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Current Vascular Pharmacology, 2013, 11, 000-000 1

Diet and Metabolic Syndrome: An Overview

Deirdre Keane, Stacey Kelly, Niamh P. Healy, Maeve A. McArdle, Kieran Holohan and Helen M. Roche*

Nutrigenomics Research Group, Food for Health Ireland, UCD Conway Institute & UCD Institute of Food and Health,
University College Dublin, Dublin 4, Ireland

Abstract: The metabolic syndrome (MetS) is a complex multifactorial disorder and its incidence is on the increase
worldwide. Due to the definitive link between obesity and the MetS weight loss strategies are of prime importance in halt-
ing the spread of MetS. Numerous epidemiological studies provide evidence linking dietary patterns to incidence of MetS
symptoms. As a consequence of the epidemiology studies, dietary intervention studies which analyse the effects of sup-
plementing diets with particular nutrients of interest on the symptoms of the MetS have been conducted. Evidence has
shown that lifestyle intervention comprising changes in dietary intake and physical activity leads to an improved meta-
bolic profile both in the presence or absence of weight loss thus highlighting the importance of a multi-faceted approach
in combating MetS. Nutritional therapy research is not focused solely on reducing energy intake and manipulating macro-
nutrient intake but is investigating the role of functional foods or bioactive components of food. Such bioactives which
target weight maintenance and /or insulin sensitivity may have a potentially positive effect on the symptoms of the MetS.
However the efficacy of different functional nutrients needs to be further defined and clearly demonstrated.
Keywords: Diets, fatty acids, functional foods, glycaemic index, metabolic syndrome, nutrition.

1. DEFINITION OF METS matter of course once diagnosed [5]. Notwithstanding the

The term Metabolic Syndrome (MetS) is used to de-
scribe a combination of medical disorders which confer an
increased risk on individuals of coronary heart disease
(CHD) [1], stroke and type 2 diabetes mellitus (T2DM) [2].
A single definition of the MetS has yet to find worldwide
acceptance. In the absence of this gold standard there were
a number of closely related but individual definitions put
forward by various respected worldwide organisations. In
2001 the National Cholesterol Education Program (NCEP)
published the results of their Adult Treatment Panel III (ATP
III) including their definition of MetS [3]. The NCEP diag-
nosed MetS when three or more of the following risk factors
occurred together; abdominal obesity, atherogenic dyslipi-
demia, hypertension, insulin resistance, pro-inflammatory
state and/or pro-thrombotic state [3]. The International Dia-
betes Federation (IDF) defined MetS as being central obesity
in addition to any two of the following factors, raised tria-
cylglycerol (TAG) levels, reduced HDL-cholesterol,
hypertension or elevated fasting plasma glucose [4].
Despite the coordinated work of many organisations in
defining the MetS there is ongoing controversy over whether
the term should be in use at all. The American Diabetes As-
sociation (ADA) in conjunction with the European Associa-
tion for the Study of Diabetes (EASD) put forward the asser-
tion that there was no need for the term MetS due to the fact
that all its associated factors are treated individually as a
*Address correspondence to this author at the Nutrigenomics Research
Group, Food for Health Ireland, UCD Conway Institute & UCD Institute of
Food and Health, University College Dublin, Dublin 4, Ireland;
Tel: +353 1 7166845; E-mail: Helen.roche@ucd.ie
debate over the use of the term MetS as a clinical diagnosis
which the World Health Organisation (WHO) has also com-
mented on recently [6], what is not disputed is that the fac-
tors that contribute to the MetS are increasing worldwide [7,
8]. More recently there has been an attempt to reconcile
these definitions [9]. This integrated definition of the MetS
assigns equal levels of importance to the elements involved
and removes central obesity as a core component. This most
up to date definition includes abdominal obesity as measured
by waist circumference, elevated TAG, low HDL choles-
terol, elevated blood pressure and elevated fasting glucose
levels [9].
2. AETIOLOGY & PATHOGENESIS OF THE METS
2.1. Obesity
The precise molecular mechanisms which lead to the
pathogenesis and progression of the MetS have yet to be
fully defined. Obesity, T2DM and the MetS are complex
multi-factorial disorders with no single derangement driving
the epidemic. What is clear is that there are both genetic and
environmental influences (See Fig. 1). As there are numer-
ous symptoms of the MetS so too are there numerous causes
all inextricably linked.
Traditionally adipose tissue was thought of purely as an
energy store wherein excess nutrients were stored princi-
pally in the form of TAG. More recently our knowledge of
adipose tissue has expanded with the demonstration that adi-
pose tissue is not simply an energy sink but a functioning
endocrine organ. Correct adipose tissue function to allow for
both these roles is a crucial aspect of whole body glucose
and fatty acid (energy) homeostasis. Obesity is the result of a

1570-1611/13 $58.00+.00 2013 Bentham Science Publishers

2 Current Vascular Pharmacology, 2013, Vol. 11, No. 00
Fig. (1). Representation of the main features of the MetS.
pathological increase in adipose tissue mass, either as the
result of adipocyte hyperplasia or hypertrophy. Concurrent
with this increase in adipose tissue mass there are important
and detrimental changes in adipose tissue function which are
important in the etiology of MetS. Obesity is an important
risk factor for the MetS which shows strong inheritance pat-
terns [10], and increases the chances of developing type 2
diabetes [11] and MetS [3, 4, 12]. The environmental factors
associated with development of insulin resistance and MetS
include obesity, poor diet excessive in energy, lack of physi-
cal activity and age. Obesity is not an isolated disorder.
When adipocyte biology is perturbed, important systemic
effects and alterations in adipose derived cytokines (or adi-
pokines) are evident. Obesity impedes adiponectin secretion.
On the other hand leptin secretion is seemingly unaltered
resistance to its signalling is associated with obesity and also
with increased fatty acid release. The current literature states
that obesity is associated with elevated release of free fatty
acids (FFA) or non-esterified fatty acid (NEFA). The con-
ventional wisdom in this area of obesity is starting to be
questioned. Whilst recent studies are exploring the possibil-
ity of normalised plasma NEFA levels in some obese pa-
tients, elevated NEFA in the peripheral tissues still exists
[13]. Immune cell infiltration with subsequent chronic low
grade inflammation promotes insulin resistance in adipose
and other peripheral tissues. The term meta-inflammation is
used to describe the situation of chronic low grade inflamma-
tion associated with an obese and MetS phenotype [14].
Chronic low grade inflammation is associated with increased
levels of IL-1, IL-6, TNF-
and C-Reactive Protein (CRP),
among other pro-inflammatory cytokines upon macrophages
infiltration of the adipose tissue. There is also a decrease in
the secretion of anti-inflammatory cytokines and so called
protective adipokines e.g. adiponectin [15].
Keane et al.
2.2. Insulin Resistance
Insulin resistance results in impaired glucose uptake by
the peripheral tissues e.g. muscle and adipose while at the
liver gluconeogenesis is unchecked resulting in hyperglyce-
mia and possibly at a later stage diabetes [16, 17]. Insulin
resistance exists when a normal concentration of insulin elic-
its a subnormal biological response [18]. Many years prior to
manifestation of the MetS or diabetes, insulin resistance is
detectable in the body [19]. It was during his Banting award
lecture in the 1980s that Reaven put forward insulin resis-
tance as the fundamental cause of what he described as
Syndrome X [20]. However Reaven did not recognise that
obesity was a core component due to the fact that he identi-
fied insulin resistance in patients who were not obese [20].
Obesity and IR both cause and exacerbate each other. There
is no clear evidence that the presence of one of these factors
alone is the cause of the MetS.
2.3. Peripheral Tissues & Biomarkers
In obesity, there is a significant increase in the produc-
tion and release of free fatty acids from adipose, leading to
lipotoxic effects at peripheral tissues. Elevated FFA levels
impair insulin signalling and increase the risk of MetS and
type 2 diabetes (See Fig. 2). FFA do this by causing insulin
resistance at the muscle and liver and they have the added
potential for damaging pancreatic -cell function [21]. Insu-
lin resistance in the adipose leads to no suppression of hor-
mone sensitive lipase (HSL) which in turn leads to increased
lipolysis exacerbating the elevated FFA situation. Lipotoxic-
ity can result not only in insulin resistance at the peripheral
tissues but also oxidative stress and inflammation as demon-
strated by elevating FFA levels in healthy individuals [22].
Analysis of data from the United Kingdom Prospective study
Diet and Metabolic Syndrome
Fig. (2). Multiple organs illustrating the pathophysiology of the MetS.
and the Paris Prospective Study emphasized the role of
dyslipidaemia amongst risk factors for CHD & therefore
MetS particularly amongst women [23, 24]. Elevated plasma
TAG and reduced HDL-cholesterol are recognised across all
definitions as factors of the MetS [3, 25]. Hypertriacylglyc-
erolemia is associated with increased hepatic output of very-
low-density lipoprotein (VLDL) particles. This hepatic pro-
duction of VLDL is increased in cases of lipotoxicity [26].
Insulin resistance also leads to a reduction in lipoprotein
lipase (LPL) activity. Without LPL, VLDL particles are not
metabolised resulting to continued elevation of TAG levels
[27]. Reduced levels of HDL-cholesterol alone is classified
as a risk factor for cardiovascular disease (CVD) [28]. This
reduction in HDL-cholesterol is thought to be due to in-
creased HDL catabolism in the presence of insulin resistance
[29]. Correlations between LDL-cholesterol and abdominal
obesity are less obvious. The Framingham study could not
define LDL-cholesterol as being associated with increased
risk of deaths from CVD in patients with MetS [30]. How-
ever the same study identified LDL-cholesterol levels as
being elevated in the MetS and this was correlated with ele-
vated TAG levels [30].
3. TREATMENT OF THE METS
The principal aim of the clinical management plan of the
MetS is to reduce the risk of T2DM and CVD. The ideal
situation would be to avoid the MetS, thereby reducing the
Current Vascular Pharmacology, 2013, Vol. 11, No. 00 3
risk of developing T2DM and CVD. This concept is known
as primordial prevention a term coined in 1978 by Strasser
and approved by the American Heart Association [31]. Un-
fortunately the number of people who manage to achieve
primordial prevention is very low less than 5% of middle
aged Americans have what is defined as ideal cardiovascular
health as set out by the American Heart Association [31].
Primordial prevention is an ideal situation which when ob-
tained is capable of conferring an additional 10 years of life
to an individual [32, 33]. However given that atherosclerosis
has an early age of onset and also that childhood obesity is
increasing worldwide the likelihood is that primordial pre-
vention percentages will not rise in the near future. With this
in mind reversal of existing risk factors becomes of critical
importance. Pharmacological agents to treat the symptoms of
the MetS are aimed at reducing LDL-cholesterol, hyperten-
sion and impaired glucose tolerance. The drug therapies
aimed at reducing these metabolic risk factors include stat-
ins, fibrates, nicotinic acid, angiotensin- converting enzyme
(ACE) inhibitors, metformin, thiazolidinediones or acarbose
[34]. The remainder of this review will focus on the role of
diet in treating the MetS and its symptoms due to the princi-
pal role played by obesity in the aetiology of the MetS.
4. INFLUENCE OF DIET ON THE METS
While primordial prevention and pharmacological inter-
vention represent extreme ends of the treatment spectrum for
4 Current Vascular Pharmacology, 2013, Vol. 11, No. 00
Table 1. Prospective Cohort Studies Identifying The role of Diet in the MetS
Study Name
Framingham Study Wolongevicz et al.
INTERHEART Study
CARDIA Study
TLGS
ARIC
Amsterdam Growth & Health Longitudinal Study
NURSES Health Study
the vast majority of cases of the MetS changes to diet and
lifestyle are suitable. In fact one study in particular high-
lighted that a change in lifestyle including increased exer-
cise and dietary changes was more effective than metformin
in reducing the risk of developing type 2 diabetes [35]. The
idea that diet can influence health is not a new one, let food
be thy medicine and medicine be thy food is a phrase attrib-
uted to Hippocrates the Ancient Greek father of modern
medicine.
There are numerous studies both ongoing and concluded
which are providing evidence for the role that diet plays in
the development or prevention of the MetS (Table 1). The
Framingham study is the primary source of information for
markers of MetS. Framingham has demonstrated that diet
quality is inextricably linked with obesity and therefore the
MetS particularly in women. A diet low in energy, carbohy-
drates and micronutrients but high in saturated fatty acids
and alcohol was found to correlate with increased obesity. In
addition women who consumed a diet which was high in
energy, derived from protein, carbohydrates and fat were
also at risk of increased obesity. On the other hand a high
intake of energy, based on high fibre and vitamin E was in-
versely related to obesity [36].
The Framingham study is a local study and fails to take
into account dietary patterns based on global location
which is precisely what the INTERHEART study has at-
tempted to do. One method which this study has made use of
is the classification of diets into Oriental, Western or
Prudent. The oriental diet contains tofu and soy and vari-
ous other sauces. The western diet is high in fried foods,
salty snacks, eggs and meat. The Prudent diet depends on
large amounts of fruit and vegetables. What they demon-
strated based on this classification system is that the Oriental
diet had no association with acute myocardial infarction
(AMI), while the Prudent diet in addition to no association
with AMI had a protective effect at higher levels. The West-
ern diet in comparison was associated with AMI [37]. As it
is the INTERHEART study which has highlighted a link
between AMI and MetS similar to the levels in type 2 diabe-
tes the link between a Western diet and MetS prevalence is
hard to ignore [38].
Keane et al.
Author Year Voluneers
2010 General Population
Iqbal et al. 2008 General Population
Mente et al. 2010
Carnethon et al. 2004 Young Adults
Mirmiran et al. 2008 General Population
Lutsey et al. 2008 General Population
Ferreira et al. 2005 Young Adults
Field et al. 2007 Female Nurses
Oh et al. 2005
There has been an increase in the number of national and
multinational prospective cohort studies all emphasising the
influence of diet on the risk of MetS, type 2 diabetes and
CVD. The coronary artery risk development in young adults
(CARDIA) study correlated increased BMI and weight gain
due to a diet high in carbohydrate and low in crude fibre with
increased risk of MetS [39]. The following years have seen
at least one study published per year which emphasises the
role that diet plays in prevalence of MetS. The Amsterdam
Growth and Health Longitudinal Study established a link
between increased energy intake rather than any one macro
or micronutrient and the MetS [40]. The Framingham study
highlighted the link between
1 soft drink daily and in-
creased waist circumference, altered glucose tolerance and
MetS [41]. The Tehran Lipid and Glucose Study (TLGS)
highlighted a dose dependent relationship between dietary
intake of carbohydrates and fats and the incidence of MetS
[42]. Confirmation of the role played by a western diet based
on meat and fried foods and the incidence of MetS was dem-
onstrated in the Atherosclerosis risk in communities (ARIC)
study this also offered further evidence of the possible pro-
tective role to be played by the prudent diet high in vegeta-
bles, fruit, fish, and poultry [43].
5. ROLE OF DIETARY COMPONENTS ALONE OR
IN CONJUNCTION WITH EXERCISE IN TREATING
THE METS
What all these prospective cohort studies have in com-
mon is that they are pointing the way towards new dietary
guidelines and a nutritional strategy to reduce the prevalence
of obesity, type 2 diabetes and the MetS and thereby reduce
the number of deaths from CVD. The evidence outlined to
date provides a convincing argument for the adverse effects
of the western diet and two macronutrients in particular fats
and carbohydrates.
5.1. Fats
Despite the recognised role of fats and fatty acids as a
vital fuel source (37 kJ or 9 kcal per gram), research shows
their potentially deleterious effects. Convention dictates that
fatty acids are classified based on double bonds within their
Diet and Metabolic Syndrome
Table 2. Dietary Intervention Studies analysing the effects of PUFA on factors of the MetS
Author Year Diet
Tierney 2011 Replacing SFA with PUFA
Meyer 2009 Seal oil and Fish oil Supplements
Cicero 2006 PUFA diet
Dangardt 2010 PUFA Supplementation
McEwen 2010 Diets higher in Fish and PUFA
Vessby 2001 Moderate
-3 Supplementation
structure. In so doing saturated fatty acids (SFA), monoun-
saturated fatty acids (MUFA) and polyunsaturated fatty acids
(PUFA) are associated with certain biological effects.
5.1.1. Trans Fats
Trans fats, for example, are unsaturated fatty acids that
are created during the industrial process of partial hydro-
genation; converting vegetable oils to semi-solids. Trans fats
are positively correlated with plasma CRP, TNF
, E-
selectin, sICAM-1 and sVCAM-1 [44, 45]. Trans fats have
been shown to be inversely related to HDL and LDL:HDL in
women [45] and positively related to total cholesterol and
serum LDL [46] and so, increased consumption of trans fats
raises the risk of CHD [46].
5.1.2. Saturated Fatty Acids & Polyunsaturated Fatty Acids
SFA are acknowledged as bad fats associated with an
increased risk of MetS. The most abundant SFA in the diet
and in the body are palmitate and stearate. Studies have
shown that replacing SFA with a diet enriched with PUFA
decreases LDL-cholesterol and total cholesterol:HDL-
cholesterol ratio [47] and reduce the risk of MetS developing
[48, 49]. There is also evidence that substituting SFA with
low-GI foods (or wholegrain carbohydrates) could lead to a
reduction in MetS incidence [50] however high GI foods or
refined carbohydrates may have the opposite effect [48]. As
opposed to SFA and MUFA, dietary intake of n-3 and n-6
PUFA are essential for normal growth and development. Of
all fatty acids n-3 PUFA are the longest recognised as having
beneficial effects on human health (Table 2) [51]. There is
strong evidence that n-3 PUFA can reduce TAG levels [52-
54], and also may improve hypertension [53, 55, 56]. In-
creased intakes of n-3 PUFA are inversely related to plasma
CRP, IL-6 and E-selectin [57]. EPA and DHA are inversely
related to the soluble adhesion molecules, sICAM-1 and
sVCAM-1 [57] Thus, n-3 PUFA reduce inflammation [58]
and decrease cardiovascular risk in diabetic patients [59].
However, despite PUFA reducing the risk of CHD, there is
no evidence that increased consumption of LC-n-3 fatty ac-
ids reduces the risk of T2DM in men and women [60].
Current Vascular Pharmacology, 2013, Vol. 11, No. 00 5
Participants Duration (Weeks) Outcome
Patients with MetS 12 PUFA improved TAG levels
General Population 6 Seal Oil & Fish Oil supplementation re-
duced plasma TAG and blood pressure
Metanalysis PUFA improve hypertension
Obese Adolescents 17 PUFA supplementation reduced inflam-
mation as measured by certain cytokines
Patients with Diabetes PUFA can be recommended as part of a
diabetes management programme
General Population 12 No effect of PUFA supplementation on
insulin secretion
5.1.3. Monounsaturated Fatty Acids
Little is known about the nutritional implications of
MUFA however, there is increasing interest into the potential
of MUFA and, in particular oleate, in benefiting health. The
MUFA in Obesity (MUFObes) study was a 6 month dietary
intervention study comparing Willets Healthy Eating Pyra-
mid (a high MUFA diet), the current recommended diet (a
low fat diet) and a control diet (typical Western diet) [61,
62]. The 6 month intervention, significantly reduced the
LDL:HDL ratio in the MUFA group with no change in the
other two groups [63] Studies into the effect of a diet en-
riched with MUFA on healthy individuals has identified
beneficial effects on MetS risk factors including reductions
in LDL-cholesterol, TAG and elevated HDL-cholesterol
levels [64, 65]. Furthermore as part of the KANWU study,
MUFA are associated with a reduction in blood pressure in
healthy subjects [66].
From the MUFObes study, it was seen that the MUFA
group had reduced fasting glucose and insulin concentrations
while the low-fat group and control group had increased
concentrations of glucose and insulin [61, 63]. The large
scale KANWU study determined the effect of substituting
SFA for MUFA on insulin sensitivity in healthy individuals
[67]. KANWU demonstrated that insulin sensitivity was re-
duced on the SFA diet but, contrary to the initial hypothesis,
insulin sensitivity was not improved by replacing SFA with
MUFA. What was interesting to note, that post hoc analysis
determined that the positive effects of the MUFA diet were
only discernible in individuals with a reduced total dietary
fat intake (< 37% of total energy) [67]. The LIPGENE pro-
ject concluded similarly indicating that there was no differ-
ence in the effect of a high MUFA diet compared to a high
SFA diet as the total fat intake at 36% of total energy was
too high regardless of quality of fat [52].
Moving on from dietary intervention studies in healthy
volunteers, there has been evidence to suggest that substitu-
tion of SFA with MUFA or carbohydrates in insulin resistant
individuals, can lead to increased insulin sensitivity associ-
ated with elevated postprandial adiponectin levels [68]. Adi-
ponectin and its association with improved insulin sensitivity
at the peripheral tissues in animal models [69]. This effect on
6 Current Vascular Pharmacology, 2013, Vol. 11, No. 00
adiponectin levels is in addition to the positive effects of
MUFA on body fat distribution as seen in diabetic patients
[70], highlighting the importance of including MUFA in a
dietary intervention for the symptoms of the MetS.
5.1.4. Mediterranean Diet
With the positive effects of MUFA being recognised
there is a renewed interest in the so called Mediterranean
Diet as an optimal healthy eating approach. It is rich in
foods common to the Mediterranean region with an emphasis
on olive oil which is approximately 75% MUFA. The Medi-
terranean diet is also high in fruits, vegetables, cereals,
beans, nuts and seeds. There is a very low amount of red
meat consumed. Red meat is associated with an increased
risk of CVD and the risk for CVD in vegetarian populations
is reduced relative to non-vegetarians [71]. The evidence in
favour of the Mediterranean Diet over the traditional West-
ern Diet points to a reduction in LDL-cholesterol and an in-
crease in HDL-cholesterol and improved insulin sensitivity
in healthy [72] and insulin resistant patients [73]. Whilst
these intervention studies are positive, long-term dietary in-
tervention studies in high-risk groups are required to confirm
the efficacy of a Mediterranean type diet as a long term
healthy eating approach.
5.1.5. Total Fat
What the studies mentioned above have highlighted is the
importance of total fat in the diet. Several studies have
shown no association between total fat intake and obesity
and the markers of the MetS [74-77], while only one pro-
spective cohort study has demonstrated a link between total
fat intake and CHD incidence [78]. While the number of
prospective cohort studies linking fat intake with MetS
symptoms may be limited there are studies which demon-
strate a loss in weight and an improvement in metabolic pa-
rameters in response to reduced total fat intake. A meta-
analysis conducted by Astrup which included 16 low fat in-
tervention studies found a maintenance of weight in normal
weight individuals and a reduction in weight of
obese/overweight individuals [79]. What is important to bear
in mind is that in order to prevent essential fatty acid defi-
ciency and to maintain normal absorption of fat soluble vi-
tamins and maintain energy levels it is recommended that
fats should account for minimum 15% of total energy intake
[80]. As for the maximum dietary intake of fats a recent
comprehensive study compiled by the Food and Agriculture
Organisation of the United Nations (FAO) and the World
Health Organisation (WHO) approved a maximum of 30-
35% of total energy intake to be derived from fats to be ac-
ceptable for most individuals [81]. The value of this maxi-
mum cut off is seen in the results of the KANWU and LIP-
GENE studies [52, 67].
5.2. Carbohydrates
5.2.1. Glycaemic Index & Glucose Load
Carbohydrates are another macronutrient which have
been investigated on the basis of their contribution to MetS
incidence. In 1981 Jenkins introduced the concept of the
glycaemic index (GI) as a classification of carbohydrates
according to their postprandial effects on blood glucose lev-
Keane et al.
els [82]. Refined grains are classed as high GI foods due to
their rapid digestion and the large fluctuations that they
cause in blood glucose and insulin. On the other hand whole-
grain foods are classed as low GI, they are digested slowly
and therefore cause a gradual increase in glucose levels and
as a result a more controlled insulin response [82]. In addi-
tion to GI measurement, studies involving carbohydrates in
the diet also take into consideration the glucose load (GL).
The GL is defined as the carbohydrate content times the GI
[83]. There is no accepted definition for dietary fibre how-
ever it is often referred to as non starch polysaccharides and
sources include whole grain cereals, legumes, fruits and
vegetables and they are associated with possible prevention
of the MetS and T2DM [84, 85].
5.2.2. Relationship between Glycaemic Index and MetS
In an eight year follow-up of 91,249 female nurses, a diet
high in rapidly absorbed, high GI foods was strongly associ-
ated with an increased risk of T2DM and this association
remained high after adjusting for BMI and other lifestyle
factors [85]. The same relationship between high GI foods
and incidence of T2DM has been demonstrated in men [86].
In a prospective study of EPIC-NL participants, diets high in
GL, GI, and starch and low in fibre were associated with an
increased diabetes risk [87]. High GI foods are positively
correlated with haemorrhagic stroke and replacing high GI
foods with low GI foods could reduce the risk [88]. A meta-
analysis of 37 prospective studies on GI and GL reported
that diets with a high GI or GL independently increased the
risk of T2DM and heart disease [89].
Plasma C-peptide is a marker of insulin secretion and
higher concentrations are associated with IR. High intakes of
high GI foods are associated with higher concentrations of
plasma C-peptide than low GI foods. A diet enriched in ce-
real fibre, demonstrated reduced levels of plasma C-peptide
[90]. High-GI is also associated with an increase in high-
sensitivity-C-reactive protein (hsCRP) concentration. hs-
CRP is a sensitive marker for inflammation, Liu et al. inves-
tigated whether this association was modified by BMI [91].
The Womens Health Study showed that GL was signifi-
cantly associated with hs-CRP and this positive association
was significantly modified by BMI [91].
5.2.3. Glycaemic Index Intervention Studies
These association studies have demonstrated a clear need
for intervention studies to establish if substituting high GI
with low GI alternatives is capable of reversing the incidence
of T2DM and the numerous symptoms of the MetS (Table
3). Some intervention studies have been carried out in
healthy individuals, however reducing the GI content of the
diet had little to no effect on the markers of the MetS. How-
ever it is important to note that these studies have been short
in duration and perhaps a more sustained low-GI diet is nec-
essary. In high-risk subjects, the impact of a low-fat, high-
carbohydrate diet, in which carbohydrate was either low-GI
or high-GI, on energy intake, body weight, composition and
risk factors for T2DM and ischemic heart disease (IHD) in
overweight healthy subjects was examined by Sloth et al.
[92]. High- versus low-GI diets had no significant effect on
fasting serum insulin, TAG and NEFA and HDL-cholesterol
concentrations, homeostasis model assessment for relative
Diet and Metabolic Syndrome Current Vascular Pharmacology, 2013, Vol. 11, No. 00 7

Table 3. Dietary intervention studies investigating the benefits of a low GI diet with regard to factors of the MetS

Author Year Diet Participants Duration Outcome

(Weeks)

Wolever 1992 Alternating Low GI and High GI Patients with Type1 & 2 2 Reduction in Blood Glucose Levels &
Diabetes Serum cholesterol levels

Frost 1996 Low Vs High GI Patients with CHD 4 Improved Insulin Sensitivity

Frost 1998 Low Vs High GI Female Family history of 3 Improved Insulin Sensitivity
CHD

Jarvi 1999 Alternating Low GI and High GI Patients with Type 2 3 Lowers Blood Glucose & Insulin Levels
Diabetes
Improved Lipid Profile Reduced LDL &
HDL-cholesterol

Heilbronn 2002 Low GI Vs High GI Patients with Type 2 8 Reduction in LDL-cholesterol but no change
Diabetes in glucose management on Low GI diet

Sloth 2004 Low GI Vs High GI Overweight but Healthy 10 No change in -cell function, TAG, NEFA
or HDL-cholesterol.

Decrease in LDL and Total cholesterol

with the Low GI.

Wolever 2008 High GI, Low GI & Low Carbo- Patients with Type 2 52 HbA1c not altered.
hydrate Diabetes
Sustained reduction in postprandial glucose
on Low GI diet.

Shikany 2009 Low GI/GL Vs High GI/GL Overweight but Healthy 4 No Significant effects on markers for MetS
Men

Larsen 2010 Varied Protein Content & GI Overweight but Healthy 26 Diet high in protein but low GI was most
who achieved initial tar- successful @ maintaining weight loss.
Diogenes
geted weight loss

Gogebakan 2011 Varied Protein Content & GI Overweight but Healthy 26 Diet low in protein or low GI reduced hs-
who achieved initial tar- CRP
Diogenes
geted weight loss

insulin resistance (HOMA) levels or homeostasis model as-
sessment for  cell function. However, a 10% decrease in
LDL-cholesterol and a trend towards a greater reduction in
TC was demonstrated in the low-GI group relative to the
high-GI subjects. Shikany et al. determined the effect of
high- or low- GI/GL diets in 24 overweight or obese men
who were otherwise healthy and showed that neither inter-
vention had a significant effect on glucose metabolism, in-
flammatory markers (CRP, IL-6, TNF-
or TNF-RII) or co-
agulation factors (plasminogen activator inhibitor-1 (PAI-I)
or fibrinogen) [93]. Fat mass reduction and an increase in
lean mass with high-GI/GL diet was significant relative to
the low-GI/GL diet, however the absolute differences be-
tween the groups was small. The high-GI/GL diet resulted in
a significant reduction in TC, LDL-cholesterol and HDL-
cholesterol compared with the low-GI/GL diet. The reduc-
tion in TC and LDL-cholesterol with the high-GI/GL inter-
vention may be attributed to the higher PUFA and lower
SFA content of this diet.
Jarvi et al. compared the effects of high-GI versus low-
GI diets in a cross-over study conducted over two consecu-
tive 24 day periods and noted that insulin sensitivity im-
proved significantly with both diets but particularly with the
low-GI diet; in addition serum TC and LDL-cholesterol were
significantly reduced with the low-GI diet relative to the
high-GI diet, however HDL-cholesterol was reduced in both
groups [94]. Heilbronn et al. determined the effect of a high
SFA diet run-in for 4weeks, followed by an 8 week low- or
high-GI intervention in T2DM patients with low, median or
high glucose tolerance. Both diets induced weight loss and
lowered fasting glucose and TAG concentrations however
this was not significant between intervention groups. The
low-GI diet resulted in a greater reduction in LDL-
cholesterol concentrations in subjects with low glucose toler-
ance [95].
Overall the low-GI intervention studies in T2DM patients
have been limited to small cohorts and therefore further re-
search is needed to establish whether or not a low-GI diet
can have a positive effect. To date, studies have shown that
the glycaemic index of a diet alone is not sufficient to re-
solve the symptoms of the MetS. The most recent attempt to
target obesity and its various associated risk factors has in-
volved a combination of altered protein intake and altered GI
levels. Diogenes (Diet, obesity and Genes), investigated the
8 Current Vascular Pharmacology, 2013, Vol. 11, No. 00
efficacy of moderate fat diets that vary in protein content and
glycaemic index in preventing weight gain and obesity re-
lated factors following an initial weight loss phase [96]. Dio-
genes aimed to investigate if improvements in hs-CRP,
TAG, TC, LDL-cholesterol, HDL-cholesterol and blood
pressure all factors involved in the MetS that were achieved
during the initial weight-loss phase of the study, could be
maintained or indeed improved with the intervention diets
and additionally whether these diets elicit additional weight
lossindependent effects [97]. hsCRP levels decreased
significantly during the run-in phase and continued to
decrease during the 26-week intervention, there were distinct
changes between the dietary groups, the low-GI group
displayed greater reduction in hsCRP when compared to the
high-GI group, a combination of low-protein and low-GI was
most beneficial in respect to hsCRP reduction. This result
corroborates that of a prospective Canadian study [98] and a
cross-sectional study of a Dutch population [99]. In this
study of a Dutch population, GI was shown to have a
significantly inverse association with HDL-cholesterol. A
low-GI diet (high in dairy and fruit, but low in potatoes and
cereals) was assoicated with improved insulin sensitivity and
lipid metabolism and with a reduction in chronic
inflammatory factors This was in agreement with a study
conducted in a female US cohort [100]. However the
findings of van Dam et al. and Oxlund et al. do not support
these associations [101, 102].
5.3. General Healthy Eating Advice
The 2010 Dietary Guidelines for Americans recommend
the DASH diet for reaching and sustaining a healthy weight
and for the prevention of diet-induced diseases. The DASH
diet was established as a means of reducing blood pressure
by dietary patterns as opposed to nutrients alone [103]. The
control diet represented a typical Western style diet and was
compared to a high fruit and vegetable diet and the DASH
diet which consisted of increased consumption of low-fat
dairy, fruit and vegetables, dietary fibre and whole grains
and decreased intake of refined grains, saturated fat and total
fat [103].
The DASH diet significantly reduced blood pressure es-
pecially in African Americans and those with existing hyper-
tension [104-106]. The DASH diet also had favourable ef-
fects on blood lipids by lowering total, LDL and HDL cho-
lesterol but it had no effect on TAG concentrations in over-
weight people [107]. Blood pressure and blood lipids were
markedly improved in diabetic patients [108]. Among dia-
betic individuals, the DASH diet reduced the inflammatory
markers CRP, fibrinogen, alanine aminotransferase and as-
partate aminotransferase more so than the standard diet for
diabetic patients after just eight weeks [109]. A longer-term
study showed that the DASH diet may prevent the occur-
rence of T2DM, but the effect was greater for white indi-
viduals than for minority groups [110]. Positive outcomes
were noted for weight and fasting blood glucose as well as
for blood pressure and HDL cholesterol among men and
women with existing MetS [111]. The DASH could prove to
be effective at not only preventing the risk factors associated
with the MetS but also treating them.
Keane et al.
5.4. Lifestyle Interventions Combining Exercise and Die-
tary Advice
Alterations to diet alone have demonstrated an improve-
ment in markers of the MetS as outlined above. Further stud-
ies investigated the role of dietary intervention in conjunc-
tion with physical activity as a treatment option for MetS
[35, 112-115]. One of the first controlled, individually ran-
domised trials to test the effect of lifestyle intervention on
components of the Metabolic Syndrome was the Diabetes
Prevention Study, a multi-centre study based in Finland
[116]. In the intervention group, a frequent individual con-
sultation with a nutritionist was provided and subjects were
recommended to follow a lifestyle intervention (Table 4).
There was a significant reduction in body weight and
waist circumference in response to intervention compared to
the control cohort in years 1, 2 and 3 [116, 117]. The inci-
dence of the MetS and risk factors associated with the MetS,
including abdominal obesity, blood pressure, HDL-
cholesterol and TAG concentrations were significantly im-
proved in the intervention but not in the control group [118].
Importantly, the diet and lifestyle intervention led to a re-
duced number of patients with MetS and T2DM at the end of
3, 4 or 6 years [117] [118] [119]. The most significant die-
tary predictor for achieving large weight reduction was en-
ergy density. In particular low-fat and high-fibre intakes pre-
dicted decreased diabetes risk independently of body weight
change and physical activity [120].
The results of the Diabetes Prevention Study were com-
plimented by a similar lifestyle intervention the Diabetes
Prevention Programme (DPP) in the US, which focused on
the relative efficacy of lifestyle intervention versus pharma-
cological therapy (metformin) to prevent or delay the onset
of diabetes in individuals with impaired glucose tolerance
[121]. The DPP showed that for every 5% reduction in die-
tary fat intake (%fat) during follow-up, diabetes incidence
was reduced by 25% [122]. The DPP suggest that lifestyle
intervention may have the potential to preserve
-cell func-
tion and prevent T2DM. Weight loss in the lifestyle interven-
tion group was particularly associated with increased adi-
ponectin levels [123] [124]. Persons with impaired glucose
tolerance have elevated levels of C-reactive protein which
has been shown to predict the development of type 2 diabe-
tes and MetS [125, 126]. In the DPP study, levels of CRP
were reduced in the lifestyle intervention and in response to
metformin treatment but not in the control group [127]. The
control group had increased prevalence of hypertension and
dyslipidemia the lifestyle intervention was more successful
even than the metformin treatment in reducing hypertension
and dyslipidemia [128, 129]. The results show that a reduc-
tion in diabetes incidence by either lifestyle intervention or
metformin treatment persists for at least ten years [130].
The positive effects of lifestyle intervention seen in the
DPS and DPP studies were corroborated further by another
detailed study The study on lifestyle-intervention and im-
paired glucose tolerance Maastricht (SLIM) [131]. Dietary
recommendations were based on the Dutch guidelines for a
healthy diet (Dutch Nutrition Council 1992). Lifestyle inter-
vention again led to a reduction in weight and BMI [131,
132]. Total cholesterol, HDL and LDL concentrations did
not change over time within the two groups. Prevalence of
Diet and Metabolic Syndrome
Table 4. Outline of dietary and physical interventions to achieve goals of the DPS study.
Dietary Intervention Carbohydrate
Fat
Protein
Fibre
Physical Intervention Moderately intense physical activity for  30 minutes per day.
Weightloss Goal At least 5 % decrease in bodyweight if subject was obese.
the MetS (as defined by the National Cholesterol Education
Programme) rose from 61.4% to 66% after three years in the
intervention group and from 58.3% to 68.8% in the control
group. Overall the outcome of the intervention programme
resulted in an improvement in dietary composition, increase
in VO2 max and had a beneficial effect on glucose tolerance
and insulin sensitivity when compared to a control group that
did not receive a structured dietary and physical activity pro-
gramme [115]. These studies advocate the use of lifestyle
intervention, combining a dietary and physical activity re-
gime with resultant weight loss, as the ultimate success to
reduced MetS incidence. These studies have highlighted the
overwhelming long-term (>10 years) benefits of lifestyle
intervention and the fundamental role of physical activity in
conjunction with dietary modifications in reducing the preva-
lence of the MetS.
5.5. Functional Foods bioactives for Treating MetS
5.5.1. Definition of Functional Food
The term functional food was first coined in Japan to
describe foods which were fortified to have a positive
physiological effect [133-135]. Therefore a functional food
can be defined as a food that contains bioactive compounds
present as natural constituents or added as fortificants which
have the potential to exert health benefits beyond the basic
nutritional value of the product [136]. The bioactive com-
pound is defined as an extranutraceutical and is where the
potential for health benefits lies [137]. Bioactive compounds
normally occur naturally in small quantities and they can be
isolated from marine, animal or plant sources [136, 138,
139]. The bioactive components of functional foods are re-
leased either by digestion processes in vivo or through food
processing methods. Functional food research is being driven
by commercial benefits for the food industry and a need to
reduce healthcare costs in an increasingly ageing population.
What is important to note is that the power of foods to have
physiological effects both positive and negative has been
realised and therefore worldwide there is an effort to define
these foods more rigidly and to formulate and apply legisla-
tion to their production [140]. The original bioactives were
what we know of as micronutrients vitamins and minerals
which were used to fortify existing food stuffs in order to
maintain or enhance normal physiological functions [140].
Current Vascular Pharmacology, 2013, Vol. 11, No. 00 9
>50 % of energy derived from carbohydrate
Amount of total fat
30 % of energy
<10 % calories derived from saturated fat
1 g/kg ideal body weight/day
15 g/1000 kcal or more
Long chain (LC) n-3 PUFA, derived from fish oils, may also
be considered as bioactives as they have multiple potential
health benefits which when incorporated into a food matrix
that would not usually contain LC n-3 PUFA can also be
classed as functional foods. Evidence from in vitro studies
has demonstrated that LC n-3 PUFA have anti-inflammatory
potential which results in improved insulin sensitivity in adi-
pose tissue [141]. With the rising health costs associated
with the MetS and the recognised links between food and the
symptoms of the MetS there have been attempts to identify
bioactive compounds and functional foods which might be
able to attenuate the risk factors for MetS. The bioactive
components of various functional foods have been found to
have beneficial effects on risk factors associated with MetS.
For example, beta-glucan a soluble dietary fibre readily
found in oat and barley bran has been associated with re-
duced insulin resistance, dyslipidemia, hypertension and
obesity [142].
5.5.2. Animal Derived Bioactives
Bioactive peptides from milk, meat, soy and plant
sources have also shown favourable effects on risk factors
associated with MetS [143]. For example, milk casein BPs
such as Val-Pro-Pro and Ile-Pro-Pro both have shown anti-
hypertensive effects through inhibiting angiotensin I-
converting enzyme (ACE) [144, 145]. Furthermore, lactofer-
rin, a bioactive component of the whey fraction of milk has
shown anti-inflammatory activity in vitro and, in clinical
studies has been found to reduce visceral fat in men and
women with abdominal obesity [146-148]. Studies have also
assessed the effects of glycomacropeptide (GMP), a -casein
fragment on weight loss and cardiovascular disease risk.
Total and LDL-cholesterol, TAG, glucose, insulin, and sys-
tolic and diastolic blood pressure have been shown to de-
crease at 6 and 12 months compared to baseline with an ad-
ditional increase in HDL-cholesterol at 12 months compared
with baseline using meal replacements containing GMP-
enriched whey protein isolate (GMP-WPI) containing 90%
GMP [149]. Whey-born multifunctional peptides called
-
lactorphin and -lactorphin affect adipocyte lipogenesis due
to their ACE-inhibitory activities and also they may reduce
food intake via peripheral opioid receptors, similarly to ca-
sein and soy protein hydrolysates [150, 151]. Meat derived
10 Current Vascular Pharmacology, 2013, Vol. 11, No. 00
BPs have also shown anti-thrombotic, anti-inflammatory and
antihypertensive properties in rodent models [152-154].
5.5.3. Plant Derived Bioactives
Phytochemical or plant derived bioactives such as cin-
namon, green tea, berberine and ginseng have all demon-
strated an ability to modulate signalling pathways in metab-
olically challenged in vitro cell models and animal studies
[155-160]. Cinnamon extract decreased oxidative stress,
body fat and improved fasting glucose levels in glucose in-
tolerant subjects, however these studies involved a relatively
small cohort and due to the reliance on self reported food
diaries it is not clear if those involved had reduced their en-
ergy intake thus the reduction in body fat observed [161,
162]. Epigallocatechingallate (EGCG), the major bioactive
in green tea, lowered cholesterol and improved insulin sensi-
tivity in obese mice, and lowered blood pressure in sponta-
neous hypertensive rats [163, 164]. Epidemiological studies
have found that regular consumption of green tea is inversely
associated with cardiovascular mortality, risk of hyperten-
sion and of diabetes, and with percent body fat and body fat
distribution [165]. Supplementation of an exercise regime
based on walking with the same green tea extract has dem-
onstrated improvement in glycaemic control and a reduction
in heart rate in overweight females however this study rec-
ognised that the dose given was not sufficient to induce fat
loss [166]. Berberine has traditionally been recognised for its
antibiotic properties however recent studies have demon-
strated that supplementation with berberine can improve
blood glucose levels and improve dyslipidemia in diabetic
patients [167, 168].
Two bioactive polyphenols found in fruits, resveratrol
and quercetin have been noted for their favourable effects on
components of MetS. Both bioactives improved insulin sen-
sitivity and glucose metabolism in cell culture models, in-
cluding 3T3-L1 adipocytes and adipose tissue isolated from
rats and cultured ex vivo [142, 169, 170]. Quercetin given to
obese rats improved inflammation, dyslipidemia, hyperten-
sion, and hyperinsulinemia [171]. In a human study, quer-
cetin supplements given to overweight subjects with MetS
traits reduced systolic blood pressure and LDL-cholesterol
concentration [172]. Mice fed a high fat diet and supple-
ments of resveratrol lived longer, weighed less and, had in-
creased insulin sensitivity compared to control mice. In an-
other study, obese rats given supplements of resveratrol had
lowered blood pressure, plasma glucose, cholesterol and
TAG compared to control animals [139]. Recent evidence in
healthy obese adults has corroborated the early work con-
ducted in animal models of obesity [173]. Epidemiological
and experimental studies have revealed that drinking red
wine attenuates cardiovascular risk factors, highlighting res-
veratrol as a protective agent [174, 175]. Human intervention
studies have demonstrated a beneficial effect of resveratrol
supplements (10mg) on symptoms of CAD [176], and an
improvement in insulin sensitivity [177]. However there are
questions about the bioavailability of resveratrol and quer-
cetin, with evidence that even massive supplementation
doses may not be able to achieve the concentrations needed
for biological effects to occur. This research also questions
the use of polyphenols alone but rather stresses that their
Keane et al.
glucuronide and sulfate conjugates would be more effective
due to the fact that they are absorbed as conjugates [178].
Bioactive compounds are reinforcing the concept of you
are what you eat. There is rapid progress being made in
isolating and understanding bioactive compounds and the list
of functional foods is being added to at pace. Functional
foods occupy the market between traditional foods and what
we consider to be medicine. They have demonstrated that
they have the potential to reduce the risk of disease or im-
prove markers of health. However there is much more work
to do to classify these compounds and regulatory bodies are
putting in place the necessary legislation to ensure that there
are no health scares as a result of functional foods cross reac-
tion with normal foods or prescribed medication. There are
a number of ongoing studies evaluating the benefit or risk of
foods and functional foods e.g. BEPRARIBEAN,
PLANTLIBRA and BRAFO. In the USA, functional foods
are under the regulation of the Food and Drug Administra-
tion (FDA). In Europe, the European Food Safety Authority
(EFSA) is responsible for evaluating health and nutritional
claims for functional foods. Aside from issues of food safety
further research is needed to establish scientific proof of effi-
cacy and bioavailability of the bioactive components of func-
tional foods in human studies. Human intervention studies
into functional foods must take into consideration subject
selection, background diets, length of intervention, maxi-
mum effective dose of the active ingredient, possible food
matrices, appropriate controls, methods of establishing com-
pliance and finally the biological markers of the endpoint
[179].
6. CONCLUSION AND FUTURE PERSPECTIVES
The MetS is a complex disorder involving physiological
dysfunction in multiple organs and systems and which is
caused by both genetic and environmental influences. The
multi-factorial nature of the MetS means that there are nu-
merous targets for therapy which is positive however it
also makes it difficult to treat as no single therapy can possi-
bly hope to affect all available targets. Studies put forward
the theory of primordial prevention as a way to avoid the
symptoms and outcomes of the MetS altogether. However
with the worldwide increase in childhood obesity this option
is already taken out of most individuals control. Pharmacol-
ogical agents can be used to treat the MetS at its latter stages
however they should be a last resort, following lifestyle
interventions, as none currently available are an outright cure
for the MetS. In the early stages of metabolic disturbance it
is possible to reverse the symptoms and prevent outright
T2DM development or to reduce the risk of death from car-
diovascular complications. As the cost of treating MetS is
increasing worldwide and therefore straining already con-
strained health budgets there has been an increase in the
number of studies analysing alternative treatment options.
The literature supports weight management through dietary
and lifestyle interventions as early as possible to prevent
disease progression. While initial studies focused on individ-
ual nutrients, the outcomes of these studies were insufficient.
There has been considerably more success with the combina-
tion of exercise and dietary interventions in treating symp-
toms of the MetS. The functional food area may have further
potential within the context of designing novel foods en-
Diet and Metabolic Syndrome Current Vascular Pharmacology, 2013, Vol. 11, No. 00 11

riched with bioactives or compounds which when isolated TAG = Triacylglycerol

from their natural source have added health benefits which
TC = Total Cholesterol
ameliorate one or more components of the MetS. Whilst
there is the potential to develop bioactives that target the VLDL = Very-low-density lipoprotein
insulin resistant component of the MetS and this would WHO = World Health Organisation
attenuate the metabolic risk factors such as T2DM and CVD
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Received: ?????? 29, 2012 Revised: ?????? 1, 2012 Accepted: ?????? 15, 2012
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