Download Dietary management of the metabolic syndrome beyond macronutrients

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: [email protected], 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
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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,
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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
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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
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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
REFERENCES
1. Sullivan VK. Prevention and treatment of the metabolic syndrome with lifestyle intervention: where do we start? J Am
Diet Assoc. 2006;106:668–671.
2. Fitch K, Pyenson B, Iwasaki K. Metabolic syndrome and
employer sponsored medical benefits: an actuarial analysis.
Value Health. 2007;10(Suppl):S21–S28.
3. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and
management of the metabolic syndrome. An American
Heart Association/National Heart, Lung, and Blood Institute
scientific statement. Executive summary. Cardiol Rev.
2005;13:322–327.
4. Pi-Sunyer FX. Use of lifestyle changes treatment plans and
drug therapy in controlling cardiovascular and metabolic
risk factors. Obesity (Silver Spring). 2006;14(Suppl 3):S135–
S142.
5. Orchard TJ, Temprosa M, Goldberg R, et al. The effect of
metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann Intern Med. 2005;142:611–619.
6. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in
the incidence of type 2 diabetes with lifestyle intervention
or metformin. N Engl J Med. 2002;346:393–403.
7. Lindstrom J, Ilanne-Parikka P, Peltonen M, et al. Sustained
reduction in the incidence of type 2 diabetes by lifestyle
intervention: follow-up of the Finnish Diabetes Prevention
Study. Lancet. 2006;368:1673–1679.
8. Zivkovic AM, German JB, Sanyal AJ. Comparative review
of diets for the metabolic syndrome: implications for
nonalcoholic fatty liver disease. Am J Clin Nutr. 2007;86:
285–300.
9. Muzio F, Mondazzi L, Harris WS, et al. Effects of moderate
variations in the macronutrient content of the diet on
cardiovascular disease risk factors in obese patients
439
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
440
with the metabolic syndrome. Am J Clin Nutr. 2007;86:946–
951.
Lichtenstein AH, Appel LJ, Brands M, et al. Diet and lifestyle
recommendations revision 2006: a scientific statement from
the American Heart Association Nutrition Committee. Circulation. 2006;114:82–96.
National Cholesterol Education Program (NCEP) Expert
Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults (Adult Treatment Panel III). Third
report of the National Cholesterol Education Program
(NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment
Panel III) final report. Circulation. 2002;106:3143–3421.
Ordovas JM, Kaput J, Corella D. Nutrition in the genomics
era: cardiovascular disease risk and the Mediterranean diet.
Mol Nutr Food Res. 2007;51:1293–1299.
Knopp RH, Fish B, Dowdy A, et al. A moderate-fat diet for
combined hyperlipidemia and metabolic syndrome. Curr
Atheroscler Rep. 2006;8:492–500.
Lukaczer D, Liska DJ, Lerman RH, et al. Effect of a low glycemic index diet with soy protein and phytosterols on CVD risk
factors in postmenopausal women. Nutrition. 2006;22:104–
113.
Forsythe CE, Phinney SD, Fernandez ML, et al. Comparison
of low fat and low carbohydrate diets on circulating fatty
acid composition and markers of inflammation. Lipids.
2008;43:65–77.
Feldeisen SE, Tucker KL. Nutritional strategies in the prevention and treatment of metabolic syndrome. Appl Physiol
Nutr Metab. 2007;32:46–60.
Dreon DM, Fernstrom HA, Williams PT, et al. A very low-fat
diet is not associated with improved lipoprotein profiles in
men with a predominance of large, low-density lipoproteins. Am J Clin Nutr. 1999;69:411–418.
Krauss RM, Dreon DM. Low-density-lipoprotein subclasses
and response to a low-fat diet in healthy men. Am J Clin
Nutr. 1995;62(Suppl):S478–S487.
Reaven GM. The insulin resistance syndrome: definition and
dietary approaches to treatment. Annu Rev Nutr. 2005;25:
391–406.
Krauss RM, Eckel RH, Howard B, et al. AHA Dietary Guidelines: revision 2000: A statement for healthcare professionals from the Nutrition Committee of the American Heart
Association. Circulation. 2000;102:2284–2299.
Brinkworth GD, Noakes M, Keogh JB, et al. Long-term effects
of a high-protein, low-carbohydrate diet on weight
control and cardiovascular risk markers in obese hyperinsulinemic subjects. Int J Obes Relat Metab Disord. 2004;
28:661–670.
Farnsworth E, Luscombe ND, Noakes M, et al. Effect of a
high-protein, energy-restricted diet on body composition,
glycemic control, and lipid concentrations in overweight
and obese hyperinsulinemic men and women. Am J Clin
Nutr. 2003;78:31–39.
Garg A, Bantle JP, Henry RR, et al. Effects of varying carbohydrate content of diet in patients with non-insulindependent diabetes mellitus. JAMA. 1994;271:1421–1428.
Piatti PM, Monti F, Fermo I, et al. Hypocaloric high-protein
diet improves glucose oxidation and spares lean body mass:
comparison to hypocaloric high-carbohydrate diet.
Metabolism. 1994;43:1481–1487.
Sargrad KR, Homko C, Mozzoli M, et al. Effect of high protein
vs high carbohydrate intake on insulin sensitivity, body
weight, hemoglobin A1c, and blood pressure in patients
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
with type 2 diabetes mellitus. J Am Diet Assoc. 2005;
105:573–580.
Merchant AT, Kelemen LE, de Koning L, et al. Interrelation of
saturated fat, trans fat, alcohol intake, and subclinical atherosclerosis. Am J Clin Nutr. 2008;87:168–174.
Ebbesson SO, Tejero ME, Nobmann ED, et al. Fatty acid consumption and metabolic syndrome components: The
GOCADAN study. J Cardiometab Syndr. 2007;2:244–249.
Kallio P, Kolehmainen M, Laaksonen DE, et al. Dietary carbohydrate modification induces alterations in gene expression in abdominal subcutaneous adipose tissue in persons
with the metabolic syndrome: the FUNGENUT Study. Am J
Clin Nutr. 2007;85:1417–1427.
Bjorntorp P, Rosmond R. The metabolic syndrome – a neuroendocrine disorder? Br J Nutr. 2000;83(Suppl 1):S49–S57.
Salsberg SL, Ludwig DS. Putting your genes on a diet:
the molecular effects of carbohydrate. Am J Clin Nutr.
2007;85:1169–1170.
Monro JA, Shaw M. Glycemic impact, glycemic glucose
equivalents, glycemic index, and glycemic load: definitions,
distinctions, and implications. Am J Clin Nutr. 2008;
87(Suppl):S237–S243.
Wolever TM, Jenkins DJ, Jenkins AL, et al. The glycemic
index: methodology and clinical implications. Am J Clin
Nutr. 1991;54:846–854.
Venn BJ, Green TJ. Glycemic index and glycemic load: measurement issues and their effect on diet-disease relationships. Eur J Clin Nutr. 2007;61(Suppl 1):S122–S131.
Riccardi G, Rivellese AA, Giacco R. Role of glycemic index
and glycemic load in the healthy state, in prediabetes, and
in diabetes. Am J Clin Nutr. 2008;87(Suppl):S269–S274.
Livesey G, Taylor R, Hulshof T, et al. Glycemic response and
health – a systematic review and meta-analysis: relations
between dietary glycemic properties and health outcomes.
Am J Clin Nutr. 2008;87(Suppl):S258–S268.
Livesey G, Taylor R, Hulshof T, et al. Glycemic response and
health – a systematic review and meta-analysis: the database, study characteristics, and macronutrient intakes. Am J
Clin Nutr. 2008;87(Suppl):S223–S236.
Qi L, Hu FB. Dietary glycemic load, whole grains, and systemic inflammation in diabetes: the epidemiological
evidence. Curr Opin Lipidol. 2007;18:3–8.
Augustin LS, Franceschi S, Jenkins DJ, et al. Glycemic index
in chronic disease: a review. Eur J Clin Nutr. 2002;56:1049–
1071.
Panagiotakos DB, Pitsavos C, Skoumas Y, et al. The association between food patterns and the metabolic syndrome
using principal components analysis: The ATTICA Study.
J Am Diet Assoc. 2007;107:979–987.
Esmaillzadeh A, Kimiagar M, Mehrabi Y, et al. Dietary patterns, insulin resistance, and prevalence of the metabolic
syndrome in women. Am J Clin Nutr. 2007;85:910–918.
Baxter AJ, Coyne T, McClintock C. Dietary patterns and
metabolic syndrome – a review of epidemiologic evidence.
Asia Pac J Clin Nutr. 2006;15:134–142.
Sonnenberg L, Pencina M, Kimokoti R, et al. Dietary patterns
and the metabolic syndrome in obese and non-obese
Framingham women. Obes Res. 2005;13:153–162.
Hu FB, Willett WC. Optimal diets for prevention of coronary
heart disease. JAMA. 2002;288:2569–2578.
Bazzano LA. The high cost of not consuming fruits and vegetables. J Am Diet Assoc. 2006;106:1364–1368.
Williams DE, Wareham NJ, Cox BD, et al. Frequent salad
vegetable consumption is associated with a reduction in
Nutrition Reviews® Vol. 66(8):429–444
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
the risk of diabetes mellitus. J Clin Epidemiol. 1999;52:329–
335.
Esmaillzadeh A, Kimiagar M, Mehrabi Y, et al. Fruit and vegetable intakes, C-reactive protein, and the metabolic syndrome. Am J Clin Nutr. 2006;84:1489–1497.
Craig WJ. Phytochemicals: guardians of our health. J Am
Diet Assoc. 1997;97(Suppl):S199–S204.
Blanck HM, Gillespie C, Kimmons JE, et al. Trends in fruit and
vegetable consumption among U.S. men and women,
1994–2005. Prev Chronic Dis. 2008;5:A35.
Serra-Majem L, Roman B, Estruch R. Scientific evidence of
interventions using the Mediterranean diet: a systematic
review. Nutr Rev. 2006;64(Suppl):S27–S47.
Lairon D. Intervention studies on Mediterranean diet and
cardiovascular risk. Mol Nutr Food Res. 2007;51:1209–1214.
Esposito K, Ciotola M, Giugliano D. Mediterranean diet and
the metabolic syndrome. Mol Nutr Food Res. 2007;51:1268–
1274.
Esposito K, Ciotola M, Giugliano F, et al. Mediterranean diet
improves sexual function in women with the metabolic syndrome. Int J Impot Res. 2007;19:486–491.
Soriguer F, Rojo-Martinez G, de Fonseca FR, et al. Obesity
and the metabolic syndrome in Mediterranean countries: a
hypothesis related to olive oil. Mol Nutr Food Res.
2007;51:1260–1267.
Tortosa A, Bes-Rastrollo M, Sanchez-Villegas A, et al. Mediterranean diet inversely associated with the incidence of
metabolic syndrome: the SUN prospective cohort. Diabetes
Care. 2007;30:2957–2959.
Alvarez Leon EE, Henriquez P, Serra-Majem L. Mediterranean diet and metabolic syndrome: a cross-sectional study
in the Canary Islands. Public Health Nutr. 2006;9:1089–
1098.
Esposito K, Ciotola M, Giugliano D. Mediterranean diet,
endothelial function and vascular inflammatory markers.
Public Health Nutr. 2006;9:1073–1076.
Giugliano D, Esposito K. Is the whole-diet approach better
than a low-fat diet in cardiovascular risk reduction? Am J
Clin Nutr. 2006;83:921; author reply 921–922.
Meydani M. A Mediterranean-style diet and metabolic syndrome. Nutr Rev. 2005;63:312–314.
Bautista MC, Engler MM. The Mediterranean diet: is it cardioprotective? Prog Cardiovasc Nurs. 2005;20:70–76.
Panagiotakos DB, Polychronopoulos E. The role of Mediterranean diet in the epidemiology of metabolic syndrome;
converting epidemiology to clinical practice. Lipids Health
Dis. 2005;4:7.
Panagiotakos DB, Pitsavos C, Chrysohoou C, et al. Impact of
lifestyle habits on the prevalence of the metabolic syndrome among Greek adults from the ATTICA study. Am
Heart J. 2004;147:106–112.
Pitsavos C, Panagiotakos DB, Chrysohoou C, et al. The adoption of Mediterranean diet attenuates the development of
acute coronary syndromes in people with the metabolic
syndrome. Nutr J. 2003;2:1.
Fito M, Guxens M, Corella D, et al. Effect of a traditional
Mediterranean diet on lipoprotein oxidation: a randomized
controlled trial. Arch Intern Med. 2007;167:1195–1203.
Knoops KT, de Groot LC, Kromhout D, et al. Mediterranean
diet, lifestyle factors, and 10-year mortality in elderly
European men and women: the HALE project. JAMA. 2004;
292:1433–1439.
Psaltopoulou T, Naska A, Orfanos P, et al. Olive oil, the Mediterranean diet, and arterial blood pressure: the Greek Euro-
Nutrition Reviews® Vol. 66(8):429–444
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
pean Prospective Investigation into Cancer and Nutrition
(EPIC) study. Am J Clin Nutr. 2004;80:1012–1018.
Waterman E, Lockwood B. Active components and
clinical applications of olive oil. Altern Med Rev. 2007;12:
331–342.
Paniagua JA, de la Sacristana AG, Sanchez E, et al. A MUFArich diet improves postprandial glucose, lipid and GLP-1
responses in insulin-resistant subjects. J Am Coll Nutr.
2007;26:434–444.
Tierney AC, Roche HM. The potential role of olive oil-derived
MUFA in insulin sensitivity. Mol Nutr Food Res. 2007;51:
1235–1248.
Perez-Jimenez F, Ruano J, Perez-Martinez P, et al. The influence of olive oil on human health: not a question of fat
alone. Mol Nutr Food Res. 2007;51:1199–1208.
Covas MI, Nyyssonen K, Poulsen HE, et al. The effect of
polyphenols in olive oil on heart disease risk factors: a randomized trial. Ann Intern Med. 2006;145:333–341.
Trichopoulou A, Dilis V. Olive oil and longevity. Mol Nutr
Food Res. 2007;51:1275–1278.
Bendini A, Cerretani L, Carrasco-Pancorbo A, et al. Phenolic
molecules in virgin olive oils: a survey of their sensory properties, health effects, antioxidant activity and analytical
methods. An overview of the last decade. Molecules.
2007;12:1679–1719.
Perona JS, Vogler O, Sanchez-Dominguez JM, et al. Consumption of virgin olive oil influences membrane lipid composition and regulates intracellular signaling in elderly
adults with type 2 diabetes mellitus. J Gerontol A Biol Sci
Med Sci. 2007;62:256–263.
Fickova M, Hubert P, Klimes I, et al. Dietary fish oil and olive
oil improve the liver insulin receptor tyrosine kinase activity
in high sucrose fed rats. Endocr Regul. 1994;28:187–197.
Dandona P, Aljada A, Chaudhuri A, et al. Metabolic syndrome: a comprehensive perspective based on interactions
between obesity, diabetes, and inflammation. Circulation.
2005;111:1448–1454.
Iwasaki Y, Kambayashi M, Asai M, et al. High glucose alone,
as well as in combination with proinflammatory cytokines,
stimulates nuclear factor kappa-B-mediated transcription in
hepatocytes in vitro. J Diabetes Complications. 2007;21:56–
62.
Brunelleschi S, Bardelli C, Amoruso A, et al. Minor polar
compounds extra-virgin olive oil extract (MPC-OOE)
inhibits NF-kappaB translocation in human monocyte/
macrophages. Pharmacol Res. 2007;56:542–549.
Perez-Martinez P, Lopez-Miranda J, Blanco-Colio L, et al. The
chronic intake of a Mediterranean diet enriched in virgin
olive oil, decreases nuclear transcription factor kappaB activation in peripheral blood mononuclear cells from healthy
men. Atherosclerosis. 2007;194:e141–146.
Bellido C, Lopez-Miranda J, Blanco-Colio LM, et al. Butter
and walnuts, but not olive oil, elicit postprandial activation
of nuclear transcription factor kappaB in periphera
l blood mononuclear cells from healthy men. Am J Clin Nutr.
2004;80:1487–1491.
Opie LH, Lecour S. The red wine hypothesis: from concepts
to protective signalling molecules. Eur Heart J. 2007;
28:1683–1693.
Frojdo S, Cozzone D, Vidal H, et al. Resveratrol is a class IA
phosphoinositide 3-kinase inhibitor. Biochem J. 2007;
406:511–518.
Zhang J. Resveratrol inhibits insulin responses in a SirT1independent pathway. Biochem J. 2006;397:519–527.
441
83. Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves
health and survival of mice on a high-calorie diet. Nature.
2006;444:337–342.
84. Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the
in vivo evidence. Nat Rev Drug Discov. 2006;5:493–506.
85. Stefani M, Markus MA, Lin RC, et al. The effect of resveratrol
on a cell model of human aging. Ann N Y Acad Sci.
2007;1114:407–418.
86. Strobel P, Allard C, Perez-Acle T, et al. Myricetin, quercetin
and catechin-gallate inhibit glucose uptake in isolated rat
adipocytes. Biochem J. 2005;386:471–478.
87. Matter WF, Brown RF, Vlahos CJ. The inhibition of
phosphatidylinositol 3-kinase by quercetin and analogs.
Biochem Biophys Res Commun. 1992;186:624–631.
88. Agullo G, Gamet-Payrastre L, Manenti S, et al. Relationship
between flavonoid structure and inhibition of phosphatidylinositol 3-kinase: a comparison with tyrosine kinase
and protein kinase C inhibition. Biochem Pharmacol. 1997;
53:1649–1657.
89. Walker EH, Pacold ME, Perisic O, et al. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol
Cell. 2000;6:909–919.
90. Williams RJ, Spencer JP, Rice-Evans C. Flavonoids: antioxidants or signalling molecules? Free Radic Biol Med.
2004;36:838–849.
91. Gamet-Payrastre L, Manenti S, Gratacap MP, et al. Flavonoids and the inhibition of PKC and PI 3-kinase. Gen Pharmacol. 1999;32:279–286.
92. Gulati N, Laudet B, Zohrabian VM, et al. The antiproliferative
effect of quercetin in cancer cells is mediated via inhibition
of the PI3K-Akt/PKB pathway. Anticancer Res. 2006;26:
1177–1181.
93. Jenkins DJ, Kendall CW, Marchie A, et al. Effects of a dietary
portfolio of cholesterol-lowering foods vs lovastatin on
serum lipids and C-reactive protein. JAMA. 2003;290:502–
510.
94. Merritt JC. Metabolic syndrome: soybean foods and serum
lipids. J Natl Med Assoc. 2004;96:1032–1041.
95. Azadbakht L, Kimiagar M, Mehrabi Y, et al. Soy inclusion in
the diet improves features of the metabolic syndrome: a
randomized crossover study in postmenopausal women.
Am J Clin Nutr. 2007;85:735–741.
96. Azadbakht L, Kimiagar M, Mehrabi Y, et al. Soy consumption, markers of inflammation, and endothelial function: a
cross-over study in postmenopausal women with the metabolic syndrome. Diabetes Care. 2007;30:967–973.
97. Noriega-Lopez L, Tovar AR, Gonzalez-Granillo M, et al. Pancreatic insulin secretion in rats fed a soy protein high fat diet
depends on the interaction between the amino acid pattern
and isoflavones. J Biol Chem. 2007;282:20657–20666.
98. Rimbach G, Boesch-Saadatmandi C, Frank J, et al. Dietary
isoflavones in the prevention of cardiovascular disease – A
molecular perspective. Food Chem Toxicol. 2008;46:1308–
1319.
99. Decker EA. The role of phenolics, conjugated linoleic acid,
carnosine, and pyrroloquinoline quinone as nonessential
dietary antioxidants. Nutr Rev. 1995;53:49–58.
100. Walsh MC, Brennan L, Pujos-Guillot E, et al. Influence of
acute phytochemical intake on human urinary metabolomic profiles. Am J Clin Nutr. 2007;86:1687–1693.
101. Liu RH. Health benefits of fruit and vegetables are from
additive and synergistic combinations of phytochemicals.
Am J Clin Nutr. 2003;78(Suppl):S517–S520.
442
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
Cassidy A, Dalais F. Phytochemicals. In: Gibney MJ,
Macdonald IA, Roche HM, eds. Nutrition and Metabolism.
Oxford, UK: Blackwell Science; 2003:307–317.
Esposito K, Nappo F, Giugliano F, et al. Effect of dietary antioxidants on postprandial endothelial dysfunction induced
by a high-fat meal in healthy subjects. Am J Clin Nutr.
2003;77:139–143.
Jacobs DR, Jr., Tapsell LC. Food, not nutrients, is the fundamental unit in nutrition. Nutr Rev. 2007;65:439–450.
Lila MA. From beans to berries and beyond: teamwork
between plant chemicals for protection of optimal human
health. Ann N Y Acad Sci. 2007;1114:372–380.
Bastard JP, Maachi M, Lagathu C, et al. Recent advances in
the relationship between obesity, inflammation, and insulin
resistance. Eur Cytokine Netw. 2006;17:4–12.
Muniyappa R, Quon MJ. Insulin action and insulin resistance
in vascular endothelium. Curr Opin Clin Nutr Metab Care.
2007;10:523–530.
Nawrocki AR, Scherer PE. The delicate balance between fat
and muscle: adipokines in metabolic disease and musculoskeletal inflammation. Curr Opin Pharmacol. 2004;4:281–
289.
Sell H, Dietze-Schroeder D, Eckel J. The adipocyte-myocyte
axis in insulin resistance. Trends Endocrinol Metab. 2006;
17:416–422.
McGarry JD. Banting lecture 2001: dysregulation of fatty
acid metabolism in the etiology of type 2 diabetes. Diabetes. 2002;51:7–18.
Slawik M, Vidal-Puig AJ. Lipotoxicity, overnutrition and
energy metabolism in aging. Ageing Res Rev. 2006;5:144–
164.
Patiag D, Gray S, Idris I, et al. Effects of tumour necrosis
factor-alpha and inhibition of protein kinase C on glucose
uptake in L6 myoblasts. Clin Sci (Lond). 2000;99:303–307.
Plomgaard P, Bouzakri K, Krogh-Madsen R, et al. Tumor
necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt
substrate 160 phosphorylation. Diabetes. 2005;54:2939–
2945.
Ranganathan S, Davidson MB. Effect of tumor necrosis
factor-alpha on basal and insulin-stimulated glucose
transport in cultured muscle and fat cells. Metabolism.
1996;45:1089–1094.
Schinner S, Scherbaum WA, Bornstein SR, et al. Molecular
mechanisms of insulin resistance. Diabet Med. 2005;
22:674–682.
Carlson CJ, White MF, Rondinone CM. Mammalian target of
rapamycin regulates IRS-1 serine 307 phosphorylation.
Biochem Biophys Res Commun. 2004;316:533–539.
Bullock WH, Magnuson SR, Choi S, et al. Prospects for kinase
activity modulators in the treatment of diabetes and
diabetic complications. Curr Top Med Chem. 2002;2:915–
938.
Smith U. Impaired (‘diabetic’) insulin signaling and action
occur in fat cells long before glucose intolerance – is insulin
resistance initiated in the adipose tissue? Int J Obes Relat
Metab Disord. 2002;26:897–904.
Solomon TP, Blannin AK. Effects of short-term cinnamon
ingestion on in vivo glucose tolerance. Diabetes Obes
Metab. 2007;9:895–901.
Hlebowicz J, Darwiche G, Bjorgell O, et al. Effect of cinnamon on postprandial blood glucose, gastric emptying, and
satiety in healthy subjects. Am J Clin Nutr. 2007;85:1552–
1556.
Nutrition Reviews® Vol. 66(8):429–444
121. Pham AQ, Kourlas H, Pham DQ. Cinnamon supplementation
in patients with type 2 diabetes mellitus. Pharmacotherapy.
2007;27:595–599.
122. Blevins SM, Leyva MJ, Brown J, et al. Effect of cinnamon on
glucose and lipid levels in non insulin-dependent type 2
diabetes. Diabetes Care. 2007;30:2236–2237.
123. Wang JG, Anderson RA, Graham GM, 3rd, et al. The effect
of cinnamon extract on insulin resistance parameters in
polycystic ovary syndrome: a pilot study. Fertil Steril.
2007;88:240–243.
124. Suppapitiporn S, Kanpaksi N, Suppapitiporn S. The effect of
cinnamon cassia powder in type 2 diabetes mellitus. J Med
Assoc Thai. 2006;89(Suppl 3):S200–S205.
125. Baker WL, Gutierrez-Williams G, White CM, et al. Effect of
cinnamon on glucose control and lipid parameters. Diabetes Care. 2008;31:41–43.
126. Altschuler JA, Casella SJ, MacKenzie TA, et al. The effect of
cinnamon on A1C among adolescents with type 1 diabetes.
Diabetes Care. 2007;30:813–816.
127. Khan A, Bryden NA, Polansky MM, et al. Insulin potentiating
factor and chromium content of selected foods and spices.
Biol Trace Elem Res. 1990;24:183–188.
128. Qin B, Nagasaki M, Ren M, et al. Cinnamon extract (traditional herb) potentiates in vivo insulin-regulated glucose
utilization via enhancing insulin signaling in rats. Diabetes
Res Clin Pract. 2003;62:139–148.
129. Imparl-Radosevich J, Deas S, Polansky MM, et al. Regulation
of PTP-1 and insulin receptor kinase by fractions from cinnamon: implications for cinnamon regulation of insulin signalling. Horm Res. 1998;50:177–182.
130. Jarvill-Taylor KJ, Anderson RA, Graves DJ. A hydroxychalcone
derived from cinnamon functions as a mimetic for insulin in
3T3-L1 adipocytes. J Am Coll Nutr. 2001;20:327–336.
131. Kim DH, Kim CH, Kim MS, et al. Suppression of age-related
inflammatory NF-kappaB activation by cinnamaldehyde.
Biogerontology. 2007;8:545–554.
132. Cao H, Polansky MM, Anderson RA. Cinnamon extract and
polyphenols affect the expression of tristetraprolin, insulin
receptor, and glucose transporter 4 in mouse 3T3-L1 adipocytes. Arch Biochem Biophys. 2007;459:214–222.
133. Kim W, Khil LY, Clark R, et al. Naphthalenemethyl ester
derivative of dihydroxyhydrocinnamic acid, a component of
cinnamon, increases glucose disposal by enhancing translocation of glucose transporter 4. Diabetologia. 2006;49:
2437–2448.
134. Qin B, Nagasaki M, Ren M, et al. Cinnamon extract prevents
the insulin resistance induced by a high-fructose diet. Horm
Metab Res. 2004;36:119–125.
135. Shankar S, Ganapathy S, Srivastava RK. Green tea polyphenols: biology and therapeutic implications in cancer. Front
Biosci. 2007;12:4881–4899.
136. Wolfram S. Effects of green tea and EGCG on cardiovascular
and metabolic health. J Am Coll Nutr. 2007;26(Suppl):S373–
S388.
137. Wolfram S, Wang Y, Thielecke F. Anti-obesity effects of
green tea: from bedside to bench. Mol Nutr Food Res.
2006;50:176–187.
138. Iso H, Date C, Wakai K, et al. The relationship between green
tea and total caffeine intake and risk for self-reported type 2
diabetes among Japanese adults. Ann Intern Med.
2006;144:554–562.
139. Hill AM, Coates AM, Buckley JD, et al. Can EGCG reduce
abdominal fat in obese subjects? J Am Coll Nutr. 2007;
26(Suppl):S396–S402.
Nutrition Reviews® Vol. 66(8):429–444
140. Fukino Y, Ikeda A, Maruyama K, et al. Randomized controlled trial for an effect of green tea-extract powder supplementation on glucose abnormalities. Eur J Clin Nutr.
2007;[Epub ahead of print]. doi:10.1038/sj.ejcn.1602806
141. Fukino Y, Shimbo M, Aoki N, et al. Randomized controlled
trial for an effect of green tea consumption on insulin resistance and inflammation markers. J Nutr Sci Vitaminol
(Tokyo). 2005;51:335–342.
142. Ryu OH, Lee J, Lee KW, et al. Effects of green tea consumption on inflammation, insulin resistance and pulse wave
velocity in type 2 diabetes patients. Diabetes Res Clin Pract.
2006;71:356–358.
143. Hsu SP, Wu MS, Yang CC, et al. Chronic green tea extract
supplementation reduces hemodialysis-enhanced production of hydrogen peroxide and hypochlorous acid, atherosclerotic factors, and proinflammatory cytokines. Am J Clin
Nutr. 2007;86:1539–1547.
144. Mackenzie T, Leary L, Brooks WB. The effect of an extract of
green and black tea on glucose control in adults with type 2
diabetes mellitus: double-blind randomized study. Metabolism. 2007;56:1340–1344.
145. Hino A, Adachi H, Enomoto M, et al. Habitual coffee but not
green tea consumption is inversely associated with metabolic syndrome: an epidemiological study in a general
Japanese population. Diabetes Res Clin Pract. 2007;76:383–
389.
146. Moon HS, Lee HG, Choi YJ, et al. Proposed mechanisms of
(–)-epigallocatechin-3-gallate for anti-obesity. Chem Biol
Interact. 2007;167:85–98.
147. Waltner-Law ME, Wang XL, Law BK, et al. Epigallocatechin
gallate, a constituent of green tea, represses hepatic glucose
production. J Biol Chem. 2002;277:34933–34940.
148. Serisier S, Leray V, Poudroux W, et al. Effects of green tea on
insulin sensitivity, lipid profile and expression of PPARalpha
and PPARgamma and their target genes in obese dogs. Br J
Nutr. 2007:1–9.
149. Cao H, Hininger-Favier I, Kelly MA, et al. Green tea polyphenol extract regulates the expression of genes involved
in glucose uptake and insulin signaling in rats fed a high
fructose diet. J Agric Food Chem. 2007;55:6372–6378.
150. Chan LL, Chen Q, Go AG, et al. Reduced adiposity in bitter
melon (Momordica charantia)-fed rats is associated with
increased lipid oxidative enzyme activities and uncoupling
protein expression. J Nutr. 2005;135:2517–2523.
151. Uebanso T, Arai H, Taketani Y, et al. Extracts of Momordica
charantia suppress postprandial hyperglycemia in rats.
J Nutr Sci Vitaminol (Tokyo). 2007;53:482–488.
152. Krawinkel MB, Keding GB. Bitter gourd (Momordica
charantia): a dietary approach to hyperglycemia. Nutr Rev.
2006;64:331–337.
153. Basch E, Gabardi S, Ulbricht C. Bitter melon (Momordica charantia): a review of efficacy and safety. Am J Health Syst
Pharm. 2003;60:356–359.
154. Sridhar MG, Vinayagamoorthi R, Arul Suyambunathan V,
et al. Bitter gourd (Momordica charantia) improves insulin
sensitivity by increasing skeletal muscle insulin-stimulated
IRS-1 tyrosine phosphorylation in high-fat-fed rats. Br J Nutr.
2008;99:806–812.
155. Nerurkar PV, Lee YK, Motosue M, et al. Momordica charantia
(bitter melon) reduces plasma apolipoprotein B-100
and increases hepatic insulin receptor substrate and
phosphoinositide-3 kinase interactions. Br J Nutr. 2008
Mar 5:1–9 [Epub ahead of print]. doi:10.1017/
S0007114508937430
443
156. Leng SH, Lu FE, Xu LJ. Therapeutic effects of berberine in
impaired glucose tolerance rats and its influence on insulin
secretion. Acta Pharmacol Sin. 2004;25:496–502.
157. Gao CR, Zhang JQ, Huang QL. [Experimental study on berberin raised insulin sensitivity in insulin resistance rat
models]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 1997;17:162–
164.
158. Ni YX. [Therapeutic effect of berberine on 60 patients with
type II diabetes mellitus and experimental research]. Zhong
Xi Yi Jie He Za Zhi. 1988;8:711–713, 707.
159. Xie P, Zhou H, Gao Y. The clinical efficacy of berberine in
treatment of type 2 diabetes mellitus. Chin J Clin Healthcare.
2005;8:402–403.
160. Wei J, Jiang J, Wang S, Wang Z. Clinical study on improvement of type 2 diabetes mellitus complicated with fatty liver
treatment by berberine. Zhong Xi Yi Jie He Ganbing Za Zhi.
2004;14:334–336.
161. Zhang Y, Li X, Zou D, et al. Treatment of type 2 diabetes
and dyslipidemia with the natural plant alkaloid berberine.
J Clin Endocrinol Metab. 2008;doi: 10.1210/jc.2007–2404
162. Zhou L, Yang Y, Wang X, et al. Berberine stimulates glucose
transport through a mechanism distinct from insulin.
Metabolism. 2007;56:405–412.
163. Kim SH, Shin EJ, Kim ED, et al. Berberine activates GLUT1mediated glucose uptake in 3T3-L1 adipocytes. Biol Pharm
Bull. 2007;30:2120–2125.
164. Ko BS, Choi SB, Park SK, et al. Insulin sensitizing and insulinotropic action of berberine from Cortidis rhizoma. Biol
Pharm Bull. 2005;28:1431–1437.
165. Yi P, Lu FE, Chen G. [Molecular mechanism of berberine in
improving insulin resistance induced by free fatty acid
through inhibiting nuclear transcription factor-kappaB p65
in 3T3-L1 adipocytes]. Zhongguo Zhong Xi Yi Jie He Za Zhi.
2007;27:1099–1104.
166. Yi P, Lu FE, Xu LJ, et al. Berberine reverses free-fatty-acidinduced insulin resistance in 3T3-L1 adipocytes through targeting IKKbeta. World J Gastroenterol. 2008;14:876–883.
167. Vuksan V, Sung MK, Sievenpiper JL, et al. Korean red
ginseng (Panax ginseng) improves glucose and insulin
regulation in well-controlled, type 2 diabetes: results of
a randomized, double-blind, placebo-controlled study of
efficacy and safety. Nutr Metab Cardiovasc Dis. 2008;18:46–
56.
168. Yushu H, Yuzhen C, Zhaoying Y, Peiyin Z. The effect of panax
ginseng extract (GS) on insulin and corticosteroid receptors.
J Trad Chin Med. 1988;8:293–295.
169. Yokozawa T, Kobayashi T, Oura H, et al. Studies on the
mechanism of the hypoglycemic activity of ginsenosideRb2 in streptozotocin-diabetic rats. Chem Pharm Bull
(Tokyo). 1985;33:869–872.
444
170.
171.
172.
173.
174.
175.
176.
177.
178.
179.
180.
181.
182.
183.
Attele AS, Zhou YP, Xie JT, et al. Antidiabetic effects of Panax
ginseng berry extract and the identification of an effective
component. Diabetes. 2002;51:1851–1858.
Lee WK, Kao ST, Liu IM, et al. Ginsenoside Rh2 is one of the
active principles of Panax ginseng root to improve insulin
sensitivity in fructose-rich chow-fed rats. Horm Metab Res.
2007;39:347–354.
Lee WK, Kao ST, Liu IM, et al. Increase of insulin secretion by
ginsenoside Rh2 to lower plasma glucose in Wistar rats. Clin
Exp Pharmacol Physiol. 2006;33:27–32.
Lai DM, Tu YK, Liu IM, et al. Mediation of beta-endorphin by
ginsenoside Rh2 to lower plasma glucose in streptozotocininduced diabetic rats. Planta Med. 2006;72:9–13.
Zhang Z, Li X, Lv W, et al. Ginsenoside Re reduces insulin
resistance through inhibition of c-Jun NH2-terminal kinase
and nuclear factor-kappaB. Mol Endocrinol. 2008;22:186–
195.
Park MW, Ha J, Chung SH. 20(S)-Ginsenoside Rg3 enhances
glucose-stimulated insulin secretion and activates AMPK.
Biol Pharm Bull. 2008;31:748–751.
Yoon SH, Han EJ, Sung JH, et al. Anti-diabetic effects of compound K versus metformin versus compound K-metformin
combination therapy in diabetic db/db mice. Biol Pharm
Bull. 2007;30:2196–2200.
Humulus lupus. Monograph. Altern Med Rev. 2003;8:190–
192.
Yajima H, Ikeshima E, Shiraki M, et al. Isohumulones, bitter
acids derived from hops, activate both peroxisome
proliferator-activated receptor alpha and gamma and
reduce insulin resistance. J Biol Chem. 2004;279:33456–
33462.
Tripp ML, Pacioretty L, Konda VR, Darland G, Emma D,
Bland J, Babish, J. Selective kinase response modulators
(SKRMS) from Humulus lupulus and Acacia nilotica modulate
multiple kinases and improve insulin sensitivity in vitro and
in vivo. FASEB J. 2007;21:A232.1.
Bland JS. What role has nutrition been playing in our health?
The xenohormesis connection. Integ Med. 2007;6:22–24.
Grundy SM, Hansen B, Smith SC, Jr., et al. Clinical management of metabolic syndrome: report of the American Heart
Association/National Heart, Lung, and Blood Institute/
American Diabetes Association conference on scientific
issues related to management. Arterioscler Thromb Vasc
Biol. 2004;24:e19–24.
Frame S, Zheleva D. Targeting glycogen synthase kinase-3 in
insulin signalling. Expert Opin Ther Targets. 2006;10:429–
444.
Kido Y, Nakae J, Accili D. Clinical review 125: The insulin
receptor and its cellular targets. J Clin Endocrinol Metab.
2001;86:972–979.
Nutrition Reviews® Vol. 66(8):429–444