that insulin
resistance, visceral obesity and fatty liver are strongly
interrelated, it seems that the old question concerning the
metabolic syndrome is raised again: what comes first?
THERAPEUTIC APPROACH TO PATIENTS
WITH THE METABOLIC SYNDROME
The lack of specific algorithm makes the therapeutic
approach to patients with the metabolic syndrome difficult and
heterogeneous. Weight reduction by means of dietary changes
and promotion of physical activity are widely accepted as the
main approaches. Both patients and physicians agree that
unhealthy lifestyle aggravates the underlying pathology (39-41).
However, in clinical practice lifestyle modifications are usually
not sufficient to obtain the target value of individual risk factors.
This fact underlines the therapeutic importance of
pharmacological interventions capable of reducing blood
pressure, dyslipidaemia, glucose metabolism impairment and
other abnormalities related to the metabolic syndrome.
Although a clinical diagnosis of the metabolic syndrome is
not sufficient to assess global risk for cardiovascular disease,
this syndrome involves three or more risk factors, often organ
damage and diabetes (1, 2, 8, 14). For this reason the primary
goal in the treatment of patients with the metabolic syndrome
should be the prevention of major vascular events. To achieve
this goal, physicians should pay attention to the choice of drug
in order to avoid aggravation of metabolic abnormalities.
Drugs that improve insulin sensitivity such as metformin
and glitazones are indicated in the treatment of type 2 diabetes.
They have also shown efficacy in the prevention of diabetes
and treatment of PCOS and NASH (42-44). To control
atherogenic dyslipidaemia, a combination therapy of statin and
fibrates is usually required (45). In the treatment of
hypertension a particular emphasis should be placed on ACE
inhibitors and angiotensin II receptor blockers, as these drugs
have shown efficacy in the prevention of diabetes. Central
sympatholytic agents like moxonidine exert additional
beneficial effects of increasing insulin sensitivity (46). If type
2 diabetes is present, in 2/3 of the patients target blood pressure
values can be achieved only with two or more antihypertensive
drugs (12, 13, 46).
Increased understanding of the mechanisms contributing to
the vicious cycle of the metabolic syndrome, as well as critical
analysis of the results of ongoing trials are important for
developing a logical, evidence-based treatment strategy.
CONCLUSION
Whether or not one accepts this condition as a distinct entity,
and in spite of the controversies surrounding its
pathophysiology, the concept of the metabolic syndrome
continues to gain attention. The prevalence of the metabolic
syndrome is increasing at a disturbing rate and within the context
of a proven association with cardiovascular disease, the leading
cause of mortality in the modern world.
In spite of a recent debate, the metabolic syndrome remains
important in the clinical practice, as it integrates the most
common abnormalities representing major cardiovascular risk
factors. The arguments for and against the significance of the
metabolic syndrome will continue to be a matter for debate. On
the other hand, many other conditions will be added in the
future, creating a vicious cycle of “the ongoing story of the
metabolic syndrome”.
Conflict of interests: None declared.
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R e c ei v e d: October 15, 2009
Accepted: December 11, 2009
Author’s address: Prof. Lea Duvnjak, MD, PhD, Vuk
Vrhovac University Clinic, Dugi dol 4a, Zagreb, Croatia; E-mail:
lduvnjak@idb.hr
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