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Lead Article
Dietary management of the metabolic syndrome
beyond macronutrients
Deanna M Minich and Jeﬀrey S Bland
Due to the complexity of chronic conditions like the metabolic syndrome (MetS),
tailored dietary approaches beyond macronutrient ratio modiﬁcation may be necessary to eﬀectively address metabolic measures. Mounting data on whole foodsbased, phytochemical-abundant dietary patterns, such as the Mediterranean diet,
reveal that they contain constituents, such as phytochemicals, that may be beneﬁcial
for treating MetS. The role of food-based phytochemicals on underlying mechanisms
of MetS, speciﬁcally as they impact insulin signaling, has yet to be investigated
thoroughly. This review discusses various dietary approaches for MetS, with a focus
on certain foods and dietary phytochemicals known to impact insulin signaling.
© 2008 International Life Sciences Institute
INTRODUCTION
The metabolic syndrome (MetS) has been deﬁned as a
constellation of abnormal cardiometabolic factors that
increase risk of cardiovascular disease (CVD) and
type 2 diabetes. Traditionally, these measurements have
included increases in waist circumference, blood pressure, triacylglycerols (TG), and fasting glucose, as well as
decreased HDL-cholesterol (Figure 1). In past years, the
deﬁnition of MetS has expanded to include indicators of
thrombosis and inﬂammation.
A rather complex disorder, providing a gateway to a
host of chronic diseases, MetS appears to be precipitated
by a number of underlying risk factors relating to genetics
and lifestyle, and as proposed by Sullivan,1 a mismatched,
incongruent combination of both those aspects. MetS is
the subject of a plethora of scientiﬁc publications, with
over 10,000 publications listed in the National Library
Medicine Database (accessed 14 April 2008), yet there is
continued debate over its deﬁnition and whether it is
clinically relevant. Regardless of the terminology or the
precise deﬁnition, MetS provides an intersection of
markers that leads to a spectrum of chronic diseases.
Currently, prevention and treatment of MetS are
often handled according to the presence and degree of the
individual risk factors. Fitch et al.2 assessed that individu-
als with MetS most commonly exhibit abdominal obesity
and dyslipidemia, providing support for the use of lifestyle modiﬁcation as a major cornerstone of MetS
therapy. In fact, lifestyle therapies have been speciﬁcally
recommended for reducing several cardiometabolic risk
factors beyond obesity and atherogenic dyslipidemia,
including elevated blood pressure and glucose, and treating a pro-inﬂammatory state.3,4 The Scientiﬁc Statement
proposed by the American Heart Association (AHA) and
the National Heart, Lung, and Blood Institute (NHLBI)3
states: “In the long run, the greatest beneﬁt for those with
metabolic syndrome will be derived from eﬀective lifestyle intervention.” Indeed, lifestyle intervention has
been demonstrated to be more eﬀective than metformin
for reducing the incidence of MetS5 and type 2 diabetes6,7
in high-risk populations. In 3234 nondiabetic subjects
with elevated fasting glucose, a lifestyle-modiﬁcation
program composed of a low-calorie, low-fat diet plus
physical activity, reduced the incidence of type 2 diabetes
by 58%, and metformin by 31%, compared with placebo.6
The authors concluded, “. . . the lifestyle intervention was
signiﬁcantly more eﬀective than metformin”. Similarly,
the same lifestyle-modiﬁcation program was able to
reduce the incidence of MetS in 1711 subjects by 41%
(metformin by 17%) compared with placebo.5 Considering that side eﬀects may be experienced while taking
Aﬃliations: DM Minich and JS Bland are with the Functional Medicine Research Center, MetaProteomics, LLC, Gig Harbor, Washington, USA.
Correspondence: DM Minich, Clinical Nutritionist, Functional Medicine Research Center, MetaProteomics, LLC, 9770 44th Avenue NW, Suite
100, Gig Harbor, WA 98332, USA. E-mail: deannaminich@metagenics.com, Phone: +1-253-853-7343, Fax: +1-253-851-9749.
Key words: insulin signaling, Mediterranean diet, metabolic syndrome, phytochemicals, protein kinases
doi:10.1111/j.1753-4887.2008.00075.x
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Figure 1 Constellation of factors comprising the metabolic syndrome. These six criteria compose the general
diagnostic guidelines for the metabolic syndrome according
to Grundy et al. (2004).181 Speciﬁcally, abdominal obesity is
referred to as a waist circumference of ⱖ102 cm in men and
ⱖ88 cm in women. Atherogenic dyslipidemia refers to
increased triacylglycerols of ⱖ150 mg/dL (1.7 mmol/L) or
pharmaceutical therapy for hypertriacylglyceridemia, as
well as decreased HDL-cholesterol deﬁned as ⱕ40 mg/dL
(0.9 mmol/L) in men; ⱕ50 mg/dL (1.1 mmol/L) in women or
pharmaceutical therapy for low HDL-cholesterol. Increased
fasting blood glucose refers to levels at ⱖ100 mg/dL or
pharmaceutical treatment for elevated glucose. Hypertension is ⱖ130 mmHg systolic blood pressure or ⱖ85 mmHg
dystolic blood pressure or pharmaceutical therapy for
hypertension. Finally, increased thrombosis and inﬂammation are recent additions to the metabolic syndrome
cascade. It has been suggested that elevated concentrations
of plasminogen activator inhibitor-1 and/or ﬁbrinogen, and
C-reactive protein and/or a high white blood cell count may
be potential, although not yet validated, markers for the
prothrombotic and proinﬂammatory aspects of the metabolic syndrome, respectively.19,181 It is worthwhile to note
that Grundy et al. (2004)181 remarked that other less routine
measurements have also been associated with the abovelisted components of MetS, including elevated apolipoprotein B, small LDL particles, insulin resistance and
hyperinsulinemia, and impaired glucose tolerance.
pharmaceuticals like metformin, changing diet and activity patterns may be a more attractive alternative for individuals with MetS.
HIGHS AND LOWS
In addition to physical activity, one of the aspects of lifestyle modiﬁcation for MetS is diet;3 however, researchers
430
have agreed that a uniform consensus is lacking as to
which dietary approach is most eﬃcacious.8,9 Since the
primary endpoint for treatment of MetS is to reduce the
risk of CVD,3 traditional dietary recommendations such
as those proposed by the National Cholesterol Education
Panel (NCEP)-Adult Treatment Panel (ATP) III and the
AHA have primarily emphasized the macronutrient
content of the diet with their recommendations to keep
carbohydrate energy intake to 50–60%, protein to ~15%,
and fat to 25–35%, with saturated fat at <7%, along with
an avoidance of trans fat and restriction on daily cholesterol intake (300 mg/d).10,11 In addition to a low-fat, highcarbohydrate diet, NCEP-ATP III promotes the inclusion
of fruits, vegetables, and whole grains. In a joint scientiﬁc
statement on MetS, the AHA and NHLBI advocated
“modiﬁcation of an atherogenic diet” for MetS, deﬁned as
reducing intakes of total fat (25–35 en%), saturated fat
(<7 en%), trans fat, and cholesterol (<200 mg/d).3 Additional guidance was provided as follows: “most dietary fat
should be unsaturated, simple sugars should be limited”.
Hence, the overarching recommendation for MetS
from pivotal opinion leading organizations is essentially
to follow a low-fat diet. However, it could be argued that
focusing solely on dietary macronutrient quantity and
their individual contributions to total calories, such as the
case with a low-fat diet, may not be the sole approach to a
complicated, chronic disease precursor like MetS. It is
reasonable that the low-fat diet may serve as an adequate
foundation upon which other dietary additions could be
made.
Certainly, some studies have demonstrated that lowfat diets are somewhat eﬀective for lowering certain CVD
risk markers such as LDL-cholesterol.12 On the other
hand, Knopp et al.13 commented that in combined hyperlipidemia, which is common in MetS, LDL-cholesterol
levels are only one-third as responsive to dietary fat and
cholesterol as simple hypercholesterolemia. Ordovas
et al.12 speculated that the response of total and LDLcholesterol to a low-fat diet could present a high degree of
inter-individual variability due, in part, to genetic factors.
Aside from LDL-cholesterol levels, a low-fat diet may
not completely address the full array of cardiometabolic
risk factors that comprise MetS in all individuals.9 For
example, TG and inﬂammation are two other MetS
markers that have been shown to respond diﬀerentially to
a low-fat diet. Lukaczer et al.14 reported that postmenopausal, hyperlipidemic women with MetS on a low-fat diet
for 12 weeks had a substantial decrease in TG (23.5%),
but this change was not statistically signiﬁcant from baseline. Forsythe et al.15 compared low-fat and very-lowcarbohydrate diets in a population of overweight men and
women with atherogenic dyslipidemia and found that the
low-carbohydrate diet was more eﬀective at reducing
markers of inﬂammation than the low-fat regimen.
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In a recent study by Muzio et al.,9 two diets with
altered macronutrient compositions (high-carbohydrate
vs. low-carbohydrate, high-protein and monounsaturated
fat) were tested for their ability to impact CVD risk
factors over 5 months in 100 obese patients with MetS.
Interestingly, all the components of the MetS decreased
signiﬁcantly in both groups with no signiﬁcant diﬀerence
in the net resolution of MetS on either dietary regimen.
Of note is that although no diﬀerences were found
between the groups, each of the diets impacted measures
of MetS uniquely: for example, the low-carbohydrate diet
resulted in better reductions in systolic blood pressure
and heart rate compared with the high-carbohydrate diet,
and the latter led to greater lowering of LDL cholesterol.
A complete review of the eﬀects of various macronutrient
permutations on MetS has been extensively investigated
by Feldeisen and Tucker16 and will not be repeated within
this text. Generally, it is becoming increasingly recognized that operating within the macronutrient nutritional
paradigm may not adequately prevent and treat chronic
disease.
Ultimately, recommending exceedingly high and low
quantities of macronutrients can result in an unbalanced
diet. A diet low in fat usually implies a higher reﬁned
carbohydrate intake, which has been shown to result in
elevated TG and reduced HDL-cholesterol, two important markers of cardiometabolic risk.17–19 Similarly, lowcarbohydrate, high-protein diets, which have gained
popularity in the past decade, tend to be higher in saturated fat and low in fruits, vegetables, and whole grains.3,20
Also, the increased levels of protein in this diet may
present a greater renal burden in individuals with compromised kidney function. Moreover, low-carbohydrate,
low-protein diets, even with substitution of monounsaturated fats for carbohydrate, have inconsistently been
reported to increase insulin sensitivity21–25 and blood
pressure.21,22,25 Finally, the amount of saturated fat may be
greater in low-carbohydrate diets. A recent study suggests
that higher intake of saturated fat results in increased
carotid artery intimal medial thickness.26 The authors
from the GOCADAN study27 conclude that “high consumption of saturated FAs [fatty acids] . . . may have an
adverse eﬀect on MS [metabolic syndrome]” as they
found saturated fat consumption to increase TG levels
and blood pressure.
Carbohydrate and glycemic index
Some recent studies have been instrumental in demonstrating the concept that macronutrients in the form of
carbohydrate have diﬀerent impacts on insulin signaling
and action. For example, Kallio et al.28 tested the eﬀect
of feeding two types of dietary carbohydrate, rye and
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oat-wheat-potato, in the form of breads and baked products, to subjects with MetS for 12 weeks, on gene expression of their subcutaneous adipose tissue. Findings
revealed that the rye-fed individuals displayed downregulation of 71 genes, including those responsible for insulin
signaling such as insulin-like-growth-factor binding
protein-5 and the insulin receptor (IR). Feeding oatwheat-potato led to diﬀerent results than those of the
rye-pasta diet. Speciﬁcally, there was an upregulation in
62 genes related to stress-like serum glucocorticoidregulated kinase, and mitogen-activated protein kinase.
Activation of these stress-related kinases may contribute
to the underlying pathology of MetS.29 Pathways triggering
oxidative stress, interleukins, and inﬂammation were also
expressed with this diet, providing more support for the
role of certain dietary carbohydrate in the inﬂammatory
processes that compose MetS. Furthermore, insulin
action, as measured by the insulinogenic index, improved
in individuals on the rye diet but not on the oat-wheatpotato diet (P = 0.004). Interestingly, these eﬀects
occurred in the absence of overall body weight change.
In response to the Kallio et al.28 study, Salsberg and
Ludwig30 commented: “Traditionally, food is thought to
inﬂuence human health through its nutrient content,
whereas drugs are recognized to act through molecular
pathways. However, consumption of a meal stimulates
the release of numerous hormones that can powerfully
aﬀect signal transduction and gene function.” In addition, the studies by Kallio et al.28 may point to some
other key concepts: 1) signiﬁcant metabolic changes and
gene expression can occur in the absence of weight loss,
2) carbohydrate as a macronutrient responds diﬀerently
based on its constituents. One might suggest that these
eﬀects were anticipated due to the diﬀerences in the glycemic indices of the carbohydrates used in the study.
Glycemic index is a well-recognized marker of how a
carbohydrate is processed postprandially.31,32 Several
excellent reviews have been written on this topic as it
relates to the health outcomes33–38 and, thus, will not be
repeated in this text. Although it is useful, it is a relatively gross measurement and does not provide details
of how the released glucose and insulin trigger intracellular pathways relevant to MetS. Since various dietary
carbohydrates contain diﬀerent compositions, it may be
worthwhile to investigate how the phytochemical signature of a carbohydrate can further impact glycemic
index and speciﬁc genes related to glucose and insulin
dynamics.
Available data indicate that rather than identifying
levels of particular nutrients as a percentage of calories, it
may be worthwhile to broaden the nutritional approach
to chronic clinical conditions like MetS into one that
takes into consideration the global dietary pattern of food
intake.
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DIETARY PATTERNS RICH IN PHYTOCHEMICALS
An increasing number of studies indicates that dietary
patterns high in whole, unprocessed plant foods and, as a
result, abundant in phytochemicals, may have beneﬁt for
MetS.39–42 Myriad epidemiological studies have consistently demonstrated the beneﬁts of a phytochemical-rich
diet for decreasing the development of or treating chronic
disease. Increased fruit and vegetable consumption has
been associated with reduced incidence of MetS, type 2
diabetes, and CVD.43–45 In a cross-sectional study of 486
female teachers aged 40–60 years, higher intakes of fruit
and vegetables were found to correlate with a lower risk of
MetS.46 In support of these data, lower vegetable and ﬁber
intake have been associated with a greater incidence of
MetS.42 Using results from three large epidemiological
studies, Baxter et al.41 noted that certain dietary patterns
are associated with the development of MetS: diets high in
meat and reﬁned grains were associated with high incidence of MetS while diets high in fruits, vegetables, and
minimally processed grains were found to be inversely
associated with MetS. The overall conclusion from this
review was that “no individual dietary component could
be considered wholly responsible for the association of
diet with MetS”. In the authors’ opinion, the quality of the
diet conferred the most protection against MetS compared
with these individual foods.After examining food patterns
within a population of 1514 men and 1528 women, Panagiotakos et al.39 similarly demonstrated that consumption
of ﬁsh, cereals, legumes, vegetables, and fruits was
inversely associated with the following MetS markers:
waist circumference,systolic blood pressure,TG,and positively associated with HDL-cholesterol levels, whereas
meat and alcohol intake showed the opposite results.
One of the common denominators in these studies is
the role of fruits and vegetables. An observation to note is
that the rise of obesity and MetS has appeared to parallel
the staggering low consumption of fruits and vegetables
in the United States population. Despite the nationwide
campaign to increase consumption of fruits and vegetables, the average American continues to eat only about
1½ servings of vegetables and less than one serving of
fruit per day.47 Blanck et al.48 recently assessed the
consumption of fruits and vegetables of 1,227,969
adults in the United States and found that the number
of men and women eating these foods ﬁve or more
times daily between 1994 through 2005 was essentially
unchanged (men: 20.6% vs. 20.3%; women: 28.4% vs.
29.6%, respectively).
Mediterranean-style diets
An example of a high phytochemical dietary pattern that
has been studied extensively for MetS in the past 5 years,
432
and has been shown to favorably impact markers of MetS
is the well-recognized “Mediterranean diet”.49–63 In a
noteworthy study by Knoops et al.,64 the Mediterranean
diet was found to be associated with a more than 50%
lower rate of all-cause and cause-speciﬁc mortality in
elderly European adults aged 70–90 years, suggesting it
has the ability to signiﬁcantly impact overall health.
Despite the fact that it is widely referred to as such,
the “Mediterranean diet” is not well deﬁned since it
reﬂects the eating characteristics of more than 15 countries in the Mediterranean Basin. However, there is
general consensus that it includes 1) copious quantities of
minimally processed, fresh, plant-based foods such as
fruits, vegetables, whole grains, seeds, and nuts; 2) olive oil
as the principal source of dietary fat; 3) minimal consumption of red meat and dairy products; and 4) wine in
low to moderate amounts with meals.49 Individual foods
that compose the Mediterranean diet may be uniquely
responsible for addressing speciﬁc MetS criteria. For
example, in one study, fruit intake was shown to be protective for TG levels55 and in another, olive oil, vegetables,
and fruit were inversely associated with systolic and diastolic blood pressure.65 A general distillation of the Mediterranean dietary pattern into some general beneﬁcial
constituents for MetS could include the following: 1)
high monounsaturated fat and polyphenol (tyrosol and
hydroxytyrosol) content found in extra virgin olive oil; 2)
high ﬁber, complex carbohydrates, vitamins C and E,
minerals, polyphenols, and thousands of phytonutrients
from cereals, legumes, vegetables and fruits.
Some researchers contend that olive oil is the major
component of the Mediterranean diet and that it provides
the most therapeutic beneﬁt.53,66 In fact, the monounsaturated fat (i.e., oleic acid) content of olive oil fueled the
preliminary interest in the Mediterranean way of eating,
and has been purported to be one of the most relevant
foods in the Mediterranean diet for individuals with
MetS53,67,68 as it appears to improve insulin sensitivity.68
However, the advantages of olive oil consumption may
extend beyond its monounsaturated fat content.69–71
Virgin olive oil is particularly high in a plethora of phytochemicals that encompass phenolic compounds that
belong in a variety of classes: phenolic acids, phenyl ethyl
alcohols, hydroxyl-isochromans, ﬂavonoids, lignans, and
secoiridoids.72 Three phenolics have been given increased
attention for their potent antioxidant activity: hydroxytyrosol, tyrosol, and oleuropein.66 Covas et al.70 studied
the eﬀect of olive oils varying in phenolic content on
heart disease risk factors in 200 healthy male volunteers.
MetS marker, HDL-cholesterol, increased linearly
for low-, medium-, and high-polyphenol olive oil. TG
levels reduced to the same extent for all three oils.
It would be valuable to repeat this study in individuals
with MetS.
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Since fatty acids can aﬀect lipid membrane composition, one of the pivotal ways that olive oil can impact signal
transduction would be through modiﬁcation of signaling
proteins embedded in the plasma membrane. Perona
et al.73 fed virgin olive oil to elderly individuals who were
healthy or who had type 2 diabetes. Consumption of olive
oil increased the monounsaturated fatty acid content of
erythrocyte membranes in both groups. Perhaps more
importantly, levels of G proteins and protein kinase Ca
were decreased in both groups to varying degrees (reductions: 46–59% in control group; 17–72% in diabetics).
Along similar lines, Ficková et al.74 found that feeding rats
mono- and polyunsaturated oils like olive oil resulted in
alteration of insulin tyrosine kinase.
Additionally, another means by which olive oil may
work mechanistically in MetS via signal transduction is
through reduction of nuclear factor-kappa beta (NF-kb).
An insulin-resistant, hyperglycemic state leads to the
manufacture of pro-inﬂammatory transcription factors
like NF-kb.75,76 Extra-virgin olive oil extract has been
shown to aﬀect intracellular signaling by inhibiting NF-kb
translocation in human monocytes and monocytederived macrophages from healthy human volunteers.77
When healthy humans were fed a variety of diets, including a Mediterranean diet, NF-kb activation in mononuclear cells was signiﬁcantly reduced relative to when a
Western diet was followed.78 Following a Western diet led
to a 2.7-fold increase in NF-kb compared with the Mediterranean diet.78 In a separate study, olive oil was found to
prevent postprandial activation of NF-kb in peripheral
blood mononuclear cells compared with either butter or
walnuts.79
Similar to olive oil, red wine polyphenols, including
ﬂavonoids (e.g., quercetin, proanthocyanidins) and nonﬂavonoids (e.g., resveratrol, gallic acid), have been highlighted for their role in the health beneﬁts of the
Mediterranean diet. An excellent review on this topic has
been published previously.80 Of all the polyphenols, resveratrol has been studied the most extensively and found
to have antioxidant, vascular, protective actions, and even
metabolic eﬀects. With respect to MetS, a study using
middle-aged mice on a high-calorie diet showed that resveratrol consumption resulted in improved survival
similar to mice on a standard diet via a number of eﬀects,
including increasing insulin sensitivity. Resveratrol’s
eﬀects on these diverse actions are thought to be mediated
through downregulation of the phosphatidylinositol-3
kinase (PI3K)-Akt signaling cascade,81,82 ultimately
aﬀecting the activity of the anti-senescence sirtuin
deacetylases.83–85 Fröjdö et al.81 elegantly demonstrated
that resveratrol inhibits, both in vitro and in cultured
muscle cells, insulin receptor substrate (IRS)-1-associated
class IA PI3K activity and its subsequent phosphorylation
of downstream targets, such as Akt and forkhead tranNutrition Reviews® Vol. 66(8):429–444
scription factor, thereby potentially promoting healthy
intracellular glucose metabolism and lifespan control.
Second to resveratrol are the eﬀects of quercetin on
intracellular glucose metabolism. Strobel et al.86 report
that ﬂavonoids such as quercetin and myricetin (a metabolite derived from quercetin) interact directly with the
glucose transporter GLUT4 to inhibit its uptake of glucose
into the cell. Quercetin and myricetin also work on multiple targets within the insulin signaling pathway directly
by inhibiting PI3K at relatively low concentrations87–89 and
modulating activity of Akt/protein kinase B (PKB) and
PKC.90–92
Plant food diets rich in soy, ﬁber, and phytosterols
Phytochemical-rich foods with recognized health beneﬁts
have been explored for their application to MetS parameters. Jenkins et al.93 studied a dietary portfolio of
cholesterol-lowering foods versus a statin (Lovastatin) on
lipid levels in healthy, hyperlipidemic adults (n = 46).
The diet was high in particular foods known to be beneﬁcial for CVD prevention: plant sterols (1 g/1000 kcal),
soy protein (21.4 g/1000 kcal), viscous ﬁbers (9.8 g/
1000 kcal), and almonds (14 g/1000 kcal). These foods are
in alignment with the dietary recommendations from the
NCEP-ATP III of 2 g/d plant sterols and 10–25 g/d
viscous ﬁbers. The US Food and Drug Administration’s
health claims on viscous ﬁbers, soy protein, plant sterols,
and nuts indicate that substantial research of these foods
supports their ability to lower serum lipids and, as a
result, reduce the risk of heart disease. Impressively,
results from this study indicated that subjects on the
dietary portfolio had signiﬁcant reductions in LDLcholesterol similar to results achieved through treatment
with a statin (28.6% and 30.9%, respectively).
Similarly, Lukaczer et al.14 demonstrated that a beverage consisting of 30 g soy protein and 4 g phytosterols
added to a Mediterranean-style, low-glycemic-index
diet led to better improvements in MetS lipid markers,
such as TG, in hyperlipidemic, postmenopausal, overweight women than a low-fat diet without these key
phytochemical-rich foods. At baseline, both groups had
Framingham risk scores for coronary heart disease that
were not statistically diﬀerent; however, after the intervention, subjects in the group provided with soy protein
and phytosterols had a much lower CVD risk compared
with the group on the low-fat diet (median 6.0, 95% CI
4.4–7.6 and 9.0, 95% CI 7.9–10.1, respectively).
Soy foods
Soy is becoming increasingly recognized as a food that is
beneﬁcial for MetS, particularly for its eﬀects on serum
433
lipids and inﬂammatory cytokines. An extensive body of
literature indicates that soy food consumption leads to
signiﬁcant decreases in total cholesterol (10–19%), LDL
cholesterol (14–20%), and TG (8–14%).94 Despite these
key ﬁndings in the hyperlipidemic population, very
few clinical studies have examined the eﬀect of soy
food consumption in subjects with MetS. In a crossover
study with 42 postmenopausal women with MetS, Azadbakht et al.95 implemented three dietary treatments: a
control diet (Dietary Approaches to Stop Hypertension,
DASH), a soy-protein diet, and a soy-nut diet, each for a
total of 8 weeks. Consumption of soy nuts resulted in
the most favorable impact on MetS markers relative to
the other dietary therapies, including decreasing the
homeostasis model of assessment-insulin resistance
score, fasting plasma glucose, LDL-cholesterol, and serum
C-peptide concentrations. Markers of endothelial function and inﬂammation also improved more signiﬁcantly
with the soy-nut diet than with the DASH diet or the soy
protein diet.96 These results allude to the importance
of the contribution of the entire food matrix (soy nuts
vs. soy protein) in addressing the complexity of MetS
markers.
In further support of the application of food matrices
and complexity, Noriega-López et al.97 demonstrated that
the eﬀects of soy isoﬂavones in rats were determined by
their interaction with a pattern of amino acids. When
amino acids were added to pancreatic islets that paralleled
the appearance of amino acids in the plasma of animals
fed either a soy or casein diet, diﬀerent responses were
obtained. Interestingly, the soy protein group stimulated
insulin secretion to a lesser extent, and reduced GLUT-2
expression compared to when the isoﬂavones accompanied the casein amino acid proﬁle.
Finally, soy isoﬂavones may help combat inﬂammatory processes that are active in MetS by inhibiting proinﬂammatory cytokines, cell adhesion proteins, and
inducible nitric oxide production.98
THE PROOF IS IN THE PIGMENT
A closer examination of dietary patterns that inﬂuence
MetS, such as the Mediterranean diet or vegetarian-style
diets that are high in soy, phytosterols, and ﬁber, reveals a
generous palette of whole foods of plant origin. One
might propose that phytochemicals, or non-nutritive substances in plants that possess health eﬀects, are an essential component of a diet for MetS. Certainly, fruit and
vegetable consumption has declined slightly between
1994 and 200548; in parallel, there has been a rise in the
incidence of chronic diseases such as MetS. Although
eating more fruits and vegetables may not be the simple
answer to a complex issue like MetS, one could question
434
whether consumption of the Western-style, oft-called
“standard American diet”, has created a state of “phytochemical deﬁciency” as it contains an array of processed foods devoid of the colors embodied by naturally
occurring phytochemicals.
A body of literature attests to how food-derived pigments provide color, enhance the enjoyment of eating,
and, most importantly, protect organisms from disease.
Decker99 has identiﬁed almost 2000 known plant pigments in food, including over 800 ﬂavonoids, 450 carotenoids, and 150 anthocyanidins. More recent numbers
from Walsh et al.100 indicate there are 5000–10,000 phytochemicals present in human food, and a large percentage most likely remains unknown.101 On average, an
individual receives about 1.5 g of phytochemicals in their
diet.102 Although the quantity may seem negligible relative to the several hundred grams of macronutrients
typically ingested, the immense diversity and potential
interaction of these compounds occurring in the food
supply could conceivably result in a signiﬁcant number of
cellular reactions within the body after ingestion. Certainly, the literature is headed towards supporting the
concept that food is more than simply energy and that
phytochemicals may play a larger role than originally
assumed, especially for MetS. As a case in point, a recent
report by Walsh et al.100 demonstrated that dietary phytochemicals signiﬁcantly impact human urinary metabolomic proﬁles within a couple of days.
Taking phytochemicals into account together with
macronutrients more accurately reﬂects how individuals
eat, i.e., foods containing a plethora of phytochemicals
along with a base of macronutrients, all in a certain proportion.Accordingly, extending the dietary focus for MetS
(and other chronic conditions) beyond macronutrients
seems warranted. Macronutrients obtained through diet
may have limited eﬀects on their own without any accompanying phytochemicals. Furthermore, the resulting
physiological eﬀects of complex cell-signaling patterns
could be dramatically altered by the presence or absence
of the multitude of phytochemicals occurring in their
usual proportions. An example of this concept has been
illustrated in the study by Esposito et al.103 in which 25
healthy subjects were given three meals randomly for 1
week intervals: a high-fat meal, an isocaloric highcarbohydrate meal, and the same high-fat meal plus 100 g
tomatoes, 200 g carrots, and 100 g peppers. Postprandial
endothelial function was shown to be impaired in subjects
fed the high-fat diet; however, most interestingly, the
addition of vegetables to the diet partially prevented this
dysfunction.
Some researchers104 have suggested a return to the
concept of food synergy and the value of the food matrix
as a pivotal cornerstone of nutrition. As Lila105 states:
“. . . what many people don’t fully appreciate is that it is
Nutrition Reviews® Vol. 66(8):429–444
not a single component in these plant-derived foods, but
rather complex mixtures of interacting natural chemicals,
that produce such powerful health-protective eﬀects.”
EFFECTS OF PHYTOCHEMICALS ON INSULIN SIGNALING
The previous descriptions of dietary patterns brieﬂy
discussed some of the food-based phytochemicals that
may potentially impact, in a variety of ways, cell-signaling
pathways related to MetS. Despite the fact that intakes of
fruits, vegetables, and whole grains appear to be important for reducing the incidence of chronic diseases, the
mechanisms related to their action(s) remain, for the
most part, unclear. The eﬀect of speciﬁc food-based phytochemicals on the underlying pathology of MetS has not
been adequately explored. Current evidence suggests that
markers of MetS appear to be uniﬁed by dysfunctional
insulin action,19 which may, in part, arise due to heightened inﬂammatory processes106–109 and overspill of
lipid from adipose tissue leading to chronic lipotoxicity
(Figure 2).110,111
In MetS, adipocytes are inﬁltrated by macrophages
to produce pro-inﬂammatory cytokines, such as tumor
necrosis factor-alpha (TNF-a), resistin, leptin, and
interleukin-6 (IL-6), that can crosstalk with skeletal
muscle, signiﬁcantly altering insulin signaling.106–109
Adding to the pathophysiology induced via the inﬂuence
of adipokines on muscle, chronic, excessive caloric intake
results in a surplus of glucose and lipid that overﬂows
from adipose to non-adipose tissue (e.g., skeletal muscle
and liver). The overabundance of energy engages nonoxidative pathways, producing reactive lipid species and,
ultimately, a state of intramyocellular lipid accumulation
and chronic lipotoxicity.111 Lipotoxicity exacerbates dysfunctional protein kinase activity related to controlling
inﬂammatory pathways. Through negative feedback,
hyperactive PI3K, PKC, and glycogen synthase kinase
(GSK)-3 terminate insulin signaling,110 causing insulin
resistance.112–114
Thus, in MetS, there is increased resistance of target
tissues to the eﬀects of insulin,115 which is the reﬂection of
cumulative changes in the activity of cell membranebound IRS docking proteins. When IRS-1 is phosphorylated upon serine 307 via cellular stressors such as
TNF-a, insulin signal transduction is negatively regulated
through inhibition of IRS-1-associated stimulation of
Figure 2 General diagrammatic representation of the insulin-signaling cascade. Insulin is the central substrate that leads
to a cascade of cellular reactions responsible for glucose and lipid metabolism. Insulin stimulates the insulin receptor (IR)
tyrosine kinase, leading to the tyrosine phosphorylation of the insulin receptor substrate (IRS) family of proteins. Activated IRS
then displays binding sites for numerous signaling partners such as phosphatidylinositol-3 kinase (PI3K), a key player in insulin
function through the activation of the Akt/protein kinase B (PKB). When stimulated, Akt/PKB promotes glycogen synthesis via
upregulation of the glycogen synthase enzyme, which occurs with inhibition of glycogen synthase kinase (GSK)-3. Additionally,
insulin activates glucose uptake via a family of glucose transporters (GLUT). Through negative feedback, PI3K, Akt/PKB, and
GSK-3 can result in serine phosphorylation of IRS, and subsequent inactivation. Activation of G-protein receptors can lead to
activation of protein kinase C (PKC). Excessive stress through inﬂammatory mediators ,such as tumor necrosis factor-a (TNF-a),
or through metabolic overﬂow of lipid from adipose tissue could also impact the insulin signaling cascade. Schematic adapted
from Frame and Zheleva (2006),182 Schinner et al. (2005),115 and Kido et al. (2001).183
Nutrition Reviews® Vol. 66(8):429–444
435
PI3K.116 Kinases such as PI3K are essential for tranducing
intracellular communication signals that eventually culminate in an overall cellular action. If PI3K is inhibited,
other kinases such as Akt/PKB and GSK-3 will also be
impacted, resulting in the cell not being able to transport
glucose or synthesize glycogen.117 These ﬁndings are supported by clinical observation: individuals with type 2
diabetes have ~50% and ~70% reduction in PI3K activity
in skeletal muscle and adipose tissue, respectively. More
notably, even those who are normoglycemic but have a
genetic predisposition for type 2 diabetes, as deﬁned by
two ﬁrst-degree relatives with the disease, also have
impaired insulin-stimulated PI3K activity, as measured in
their adipocytes.118
Whereas some agents may inhibit kinases directly,
leading to complete cessation of activity and causing
undesirable side eﬀects, it would be worthwhile from a
safety point of view to identify less potent food-derived
actives which selectively modulate (rather than completely block) activity of certain kinases. The concept of
identifying and leveraging phytochemicals to impact
kinase activity speciﬁcally for MetS has not been
researched thoroughly. However, there are some traditional foods that have been researched for their molecular
eﬀects on processes related to defective insulin signaling
that may prove to be worthwhile from a therapeutic
standpoint, including the following: cinnamon, green tea,
bitter melon, berberine, ginseng, and hops.
Cinnamon
Clinical trials suggest that modest amounts (1–6 g) of
cinnamon can favorably impact glucose and/or lipid
levels in healthy subjects119,120 and individuals with conditions related to insulin dysregulation.121–123 Conversely,
some reports have also concluded that cinnamon had no
eﬀect on reducing these measurements.124–126 This discrepancy may be due to the varied population of subjects,
or even the diﬀerent types of cinnamon that are used,
which may contain a diﬀerent panel of actives.
The insulin-signaling mechanisms behind cinnamon’s long-recognized insulin sensitizing properties,127
have been elucidated in several in vivo studies.128–134
Speciﬁcally, cinnamon bioactives aﬀect protein
phosphorylation-dephosphorylation reactions in the adipocyte and may impact activity of PI3K through its
upstream eﬀects.129 In rats fed 300 mg/kg bw cinnamon
extract, IRb and IRS-1 tyrosine phosphorylation levels
in the skeletal muscle were 18% and 33%, respectively,
greater than those of controls, indicating that insulin
action and glucose uptake might be improved in these
rats.128 Further, in a later study, Qin et al.134 detected that
a cinnamon extract fed to rats on a high-fructose diet was
eﬀective in improving IRb stimulation by insulin, IRS-1
436
tyrosine phosphorylation, and PI3K activation in skeletal
muscle relative to control rats.
The diﬀerent fractions of cinnamon have been
studied for their eﬀects on insulin signal transduction.
HPLC-puriﬁed cinnamon polyphenols and a watersoluble cinnamon extract were tested in mouse 3T3-L1
adipocytes132 for their eﬀects on mRNA levels of IR and
GLUT4. At relatively high concentrations, the extract
decreased IRb protein and IR mRNA. GLUT4 mRNA
levels were also modiﬁed by addition of the extract. In the
same 3T3-L1 adipocyte model, Jarvill-Taylor et al.130 demonstrated that treatment with a hydroxychalcone from
cinnamon triggered insulin transduction via activating
glycogen synthase and IR, and inhibiting GSK-3b.
Interestingly, when insulin was added together with
the cinnamon-derived hydroxychalcone, a synergistic
response was obtained. Similarly, research by Kim et al.133
demonstrated that of a series of cinnamon-derived, phytochemical synthetic derivatives, a naphthalenemethyl
ester of 3,4-dihydroxyhydrocinnamic acid displayed a
signiﬁcant impact on glucose transport in epididymal
adipocytes through its eﬀects on IRb phosphorylation
and subsequent activation of PI3K and Akt/PKB.
Green tea (Camellia sinesis)
Green tea, a common staple of the Asian dietary pattern,
has a well-documented reputation as a health-promoting
beverage, particularly for chronic diseases such as cancer
and type 2 diabetes.135,136 Consistent consumption of 5–6
or more cups daily or 200–300 mg of epigallocatechin
gallate (EGCG), the primary polyphenol in green tea, has
demonstrated beneﬁt for cardiovascular and metabolic
health.136 In an eloquent review by Wolfram et al.,137 it was
discussed that in cell culture and animal models of
obesity, green tea constituents have the ability to reduce
adipocyte proliferation and diﬀerentiation, as well as
important markers of MetS, like plasma levels of TG,
cholesterol, glucose, and insulin.
In a retrospective cohort study consisting of 17,413
Japanese adults, Iso et al.138 obtained data on intake of
coﬀee and black, green, and oolong teas and assessed
whether consumption of any of these beverages was associated with type-2 diabetes occurrence after a 5-year
follow-up. Results showed that green tea (and coﬀee) was
inversely associated with risk for diabetes. Hill et al.139
evaluated the eﬀect of EGCG supplementation on
abdominal fat in overweight or obese postmenopausal
women in conjunction with regular aerobic exercise.Waist
circumference (one of the MetS criteria) and adipose
tissue were reduced in the control and EGCG groups;
however, those subjects on EGCG experienced a decrease
in plasma glucose if glucose intolerance was present. Prospective studies have yielded mixed results for the eﬀect of
Nutrition Reviews® Vol. 66(8):429–444
green tea on insulin or inﬂammation markers.140–145 Of
note, some of these studies used green tea extract rather
than the beverage preparation.140,141,143,144
The mechanisms of green tea are diverse. EGCG has
been studied extensively for its chemopreventive activity
via regulating multiple signaling pathways (e.g., VEGF,
IGF-1, EGFR). In conjunction with its eﬀect on cell
growth cycles, EGCG indirectly inﬂuences inﬂammation
processes and insulin activity via inhibiting NF-kb, PI3K,
and Akt/PKB, to name a few.135 In a review of mechanisms of EGCG by Moon et al.,146 it was reported that
EGCG impacts a number of kinases. They concluded:
“. . . dietary supplementation with EGCG could potentially contribute to nutritional strategies for the prevention and treatment of type 2 diabetes mellitus”.
More speciﬁc to direct inﬂuence on insulin signaling,
published studies indicate a wide range of eﬀects by
EGCG. It has been suggested that EGCG mimics insulin
action by activating similar signaling pathways, although
to a lesser degree, in that it increases tyrosine phosphorylation (thus activation) of the IRb and IRS-1 in H4IIE
rat hepatoma cells.147 Additionally, it increases PI3K and
Akt/PKB in this cell line, ultimately impacting genes that
regulate gluconeogenic enzymes.147 Animal studies have
demonstrated that oral administration of a green tea
extract (80 mg/kg/d) for 12 weeks to obese dogs resulted
in a 60% higher insulin sensitivity index and 50% lower
TG.148 Genes involved in glucose homeostasis were
improved in the supplemented dogs, speciﬁcally GLUT4
levels in skeletal muscle relative to baseline. Cao et al.149
reported that when a green tea extract (1 and 2 g
extract/kg high-fructose diet) was fed to rats, several
changes were noted in expression of genes involved in
glucose uptake and insulin signaling, depending on the
dose given. For the 1 g feeding, mRNA increased for
GLUT1, GLUT4, GSK3b, and IRS2 by 110%, 160%, 30%,
and 60% in the liver, respectively, and elevated IRS1 in
muscle by 80%. Some diﬀerences were detected in the 2 g
group: increased mRNA in liver for GLUT4 and GSK3b
by 90% and 30%, and increased mRNA for GLUT2 and
GLUT4 by 80% and 40% in muscle, respectively.
Bitter melon (Momordica charantia L.)
Bitter melon, a common vegetable grown in tropical cultures, is widely eaten and used in traditional medicine for
its anti-diabetic properties.150 Hence, it has commonly
been referred to as “vegetable insulin”.151 Bitter melon
contains a number of constituents such as charantin,
vicine, and polypeptide-p that cause it to impact glucose
metabolism, as shown in cell, animal, and human studies.152,153 Two recent animal studies154,155 indicate that
bitter melon may have some pronounced eﬀects on the
insulin signaling cascade. Sridhar et al.154 reported that
Nutrition Reviews® Vol. 66(8):429–444
high-fat feeding of male Wistar rats for 10 weeks reduced
IRS-1 tyrosine phosphorylation in muscle compared with
control rats, while bitter melon supplementation was able
to improve IRS-1 activation after 2 weeks. In a similar
fashion, Nerurkar et al.155 documented bitter melon’s
ability to modulate IR phosphorylation and downstream
signaling in female C57BL/6 mice fed a high-fat diet.
Speciﬁcally, mice treated with bitter melon juice experienced a signiﬁcant increase of 55% in IRS-2 phosphorylation in liver over that of control. Moreover, bitter melon
juice supplementation in addition to the high-fat diet
alone resulted in an increase in interaction between IRS-1
and PI3K of 280%. Conversely, no eﬀect was seen in Akt/
PKB expression and its phosphorylation.
Berberine (Coptis chinesis)
Berberine, a naturally occurring alkaloid phytochemical
from the Chinese botanical Coptis chinesis, is well-known
in traditional medicine for its glucose-lowering eﬀects. In
addition to its therapeutic eﬀects of enhancing insulin
sensitivity in animal studies,156,157 numerous clinical
studies from China have documented signiﬁcant plasma
glucose reductions when administering berberine (1.0–
1.5 g daily dose divided throughout the day) to subjects
with type 2 diabetes.158–161 Most recent is the clinical study
by Zhang et al.,161 which indicated noteworthy reductions
in fasting and postprandial plasma glucose, hemoglobin
A1c, and relevant lipid biomarkers due to berberine
supplementation of 1.0 g daily for 3 months compared
with placebo.
The targets of berberine relative to MetS and insulin
signaling have been reasonably well explored. Zhou
et al.162 commented that berberine’s eﬀects on cellular
glucose metabolism may be more indirect in that it may
activate glucose transport in 3T3-L1 adipocytes by
increasing the activity of GLUT1, with no appreciable
eﬀect on Akt/PKB or GLUT4 or response to PI3K inhibition. In support of these ﬁndings, Kim et al.163 reported
that incubation of 3T3-L1 adipocytes with berberine led
to an 8.5-fold increase in insulin-independent glucose
uptake and a 1.3-fold increase in insulin-activated glucose
uptake. As expected, berberine increased the levels of
GLUT1 (responsible for basal, insulin-independent
glucose uptake) but had no eﬀect on GLUT4 (insulinstimulated glucose uptake) in this study. Consistent with
Zhou et al.’s ﬁndings, no eﬀect of berberine was observed
on upstream insulin signaling involving IR activation or
IRS-1 phosphorylation. In contrast to these two studies,
Ko et al.164 noted that berberine at 5 or 50 mM plus insulin
increased tyrosine phosphorylation of IRS1 to levels comparable to that produced with 10 nM insulin in 3T3-L1
adipocytes. Akt/PKB phosphorylation was stimulated in
the presence of berberine despite no change in Akt/PKB
437
protein content. Overall, glucose uptake was enhanced
with berberine plus 0.2 nM insulin through activation of
the IRS1-PI3K-Akt/PKB-GLUT4 sequence.
Finally of note are two studies165,166 that showed
berberine is eﬀective at improving free fatty acid-induced
insulin resistance in 3T3-L1 adipocytes through downstream signaling by inhibiting IkB kinase b and NF-kb.
Additionally, more current research suggests that ginsenoside Rg3 may lower blood glucose and stimulate
insulin secretion through its activation of AMP-activated
protein kinase (AMPK).175
One of the intestinal metabolites of ginsenosides,
known as compound K, was shown to be eﬀective in
combination with metformin in improving plasma
glucose and insulin levels in diabetic db/db mice.176
Ginseng (Panax ginseng)
Hops (Humulus lupulus)
Like berberine, ginseng has been used as part of traditional Chinese medicine for thousands of years, particularly as a restorative tonic to increase blood ﬂow and
decrease fatigue. Vuksan et al.167 reported improvements
in the postprandial plasma glucose measurements
(decrease of 8–11%) and fasting and postprandial insulin
(33–38%) with 6 g per day Panax ginseng in 19 individuals with controlled type 2 diabetes. Administration of
Panax ginseng extract to older rats (1.5 years) resulted in
an increased number of insulin receptors in bone marrow
cells (407 ⫾ 46 vs. 1038 ⫾ 84, for control and ginsengsupplemented rats, respectively, P < 0.01).168
One of the active anti-diabetic phytochemicals is
thought to be ginsenosides.169–171 For example, when ginsenoside Rh2 was intravenously injected into fasting
Wistar rats for 60 min, plasma glucose decreased and
insulin increased, indicating that the compound stimulated insulin secretion.172 The mechanisms behind the
action of ginsenosides have been investigated to a limited
extent. Based on animal work, Lai et al.173 reported
increased gene expression in mRNA and protein levels of
GLUT4 in soleus muscle of streptozotocin-induced diabetic rats when treated with ginsenoside Rh2 intravenously. Zhang et al.174 documented that ginsenoside Re
administration to 3T3-L1 cells leads to the activation of
IR-1, with eﬀects cascading downstream through PI3K.
Hops is a climbing perennial vine that has grown wild
since ancient times in Europe, Asia and North America,
and is primarily used in the manufacture of beer.177
Emerging research suggests that hops-based phytochemicals may impact insulin sensitivity. When diabetic KK-Ay
mice were treated with either isohumulone and isocohumulone from hops, or pioglitazone, similar reductions in
plasma glucose, TG, and free fatty acids were obtained.178
Furthermore, select hop-based constituents have been
found to impact MetS markers through speciﬁc cellular
insulin-targeted pathways. Cell-free assays conducted by
Tripp et al.179 identiﬁed one of the bittering agents of
hops, rho iso-alpha acids, as modulators of a number of
protein kinases implicated in insulin signaling, such as
PI3K-g, b, d, GSK-3a, GSK-3b, and PKC-b11.
CONCLUSION
MetS is a complex condition that may be best treated by
an array of dietary interventions. While a uniﬁed dietary
recommendation for MetS has yet to be determined, a
survey of emerging literature indicates it may ultimately
involve a diet high in phytochemicals that favorably target
kinases involved in cellular insulin signaling (Table 1).
From the aspect of prevention, chronic consumption of
Table 1 Modulation of the insulin pathway targets in various cell models
through phytochemicals.
Phytochemical
Insulin pathway targets*
IR
IRS
PI3K
Akt/PKB
PKC
GSK
GS
GLUT
Resveratrol
X
X
X
Quercetin
X
X
X
X
Cinnamon
X
X
X
X
X
X
X
Green tea
X
X
X
X
X
X
Bitter melon
X
X
X
X†
X
Berberine
X†
Ginseng
X
X
Hops
X
X
X
X
* Various phytochemicals have been shown to inﬂuence select targets in the insulin
signaling cascade.
†
In presence of insulin.164
Abbreviations: Akt/PKB, Akt/protein kinase B; GLUT, cellular glucose transporters; GS,
glycogen synthase; GSK, glycogen synthase kinase; IR, insulin receptor; IRS, insulin
receptor substrate; PKC, protein kinase C; PI3K, phosphatidylinositol-3 kinase.
438
Nutrition Reviews® Vol. 66(8):429–444
Figure 3 The interrelationship between metabolic syndrome, diet, phytochemicals, and insulin signaling. The metabolic syndrome is a conglomerate of chronic dysfunctional metabolic and inﬂammatory markers. Some or all of these factors
have been shown to be responsive to dietary treatment, such as low-glycemic foods, Mediterranean-style diets, and plantbased eating. In turn, these dietary approaches contain more than the relative ratio of macronutrients. The phytochemicals that
reside in foods inherent in these food patterns may be important for insulin-signaling pathways.
phytochemicals, whether through a whole-food diet rich
in fruits and vegetables or from speciﬁc extracts, may
provide consistent healthy insulin-signaling patterns to
ensure protection against MetS, although stronger scientiﬁc support for this premise is needed. For an individual
with MetS and a lifetime of accumulated unhealthy insulin
signaling via dietary intake, it may take more than switching from a low-phytochemical diet to one that is rich
in “phyto-signaling” potential (Figure 3). In this case,
although it has not been demonstrated, it may theoretically be clinically necessary to ingest targeted phytochemicals known to aﬀect insulin signaling positively in addition
to maintaining a healthy dietary baseline.180 Further clinical studies are required to support this concept.
Acknowledgments
The authors would like to thank Drs. Matthew Tripp,Amy
Hall, Brian Carroll and Veera Konda for their contributions to the manuscript. Thanks to Christie Clark and Jim
Planet for their assistance with the graphics.
Declaration of interest. Both authors are employees of
MetaProteomics, LLC, a wholly owned subsidiary of
Metagenics, Inc. Dr. Bland is a shareholder of Metagenics,
Inc. Metagenics is a life sciences company and the
premier manufacturer and distributor of science-based
medical foods and nutraceuticals marketed to healthcare
professionals.
Nutrition Reviews® Vol. 66(8):429–444
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