Globally metabolic syndrome (MetS) is an acceleratingclinical
and public health challenge. In previous era, MetS was considered
to be a concept instead of diagnosis [1]. Firstly, a Swedish
physician Kylin highlighted this concept in 1920’s by showing the
linkage of high blood glucose, hypertension and gout [2]. After
that in 1947 Vague exhibited that visceral obesity was commonly
related to metabolic anomalies found in cardiovascular diseases
(CVD) and diabetes [3]. In 1965 Crepaldi presented an abstract
which highlights the strong association between hyperglycemia,
high blood pressure and obesity at the European Diabetes annual
conference [4].
With the passage of time interest of scientists had increased
in the field of MetS and they started given their theories about
it. In 1988 Reaven called MetS as Syndrome X and its concept
basically was related to insulin resistance [5]. However, in 1992,
it was again renamed The Insulin Resistance Syndrome [6].
Foremost reason in the enhancement MetS trend in urbanization
is the use of excessive intake of calories and physical inactivity
which further lead towards overweight and obesity. Diabetes
and cardiovascular diseases increased the risk of developing
MetS 2 times and 5 times respectively [7]. Moreover, if patients
facing the issue of MetS they are already 2 to 4 times at risk of developing stroke and 3 to 4 times heart attack. Patients having
MetS are 2 folds more prone towards deaths as compared
to those who have not suffered from it [8,9]. MetS has many
definitions, but the most important is the one used from World
Health Organization (WHO) developed in 1999. According
to WHO, confirmation of MetS is established using abnormal
laboratory results including glucose intolerance, hypertension,
lipid profile and atherogenesis [10]. However, the International
Diabetes Federation (IDF) suggested a new definition of the MetS
in April 2005. MetS is cluster of diseases, having biochemical,
physiological and clinical factors that directly escalate the
menace of diabetes (type 2) and cardiovascular diseases [11,12].
Prevalence of metabolic syndrome varies drastically around
the globe, both on a country by country basis and at smaller
regional levels such as rural, suburban, and urban. Since the 20th
century, most countries have seen an increase in the prevalence
of metabolic syndrome in the population. Extensive studies have
been completed to track the development of the disease in the
United States and China. Other countries, such as Malaysia, India,
Philippines, Nigeria, Brazil, Turkey, and Iran have also observed
metabolic syndrome in greater than 25% of the population
[13]. Main contributing factors in the prevalence of metabolic
syndrome are high socioeconomic status, decreased physical
activity in daily life, genetics, and smoking and high body mass
index [14]. Study conducted by Ponholzer et al., demonstrated
that prevalence of metabolic syndrome among postmenopausal
women were ranges from 33-42% [15]. Results of another study,
exhibited that when the person gain 2.5kg weight over the period
of 17 years the risk of developing MetS increased by 45% [16].
Palaniappan et al., showed that when the waist circumferences
of individual increased ten cm from normal range, then an
increase in MetS prevalence in means of 80-90% was noticed
in a shorter period of time [17]. In Pakistani population, obesity
in terms of waist circumference is ranges from 45-68%, with a
strong relationship found between arm fat and insulin resistance.
Hypertriglyceridemia and dyslipidemia are present in the 28-
55% of general population, while 67–81% has decreased levels
of high density lipoprotein (HDL). Fifty percent were found to
be at high risk of metabolic syndrome due to hypertension. With the increased prevalence of all these metabolic risk factors, the
occurrence of metabolic syndrome in Pakistan according to
various definitions is reported to be from 17 to 48% [18].
Pathophysiology of metabolic syndrome
MetS is basically chronic but minute inflammation in body
that occurs due to the strong association between modifiable
and genetic factors which constitutes the metabolic syndrome (Figure 1).
Obesity
It is considered to be the chief cause of MetS results due to
the higher consumption of calorie rich foods and decreased
physical activity in daily life. When there is an excessive fat in
the body, it is stored in adipose tissues resulting in hypertrophy
of adipocytes (fat storing cells) [19]. Enlargement in fat storing
cells reduce the supply of blood towards them and increased the
rate of hypoxia in that region of adipocytes [20]. Due to hypoxia,
excessive production of adipokines, including free fatty acids,
tumor necrosis factor alpha, interleukin-6, C reactive proteins
and plasminogen activator inhibitor-1 [21]. These adipokines
results in abdominal obesity by propagating into localized area,
which further cause oxidative stress [22], dysfunctioning in
endothelial cells by exaggeration blood coagulation, developing
atherothrombotic and atherosclerotic conditions in body [23].
Greater level of adipocytes, increased the amount of free fatty
acids in abdominal region of human body, which cause the
insulin resistance by altering the functionof pancreatic beta cells
[24]. Free fatty acids also increase the amount of plasminogen
activator inhibitor-1 [25].
Tumor Necrosis Factor-a (TNF-a)
It consists one of the important adipokines, which reduces
the beta cell sensitivity [21] by apoptosis of fat storing cells. This
action of TNF-a leads to the formation of free fatty acids. This
factor has strong positive association with waist circumference,
body weight and high level of triglycerides, while it is associated
negatively with high-density lipoproteins (HDL) [26].
C-Reactive Protein (CRP)
It considered being a strong independent predictor for the
identification of the metabolic syndrome. High level of CRP in
blood is positively associated with waist circumference [27],
increased blood sugar level and insulin resistance [28]. It also
predicts the initiation of heart disease and related events later
in life [29]. Interleukin-6 is an important determinant of CRP,
having both anti-inflammatory and inflammatory characteristics.
It is found in both skeletal and adipose tissues [30]. In its
excess release it inhibits the proper functioning of enzyme called
lipo-protein lipase. It plays an important role in the development
of diabetes, having negative association with HDL [31].
Prothrombin activator inhibitor 1 (PAI-1)
This inhibitor has strong association with enzyme called
protease. PAI-1 suppresses the plasminogen activator, which
further alters the fibrinolysis leading to atherothrombosis [32]. High levels of PAI-1 are reported in obese individuals as
compared to non-obese [33].
Leptin
It is a satiety hormone which suppress the appetite and
prevents from obesity in normal individuals. In obese person’s
resistance in leptin receptors has been increased that fails to
give signals to pathway which suppresses continues eating
and individual starts to gain higher weight or body mass index
[21,34]. It is not only involved in the development of obesity,
but leptin is a basically nitric oxide dependent vasodilator which
enhances the activity of sympathetic nervous system mainly
in the kidneys. Therefore, blood pressure of human body is
increased [35]. In simple words researchers demonstrated that
leptin resistance has been associated with obesity, high blood
pressure and heart diseases [36].Obese individuals display also
insulin resistance [37]. Insulin resistance disturbs all the events
of glucose metabolism,resulting in the elevation of blood glucose
(hyperglycemia) [38]. It also affects exogenously induced insulin
in body, by reducing its action or response in muscle, adipose and
liver. To cope with hyperglycemia, beta cells of pancreas secretes
more insulin. If this conditions continuously prevails in the body,
then hyperglycemia shifts towards another serious ailment
called type II diabetes, which is the main inducer of metabolic
syndrome [39,40].
Insulin
Role of insulin in body starts by its binding with insulin
receptors, in the presence of elevated levels of glucose. After
binding to receptor insulin initiates the functioning of two
pathways named as, phosphoinositide 3-kinase (PI3K) and
mitogen activated protein kinase (MAP). Due to the disturbance
in insulin activity PI3K is affected while the other one remainsin
its normal processing. Alterations in PI3K lead towards
dysfunctioning of endothelial tissues by reducing nitric oxide
production, mainly in obese individuals as compared to normal
adults [41].
Hypertension
Studies exhibited that hyperglycemia and hyperinsulinemia
are involved in the development of hypertension, by triggering
the renin angiotensin system (RAS) and enhancing the action
of angiotensin II (AT-II) [42]. In this condition kidneys start to
reabsorb more sodium and increase the vasoconstriction in
arteries surrounding heart, which lead towards increased levels
of blood pressure. Some other studies also demonstrated the
release of aldosterone by the activation or over expression of
AT-II [43]. Aljada et al., demonstrated that individuals whose
dietary intake of fatty foods is higher, display positive relation
with oxidative stress and inflammation as compared to those
who have higher intake of fruits and vegetables or lower calories [44,45].
Treatment strategies of metabolic syndrome
Management of metabolic syndrome is very important to
reduce the risk of related diseases [46]. Key approaches to
overcome the burden of metabolic syndrome includes alteration in lifestyle by adopting multidisciplinary team approach (Table 1)
such as dietitian, physician, diet, exercise, behavioral specialists
and medicines[47]. Joint work of all these practitioners for
modificationof the severity of metabolic syndrome, showed
positive results [48]. Weight control by reducing 500 calories/
day is another strategy for treating metabolic syndrome. Results
of various researches recommend that 10% weight reduction
of the individuals having MetS, is associatedwith a decreaseof
its rate by 20% [49]. Drop in the weight is also positively linked
with the triglycerides decline while it is negatively associated
with HDL, hypertension and insulin resistance [50-52].
Mediterranean diet has shown positive influence on metabolic
syndrome by decreasing levels of LDL and triglycerides [53].
Dietary Approaches to Stop Hypertension (DASH diet) improves
the blood pressure in individuals suffering from MetS [50]. It
provides the recommendation of fat intake in the level of 25-30%
of total calories and intake of cholesterol not more than 200mg/
day [54]. Protein intake should be in moderate quantities, because
excessive protein intake has serious effect on human kidneys and
alter their normal functioning. Recommended intake of protein
is 10-20% of total calories. Meal replacement is another effective
strategy to overcome disease burden. Junk fast foods trends should
be shifted towards conventional home made foods with lower
calories.Limited intake of sugar and salt is also recommended
[55]. Increaseintake of foods rich in potassium, magnesium and
non-unsaturated fatty acids decreased the risk of developing
MetS [56] by improving the symptoms of dyslipidemia, insulin
resistance and blood pressure. Recommended intake of fiber
is 25-35g/day, in order to lower the risk of MetS [57]. Physical activity has also negative association with MetS and daily activity
of 30 minutes is recommendedto attain balance routine [58].
Results of different researches indicated that if a person targets
itself to consume 500 calories per day by physical activity then it
lowers the risk of the disease by 20%. Brisk walk is suggested to
be the best activity that lowers the LDL from body and raises the
levels of HDL in body [59].
Nowadays flavones and flavonols are primarily focused by
researchers in the prevention of cardiovascular ailments [60].
Results of ten studies exhibited that consumption of phenolic
compounds (Table 1) including flavonols, anthocyanin, flavanones
and flavones decreased the risk of developing heart diseases [61].
Another study showed that individuals (42,000) who followed
a diet rich in phenolics secure their health from death by 30%
[62]. Spanish branch of the European and McCullough et al.,
(2012) stated that mortality rate due to heart diseases decreased
by the fair consumption of flavonoids. The consumption of food
rich in polyphenol food matrices improves the resistance to
oxidativemodification of LDL in humans, and this effect can be
explained by the quick incorporation of phenolic acids in LDL [63].
Although the role of polyphenols in CVD risk is still controversial,
the majority of epidemiological and intervention studies indicate
a decrease in LDL cholesterol concentrations, increased in HDL
cholesterol concentrations, and a resistance of LDL to oxidation
following the intake of polyphenolic-rich foods in healthy humans
[64-66]. Siasos et al., (2014) reported that consumption of grape
juice for 2 weeks improves the heart functions in twenty-five
smokers [67]. Similar results were elaborated by the Barona
et al., (2012) who describe that intake of grape juice for longer duration reduce the endothelial dysfunctional properties in
men having metabolic syndrome [68]. Scientists believed that
resveratrol is the mainreason for the improvement in endothelial
functions [69]. In addition to the effect of phenolic compounds on
heart, varied range of studies also exhibited their beneficial effect
on blood lipid profile. Several studies support this aspect i.e. one
study indicated that intake of red wine for thirty-five days by
the men who were at risk of developing cardiovascular diseases.
After the study had ended results showed the positive association
between red wine intake and high density lipo-protein level [70]
and negative association with low density lipo-proteins [71].
Many studies also highlight the importance of cocoa phenolics
in lowering the blood pressure [72]. Effect of flavan 3-ol cocoa
had been observed in twenty randomized controlled trails and
results demonstrated that these products significantly lower
the blood pressure. They also improve the endothelial and
heart vasomotorfunctions by reducing the plasma nitric oxide
in smokers and in patients with heart failure respectively [73].
A meta-analysis of forty randomized studies demonstrated that
cocoa phenolics improved the HDL concentration by 0.05 mM
by decreasing the 0.08 mM of LDL ratio [74]. On the other side
berry compounds possibly enhance HDL levels in the body [75].
The tumorigenesis and carcinogenesis predominantly in the
gastrointestinal tract can be affected by phenolic constituents,
reviewed in many epidemiological studies. A decrease in
colorectal cancer has been related to the consumption of
flavone, anthocyanin (procyanidine), flavonols and flavan-3-ol
isoflavones. There is no clear suggestion between consumption of flavonoids and decreased possibility of stomach and colorectal cancer [76].
The chemoprotective properties of tea and fruits have been
also studied (Table 2). For example, short term intervention
studies showed the preventive effects against carcinogenesis of
polyphenols present in green tea. A study found that only one
tumor was diagnosed among 30 subjects, who took green tea
capsules (600mg of flavan-3ols/day) for 1 year, versus 9 cancers
was diagnosed in the same sized control group [77]. Furthermore,
the 4 weeks study on heavy smokers concluded that the number
of damaged cells was reduced by the intake of five cups of green
tea per day (400-500mg of flavan-3-ols per cup), by triggering
the apoptosis and cell growth arrest. Hakim et al., (2012) found
that the consumption of phenolics in green tea for 4 months
(4 cups/day, 146 mg total/cup) reduced the urinary level of
biomarker of oxidative DNA damage, 8- hydroxydeoxyganosine
[78]. A 12 weeks randomized, placebo-controlled study showed
that the patients with high risk oral premalignant lesions, took
green tea extracts (500, 750, or 1000mg/m2) and did not indicate
any changes in tumor occurrence [79]. Though, FDA claimed that
there are no or little sound scientific evidences to support the
qualified health claims about intake of green tea and decreased
incidence of gastric, colorectal, ovarian, prostate/breast and
esophageal cancer.
Conversely, there are the studies which concluded that the
consumption of blackcurrant juice for 3 weeks (666ml/day,
397 mg anthocyanin/day) and cranberry juices for 2 weeks
(750ml/day) have no effect on oxidation of DNA [80]. Similarly,
Giovannelli et al., (2011) investigated that procyanidinrich-
de-alcholized wine (500ml/day) which contained 7 mg
procyanidins/kg body weight have no effect of DNA damage after
4 weeks trial. The reduction in oxidative damage to DNA and
chemo-preventive effect of berries has been associated in many
human intervention studies [81]. Contrary to this, a recent trial
displayed the preventive effect of rosemary and citrus extracts
(daily consumption of 250mg, orally), through 37 % increase in
the minimal erythema dose (MED) after 8 weeks, and stronger
MED (56%) after 12 weeks [82]. However, more studies are
required in order to support the alleged protecting effects,
via appropriate and clinically significant conclusion facts. The
relation between olive oil and its effect against carcinogenesis
has also been investigated. For this, intake of virgin olive oil and
urinary excretion of ethno-DNA adducts were studied, concluding
insignificant differences between baseline and after intake of
highest phenolic content 150mg/kg [83]. Dietary polyphenols provide protection against type 2 diabetes by giving protection
of beta cells from glucose toxicity, antioxidant and antiinflammatory
effects. Polyphenols rich diet inhibits the insulin
resistance and enhances the functioning of beta cells of pancreas
[84]. Polyphenols from coffee, guava tea, olive oil, chocolate, red
wine, grape seed, and cocoa have shown anti-diabetic effects
in type 2 diabetic patients by increasing glucose metabolism,
improving vascular function, and reducing insulin resistance
and HbA1c. Anthocyanin exhibited antidiabetic property by
reducing blood glucose and HbA1c, increasing insulin secretion,
and improving insulin resistance [85]. Data on the effects of longterm
chronic consumption of flavan-3-ols on cardio-metabolic
health are scarce. In a randomized, placebo-controlled trial in 93
patients with T2D, the intake of 7 grams per day of flavonoidenriched
chocolate (containing 850 mg flavan-3-ols and 100 mg
isoflavones) for 1 year significantly improved insulin resistance.
In this long-term trial, effects on hemoglobin A1c (HbA1c) and
glucose were not observed. However, the authors acknowledged
that the dropout rate was high and limited to postmenopausal
women receiving diabetes therapy. In another study that
only considered clinical trials conducted among non-Asian
per-menopausal or postmenopausal women, soy isoflavones
supplements for 3 months to 2 years significantly reduced serum
insulin [86]. Benefits of polyphenols are summarized in Figure (2).
If a person is not able to achieve the targeted goal then physician
suggest pharmacological approach. Appetite suppressants are
mainly used and the most common is or list at which decreases
the absorption of fat by increasing stool frequency. Anti-obesity
drugs must be used in moderation because these drugs display
many side effects, including decrease of tolerating power of the
body [87].
MetS is a cluster of diseases, having biochemical, physiological and clinical factors that directly escalate the menace of diabetes
(type 2), dyslipidemia, hypertension, insulin resistance,
endothelial dysfunctioning and cardiovascular diseases.
Alterations in lifestyle remain the main intervention of choice for
this population. Modern lifestyle modification therapy combines
specific recommendations on diet and exercise with behavioral
strategies. Pharmacological treatments should be considered
for those whose risk factors are not adequately reduced with
lifestyle changes. A realistic goal for overweight/obese persons
is to reduce the body weight by >7% to 10% over a period of 6
to 12 months. Weight reduction should be combined with a daily
minimum of 30 minutes of moderate-intensity physical activity.
Nutritional therapy calls for a low intake of saturated and total
fat intake; reduced consumption of simple sugars and high
glycemic index foods; and increased intakes of fruits, vegetables,
legumes, and whole grains. Statins can be combined with fibrates
and niacin to achieve the target levels of LDL, triglycerides, and
HDL. All these approaches have positive impact on reducing the
severity of metabolic syndrome and improve the human health.