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The Metabolic Syndrome : Definition, Global Impact, and Pathophysiology

Matthew V. Potenza and Jeffrey I. Mechanick
Nutr Clin Pract 2009 24: 560
DOI: 10.1177/0884533609342436

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Invited Review
The Metabolic Syndrome: Definition,
Global Impact, and Pathophysiology
Matthew V. Potenza, MD1; and Jeffrey I. Mechanick, MD2
Financial disclosure: none declared.
The metabolic syndrome (MS) is a cluster of metabolic derange-
ments that are associated with primary disturbances in adipose
tissue. Abnormal visceral fat accumulates from physical inactiv-
ity and excess calories in genetically susceptible individuals.
This increased adipocyte mass acts as an endocrine organ
and communicates with other organ systems via increases in
inflammatory cytokines. The resulting disorders define MS as
increased waist circumference, decreased serum high-density
lipoprotein, and increased serum triglyceride levels, hyperten-
sion, and insulin resistance. MS accounts for the majority of
cardiovascular disease risk in the U.S. population. Dietary inter-
ventions, such as the Mediterranean diet, have been shown to
improve these metabolic derangements. Many substances found
G
lobal epidemics of both type 2 diabetes and obes-
ity have drawn attention to a cluster of metabolic
derangements predisposed by fat dysmetabolism.
This cluster of metabolic derangements, given the name
metabolic syndrome (MS), was initially defined by the
World Health Organization (WHO) in 1998.1 The con-
cept of such a disease state has existed for over 80 years,1
being referred to initially as “syndrome X,” “the insulin
resistance syndrome,” and “the deadly quartet.”2-4 The
initial WHO definition of MS included impractical meas-
ures of insulin resistance, such as the euglycemic clamp
technique. In an effort to establish a clinical definition,
the National Cholesterol Education Program’s Adult
Treatment Panel III (NCEP ATP III) modified the WHO
definition into a form easily applied by clinicians and
used by most researchers today (see Table 1).5 This defi-
nition requires 3 out of the 5 following metabolic derange-
ments: (1) high serum triglyceride level; (2) low serum
high-density lipoprotein (HDL) cholesterol level; (3) hyper-
tension; (4) elevated fasting blood glucose; or (5) increased
waist circumference. A third competing definition by the
International Diabetes Federation is similar to the NCEP
From the 1Mount Sinai Hospital, New York; 2Mount Sinai School
of Medicine, New York.
Address correspondence to: Matthew V. Potenza, Mount Sinai
Hospital, One Gustave L. Levy Place, New York, NY 10029;
e-mail: doctor.potenza@gmail.com.
560
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Nutrition in Clinical Practice
Volume 24 Number 5
October/November 2009 560-577
© 2009 American Society for
Parenteral and Enteral Nutrition
10.1177/0884533609342436
http://ncp.sagepub.com
hosted at
http://online.sagepub.com
in these diets are being investigated as specific therapies for
MS, and when scientific substantiation is lacking, they may be
considered as part of complementary and alternative medicine
(CAM). However, as scientific evidence accumulates, these
CAM treatments may become part of conventional medicine.
This review will scrutinize the emerging evidence behind
many, though not all, CAM treatments currently thought to
target the various derangements found in MS. (Nutr Clin Pract.
2009;24:560-577)
Keywords:   metabolic syndrome X; endocrinology; hypertension;
obesity; hyperlipidemias; diabetes mellitus; Mediterranean diet;
dietary fiber; complementary therapies
ATP III except that it calls for increased waist circumfer-
ence as a primary criterion and then requires 2 or more
of the above criteria.6
The recognition of MS as a major risk factor for vari-
ous diseases has come into focus in recent years, as its
prevalence has steadily increased. MS itself has a great
impact on morbidity and mortality. Many epidemiologic
studies have shown a marked increased risk of cardiovas-
cular disease (CVD) and type 2 diabetes with MS.7,8
Indeed, by applying the NCEP ATP III definition to the
National Health and Nutrition Examination Survey
(NHANES) III database, MS was found to be strongly
associated with both myocardial infarction and stroke.9
Another large epidemiologic study aimed to identify modi-
fiable risk factors for CVD in nearly 30,000 people from
52 countries. The group found that the elements of MS in
addition to low fruit and vegetable intake, low physical
activity, and lack of alcohol use accounted for nearly all of
the risk for myocardial infarction in both sexes.10 Mortality
from any cause is also increased 2.26-fold in men and
2.78-fold in women with MS independent of age, body
mass index (BMI), cholesterol levels, and smoking.11
The prevalence of MS varies by population (see
Figure 1). In studies looking at individuals older than 20
to 25 years, the prevalence varies from as low as 8% in
India to as high as 24% in the United States for men, and
from 7% in France to 43% in Iran for women.12 Using the
NHANES III database and the NCEP ATP III definition,
 The Metabolic Syndrome / Potenza, Mechanick   561

Table 1.   Criteria for Diagnosis and Definitions of Risk Factors for the Metabolic Syndrome,
According to the World Health Organization (WHO) and the National Cholesterol
Education Program Adult Treatment Panel III (NCEP ATP III)
Risk Factor WHO NCEP ATP III
a
Criteria for diagnosis T2DM or IGT plus 2 or more risk factors Any 3 risk factors
Obesity Waist-hip ratio >0.9 (male) or >0.85 Waist circumference >40 in (male) or >35
(female), and/or BMI >30 in (female)
Serum triglycerides (mg/dL) ≥150 ≥150
Serum high-density lipoprotein (mg/dL) <35 (male), <39 (female) <40 (male), <50 (female)
Hypertension (mm Hg) ≥140/90 ≥130/85
Fasting plasma glucose (mg/dL) No number given, uses different measures ≥100
of insulin resistance
Microalbuminuria 30 mg albumin/g creatinine Not used

BMI, body mass index; IGT, impaired glucose tolerance; T2DM, type 2 diabetes mellitus.
a
IGT = 75 g oral glucose tolerance test (2 h postload plasma glucose ≥140-199).

Figure 1.   Worldwide prevalence of the metabolic syndrome.

*Obesity criteria adjusted to waist circumference appropriate for Indian population.

the United States prevalence is 34.4% ± 0.9% overall.13 A
recent European study found the prevalence of MS to be
0.2% and 1.4% in 10- and 15-year-olds, respectively, with
elevated BMI in the mother and decreased physical activ-
ity being the major risk factors.14
Obesity leads to a state of insulin resistance through
mechanisms that have recently been identified.15
Traditionally believed to be an efficient reservoir of energy,
visceral adiposity is now known to be an active endocrine
organ in communication with other organ systems via
secretion of fatty acids and adipokines (cytokine-like mole-
cules of adipose tissue origin, including leptin, resistin, and
adiponectin). As adipose tissue accumulates, alterations in
the concentration of these adipokines in the blood upregu-
late inflammatory cytokines (tumor necrosis factor-α and
interleukin-6), which contribute to disordered insulin sign-
aling and endothelial dysfunction (Figure 2). Most agree
that the mechanism by which MS leads to increased CVD
risk is through this chronic inflammation and endothelial
dysfunction. However, markers of inflammation are part of
the definition of MS. This disordered fat physiology is likely
the primary derangement in MS, a concept that has come
to be known as adiposopathy or sick fat.16 Adiposopathy is
defined as pathogenic adipose tissue resulting from positive
caloric balance and sedentary lifestyle in genetically suscep-
tible patients. It is manifested by adipocyte hypertrophy,
visceral adipose tissue accumulation, and subsequent adi-
pose tissue growth. Adiposopathy then causes an adverse
inflammatory response, as described above, which results in
clinical MS.16
Dietary Interventions
Dietary interventions, aimed at reducing the amount of
visceral fat, seem to be the logical initial step to treat MS
and prevent its consequences. While increased physical
activity is a cornerstone of the healthy lifestyle intervention

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562   Nutrition in Clinical Practice / Vol. 24, No. 5, October/November 2009

Figure 2.   The pathophysiology of the metabolic syndrome. Genetic predisposition, decreased physical activity, and a diet low in fiber
and high in saturated fats leads to increased visceral adiposity. The visceral adipose tissue secretes inflammatory cytokines and adipok-
ines (leptin, resistin, interleukin-6, plasminogen-activator inhibitor-1, and tumor necrosis factor-α) as well as nonesterified fatty acids.
These factors create insulin resistance at the level of the skeletal muscle and liver leading to hyperinsulinemia, which contributes to
endothelial dysfunction and atherogenesis. The fatty acids also alter hepatic lipid production toward a more atherogenic profile (low
high-density lipoprotein, elevated low-density lipoprotein, and elevated triglycerides). Taken as a whole, the increased visceral adipose
tissue is at the center of the metabolic derangements that make up the metabolic syndrome. HTN, hypertension; IL, interleukin; PAI,
plasminogen-activator inhibitor-1; TNF, tumor necrosis factor.
Source: Adapted with permission from Macmillan Publishers Ltd.17

that lowered the risk developing type 2 diabetes by 58% in
the Diabetes Prevention Program18 and certainly has a
strong role in treating MS, this review focuses on the
effects of the dietary interventions described below, which
affect metabolism independently of such physical activity
in multivariate analyses.20 Interestingly, specific dietary
considerations, other than calorie restriction itself, seem
important when treating this syndrome. Both the
Mediterranean diet and the Dietary Approaches to Stop
Hypertension (DASH) diet have been shown to have a
powerful impact on MS independent of weight loss itself
(Table 2). The Mediterranean diet has been shown in
randomized controlled trials to decrease markers of
inflammation and improve endothelial dysfunction in
patients with MS.19,20 Indeed, individuals with the closest
adherence to the Mediterranean diet have the lowest
incidence of MS in large epidemiologic studies.21,22 In a
large study looking at the effects of a low-carbohydrate
diet vs the Mediterranean diet on various parameters, the
Mediterranean diet actually improved glycemic control
better than carbohydrate restriction.23 The DASH diet
was designed to target hypertension but has also been
proven to be effective in treating all aspects of the MS.24
Another study found that high intakes of red meat, fried
potatoes, nongreen vegetables, and eggs, and a low intake
of fiber and wine (all elements of a Western diet) were
associated most strongly with developing MS, which fur-
ther supports the power of switching to a DASH- and
Mediterranean-style diet.28
The Case for Complementary
and Alternative Medicine
Dietary interventions can be more effective than medica-
tions for reducing the incidence of MS.29 The observation
that elements of a diet beyond the caloric content can
affect these metabolic derangements has led many inves-
tigators to question which specific elements of food can be
harnessed to effectively treat MS. Both the Mediterranean
and the DASH diets are rich in phytochemicals and micro-
nutrients that have disease-modifying potential and are
distinct from the Western diet. For example, the DASH diet
is rich in fiber and magnesium, while the Mediterranean

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 The Metabolic Syndrome / Potenza, Mechanick   563

Table 2.   Summary of a Typical Western Diet, Mediterranean Diet, and DASH
(Dietary Approaches to Stop Hypertension) Diet
Western Dieta Mediterranean Dietb DASH Dietc
Overall content, as 10-12 grains 7-8 grains 7-8 grains
daily servings 1-2 vegetables 4-5 vegetables 4-5 vegetables
unless noted 2-3 fruits 4-5 fruits 4-5 fruits
2-3 dairy 1-2 low-fat dairy 3-4 low-fat dairy
5 or more fats, often saturated 1-2 fish <2 meat, poultry, fish
1-2 meat 3-5 fats as PUFA or MUFA 2-3 fats/oils
1-2 poultry Poultry (weekly) 1 sweet
Fish (monthly) Meat (monthly)
Soda, beer 1-2 glasses red wine
1-2 sweets 1-2 nuts or seeds
1 sweet, usually honey
Sample breakfast 1 bagel 2 whole-wheat toast with 1 tsp 1 cup oatmeal
2 fried eggs honey 8 oz low-fat milk
3 tsp butter 1 cup mixed berries ½ cup strawberries
2 oz slices bacon ½ cup yogurt 1 banana
12 oz juice ½ cup grapes ¼ cup raisins
6 oz juice 6 oz juice
Sample lunch 2 slices white bread Salad: 1 cup spinach, ½ cup Salad: 1 cup spinach, ½ cup carrots,
2 tsp mayonnaise carrots, ½ cup broccoli, ½ cup broccoli
5 oz ground meat ½ avocado 1 small whole-wheat roll
1.5 oz cheddar cheese ¼ cup olives 1.5 oz Swiss cheese
10 oz French fries 1 tsp olive oil 1 tsp oil-based dressing
12 oz soda ¼ cup almonds 1 apple
8 oz low-fat milk 8 oz low-fat milk
Sample dinner 8 oz steak 5 oz roasted salmon with 2 tsp 5 oz grilled chicken
1 potato olive oil ½ cup asparagus
1 tsp sour cream ½ cup asparagus 1 tsp butter
1 ear corn 1 cup cooked brown rice 8 oz low-fat milk
1-2 pints beer 1.5 oz feta cheese 1 cup cooked brown rice
1 slice apple pie with 1 cup ¼ cup chickpeas 1 pear
ice cream 1 peach ½ cup sorbet
1 glass red wine

MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid.

a
from Cordain et al.25
b
from Hollander and Mechanick.26
c
from Trichopoulou and Vasilopoulou.27

diet includes fish, red wine, and flavonoids. As individual
aspects of these diets are used to treat MS, these treatment
modalities tend to fall under the umbrella of complemen-
tary and alternative medicine (CAM). CAM therapies usu-
ally stem from observations like those described above,
often without science clearly supporting claims of health
benefits. CAM is also not usually taught in U.S. medical
schools and often targets symptoms rather than specific
disease states. CAM treatments stray away from the stan-
dard paradigm of drug approval by the Food and Drug
Administration after rigorous clinical trials, which results
in many unproven therapy claims.30 CAM therapies have
other potential shortcomings, as many of the CAM prod-
ucts vary from brand to brand in quality and quantity of the
proposed active compound. Other interfering ingredients
are often not listed on the product container, introducing
additional variance between brands.
This review aims to scrutinize the evidence that exists
behind many of the CAM therapies that have claimed to
treat elements of MS, from insulin resistance to weight
loss. In addition to many of the elements of the DASH
and Mediterranean diets, this review will also look at
some of the more popular CAM treatments of MS (see
Table 3). In most cases, these treatment modalities
should be considered in addition to, and not instead of,
conventional therapy.
Fish and ω-3 Polyunsaturated Fatty Acids
Both increased intake of fish and specific dietary supple-
mentation of ω-3 fatty acids are often used in treatment
of MS. The ω-3 fatty acids contain 18 to 22 carbons and
a signature double bond at the third position from the

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564   Nutrition in Clinical Practice / Vol. 24, No. 5, October/November 2009

Table 3.   CAM Therapy and Its Putative Role in Different Aspects of the Metabolic Syndromea
Possible Role of Agent in the Metabolic Syndrome
Central Insulin High Recommended
Therapy Obesity Resistance Hypertension Low HDL Triglycerides Level
ω-3 fatty acids X X X X X A
Flaxseed oil X X X X X D
Moderate red X X X B
   wine
Dark chocolate X X X X C
Cinnamon X X C
Soy X X X A
Fiber X X X X A
Chromium X X C
Magnesium X X C
Ginseng X X X X C
Bitter melon X X C
Green tea X X C
Acupuncture X X C

A, recommended in conjunction with other conventional therapy or as “first line” therapy; B, recommended if patient refuses or fails
to respond to conventional therapy—consider for “second line” therapy; C, recommended if patient refuses or fails conventional
therapy, provided there are no significant adverse effects, “no objection” to recommending their use or to continuing their use; D,
not recommended—advised to discontinue. Recommendations based on AACE level of evidence.
a
Grade recommendation protocol data from the American Association of Clinical Endocrinologists (AACE) Nutrition Task Force.30
CAM, complementary and alternative medicine; HDL, high-density lipoprotein.

methyl end (ω, or omega) of the molecule. While they can-
not be synthesized in humans, dietary sources of the 2
major ω-3 fatty acids (eicosapentaenoic acid [EPA] and
docosahexaenoic acid [DHA]) can be found in cold-water
fish (eg, mackerel, salmon, and cod). High doses of ω-3
fatty acids shut the pathway of fatty acid product synthe-
sis away from inflammatory molecules such as arachi-
donic acid and other eicosanoids (derived from ω-6 fatty
acids), and toward the synthesis of anti-inflammatory
molecules (derived from ω-3 fatty acids). When individu-
als consume a diet that is higher in ω-3 fatty acids com-
pared to ω-6 fatty acids, their plasma membrane
composition is altered to include a higher proportion of
ω-3 fatty acids, reflecting altered body stores of fatty
acids. Those individuals with higher ω-3 fatty acids store,
then have a less robust inflammatory response (as mea-
sured by neutrophil action) when challenged with inflam-
matory stimuli, believed to be a direct consequence of
altered substrate.32 Based on such findings, ω-3 fatty acid
supplementation has been investigated for roles in modi-
fying many disease states, including beneficial effects on
sepsis,33 cancer,34 vascular disease,35 inflammatory dis-
eases,36 sudden death following a myocardial infarction,37
and MS.
In addition to their effects on the inflammatory
profile, the ω-3 fatty acids reduce triglyceride levels by
downregulating hepatic synthesis and secretion of very
low-density lipoprotein (VLDL) cholesterol as well as
enhancing chylomicron clearance.38,39 While HDL cho-
lesterol remains largely unaffected by ω-3 fatty acids,
low-density lipoprotein (LDL) cholesterol levels can rise
slightly; however, LDL particle size increases from smaller,
more atherogenic particles to larger particles that are less
likely to become incorporated into plaques.39 Though
many studies have shown the benefits of ω-3 fatty acids
on lipid profile, this review will focus on 3 major trials. A
total of 42 individuals with baseline hypertriglyceridemia
(levels between 500 and 2000 mg/dL) were randomized
to ingest 4 g of concentrated ω-3 fatty acid (Omacor,
Reliant Pharmaceuticals, Inc, Liberty Corner, NJ) or
placebo.40 The treatment arm experienced an impres-
sive 45% reduction in serum triglyceride concentration
(P < .00001), 32% reduction in VLDL cholesterol levels
(P < .001), and reduction of total serum cholesterol level
by 13% (P < .001). Serum HDL and LDL cholesterol
levels rose by 13% (P = .0014) and 31% (P = .0014),
respectively. These data were replicated in a similar study
of 41 patients (serum triglyceride levels between 500 and
2000 mg/dL) who were randomized to receive 4 g of con-
centrated ω-3 fatty acid or placebo. Serum triglyceride
levels fell by 38.9% and total cholesterol levels by 9.9% in
the treatment group (P < .001).41 A recent study of ω-3
fatty acid supplementation examined patients with coro-
nary artery disease who were already taking simvasatin to
treat dyslipidemia and who had persistent serum triglyceride
levels over 200 mg/dL.42 The participants in the treatment
arm experienced a 20% to 30% reduction in serum triglyc-
eride levels (P < .005) without influence on HDL or LDL
cholesterol concentrations. The major side effects reported
from these trials were limited to dyspepsia, eructation,

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and dysgeusia. Although ω-3 fatty acids could inhibit
platelet aggregation in theory, an increased risk of bleed-
ing was not seen at the 4-g dose.
While the evidence for ω-3 fatty acid supplementa-
tion to address dyslipidemia in MS is overwhelmingly
positive, its use for other components is less robust. In a
study of postmyocardial infarction patients, those who
receive lean fish (with low ω-3 fatty acid content) 4 times
per week as opposed to those who ate fatty fish (with high
ω-3 fatty acid content) 4 times per week had decreases in
their blood pressure by 3.6% (P < .05).43 These data sug-
gest that eating fish, regardless of its polyunsaturated fat
profile, decreased blood pressure and, in fact, showed a
small benefit in the nonfatty fish over the ω-3 rich fish.
To investigate ω-3 fatty acid’s role in weight loss, 324 men
and women were randomized to a calorie-restricted diet
with either sunflower seed oil capsules (as a control), ω-3
fatty acid capsules, 4 servings of lean fish per week, or 4
servings of fatty fish per week. There was no difference
between the intervention groups, though all 3 intervention
groups lost, on average, 1 additional kg more than the
control group at 8 weeks.44 These data argue against a
weight-loss benefit of ω-3 fatty acids over other polyun-
saturated fats. A recent Cochrane review looked at 25
studies with a total of 1075 participants that investigated
supplemental ω-3 fatty acids on glycemic control in type
2 diabetes.45 No statistical difference in fasting insulin or
glycemic control was found. These data are corroborated
by experiments showing no improvement in HOMA-IR
(homeostasis assessment model of insulin resistance)46 or
β-cell function47 in participants receiving high doses of
ω-3 fatty acids vs ω-6 fatty acids.
In summary, supplementing 4 g of pure ω-3 fatty acids
has lipid-altering benefits. An individual should be advised to
take pure supplements from pharmaceutical companies
rather than preparations found in health food stores to
assure that they are receiving EPA and DHA. Eating fish can
aid in blood pressure lowering and possibly weight loss,
though this does not seem to be mediated by ω-3 fatty acids.
Flaxseed Oil
Flaxseed oil is rich in essential fatty acids (especially
α-linoleic acid) and has a ratio of ω-6:ω-3 fatty acids of
0.3:1.0. Although α-linoleic acid is an ω-3 fatty acid, it
cannot be easily converted to DHA (which, as discussed
above, is one of the biologically active ω-3 fatty acids).
Benefits of supplementing with flaxseed oil may therefore
be less than the benefits of supplementing with pure
DHA and EPA. Two small clinical trials investigating
supplemental flaxseed oil on lipid profile showed no
effect after a 4-week period.48,49 A larger study over 10
weeks showed that flaxseed oil had no effect on serum
LDL cholesterol levels and actually lowered serum HDL
cholesterol levels in men by 9% (P < .05)50 In a study in
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The Metabolic Syndrome / Potenza, Mechanick   565
postmenopausal women, flaxseed oil did help with meno-
pausal symptoms, but had no effect on lipid profile.51
LDL cholesterol particle size also is not affected by sup-
plementing flaxseed oil, as seen in a randomized con-
trolled trial of 56 individuals that showed no effect on
lipid profile.51 Unlike ω-3 fatty acids, flaxseed oil by itself
has not been shown to be efficacious in modifying dyslip-
idemia and may actually adversely affect the profile by
lowering serum HDL cholesterol levels.
Red Wine and Resveratrol
In addition to moderate wine intake being a part of the
Mediterranean diet, large epidemiologic studies have
shown associations between moderate alcohol intake and
decreased risk of developing MS. A cross-sectional analy-
sis of data collected in the NHANES III database found
that participants who consumed 1 to 19, or more than 20
drinks per month were 35% and 66% less likely to develop
MS, respectively, compared with nondrinkers (P < .05).52
The trend was strongest in wine drinkers. Another study
of 36,527 Australians, aged 40 to 69 years, correlated the
type and amount of alcoholic beverages consumed to
incident diabetes after 4 years of follow-up.53 In general,
men and women who consumed alcohol on a regular
basis were leaner and more active than abstainers. Once
these confounders were excluded in the analysis, con-
sumption of wine once daily was associated with a 34%
reduction (P < .05) in the odds of developing type 2 dia-
betes. On the other hand, men who consumed beer and
spirits trended toward a nonsignificant increase in the
risk of developing type 2 diabetes.
This negative correlation of moderate alcohol con-
sumption and MS has been replicated in other prospec-
tive epidemiologic studies, though in these studies, wine
by itself did not affect outcome distinctly from total alco-
hol consumption. A 12-year prospective study of 46,982
U.S. males looked at type 2 diabetes incidence compared
with alcohol intake and found moderate alcohol intake of any
type lowered the risk of diabetes by 36% (relative risk =
0.64; 95% confidence interval (CI) = 0.53-0.77).54 An
analysis of the Nurse’s Health Study (NHS) found that
women who drank at least 1 serving of alcohol daily were
less likely to develop type 2 diabetes, and the research
group included moderate alcohol consumption as part of
their healthy lifestyle (along with exercise, increased fiber
intake, smoking cessation, weight reduction, and low gly-
cemic load foods) to reduce the risk of developing type 2
diabetes by their model to 90%.55 When dietary patterns
of 334 monozygotic twins were compared in a study look-
ing at risk factors for MS, higher alcohol consumption
was associated with less central adiposity.56 A meta-analy-
sis of trials investigating the effects of moderate alcohol
consumption on lipid profile found an increase in serum
HDL cholesterol level to be the predominant effect. The
566   Nutrition in Clinical Practice / Vol. 24, No. 5, October/November 2009
group found an average increase in HDL level of 4.99 mg/
dL (95% CI = 3.25-4.73).57 Indeed, 1 to 2 servings of
alcohol daily seems to increase serum HDL levels by 12%
in studies of the NHANES III database.58 An analysis
of the Women’s Health Study showed an average decrease
in blood pressure with moderate alcohol intake, while
another such analysis of men in the Physicians’ Health
Study showed increases in blood pressure with alcohol
consumption, even in moderate amounts.59 Although
heavy alcohol use is clearly associated with hypertension,
these data leave moderate alcohol consumption’s effects
on blood pressure uncertain. Overall, these studies sug-
gest that moderate alcohol consumption is related to
increased levels of serum HDL cholesterol, reduced insu-
lin resistance, and less central adiposity.
While several population-based studies show associa-
tions with alcohol and decreased risk, as above, there are
no randomized controlled trials investigating alcohol’s
relationship with MS. Furthermore, the mechanisms by
which alcohol itself modifies derangements of MS are not
fully elucidated. Looking specifically at red wine, 2 major
components are responsible for its biologic activity: alco-
hol and polyphenols, specifically resveratrol.60 Most agree
that alcohol itself acts directly on the liver by increasing
the synthesis of apolipoprotein A-1 (the major component
of HDL cholesterol) and increases lipoprotein lipase activ-
ity, which together lead to elevations of HDL.61,62 Which
component of red wine exerts positive effects on endothe-
lial cell function and glycemic control is less clear. In an
euglycemic hyperinsulinemic clamp study, insulin sensi-
tivity in patients with type 2 diabetes was measured before
and after 2 weeks of red wine consumption (12 oz/day).63
Insulin-mediated whole-body glucose improved by 43%
(P = .02) after 2 weeks of red wine consumption. These
results were mimicked in a study using white wine (which
has lower amounts of resveratrol), suggesting that perhaps
alcohol by itself is affecting glycemic control.64
Many recent experiments with the compound res-
veratrol have suggested its positive effects on MS may be
related to its influence on endothelial function and
inflammation. In vitro studies have revealed that resvera-
trol inhibits the inflammatory response via a variety of
mechanisms, including: decreased prostaglandin synthe-
sis,65 decreased nuclear factor κ-ß activity with subsequent
downregulation of inflammatory cytokine expression,66
and downregulation of intracellular adhesion molecules.67
In addition, resveratrol is an agonist for sirtuins, which
are anti-enescent proteins that, when activated, can pro-
long cell life, as demonstrated in heart and brain cell
experiments.68 Calorie restriction in animal models has
been shown to prolong life through activation of sirtuins.
Researchers are currently investigating resveratrol’s abil-
ity to mimic the life span, extending effects of calorie
restriction mediated by sirtuin pathways. Interestingly, a
high-resveratrol diet can attenuate the effects of a high-
fat diet in mice (compared with a calorie-restricted diet)
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by decreasing insulin resistance, decreasing oxidative tis-
sue damage, and thereby prolonging life span.69 The
amount of resveratrol in red wine, the amount that is
absorbed into the bloodstream, and the amount needed
for the above effects has been explored with differing
results.70,71 Some suggest that 1 L of red wine can raise
serum levels of resveratrol to 100 to 200 nmol/L, which
is within the bottom end of the therapeutic range. This
large amount of wine needed to reach therapeutic levels
of resveratrol may argue against its importance in protect-
ing against MS, considering most evidence for the benefit
of wine points toward moderate consumption.
Overall, the associations of alcohol use with decreased
risk of the components of MS (except for hypertension)
need to be proven with further clinical trials. The many
proven hazards of alcohol overuse and abuse currently
outweigh possible benefits in recommending this inter-
vention to patients until more data are available. Currently,
clinical trials are underway looking at resveratrol and MS.
Dark Chocolate
As with red wine, polyphenols (in this case flavonols) seem
to be responsible for dark chocolate’s putative beneficial
effect on MS. The primary flavonoids found in dark choco-
late are catechin, epicatechin, and proanthocyanidin, with
more than 600 phytochemicals also having been identi-
fied.72 Two small studies randomized participants to receive
dark chocolate (with flavonols) or white chocolate (without
flavonols) and found increases in insulin sensitivity in the
dark chocolate group (100 g/day) using HOMA-IR.73,74
Other studies have looked for possible benefits on blood
pressure and vascular function with mixed results.75-77 A
small study showed improved vascular function in diabetic
patients as measured by flow-mediated dilation of the bra-
chial artery in patients taking flavonol-rich cocoa com-
pared with a placebo.78 Another study looked at cocoa
consumption combined with exercise and found improved
vascular function, but the exercise intervention attenuated
those effects and also led to weight loss.75 Flavonols likely
influence vascular function in ways similar to resveratrol,
as described above.79 Since foods with dark chocolate are
likely calorically dense with high levels of saturated fat,
patients should not be advised to add dark chocolate to
their diet as a means of protecting against MS, especially
with very little evidence supporting its use.
Cinnamon Extract
The logic of investigating certain botanicals, including
spices, for health benefits is based on the presumption that
human taste evolved to prefer flavors that promote health.
Following reports in 1990 that compounds found in
Cinnamomum cassia may potentiate insulin action in people

with type 2 diabetes, many preparations have been mar-
keted with claims that standard pharmaceuticals may not
be needed.80 Water-soluble polyphenols from cinnamon
extract have since been shown to enhance autophosphory-
lation of the insulin receptor as well as inhibit dephos-
phorylation (via phosphotyrosine phosphatase) of the same
receptor.81 Taken together, these compounds increase insu-
lin activity 20-fold in vitro.82 Since decreased phosphoryla-
tion of the insulin receptor is a critical defect in people with
impaired glucose tolerance, the use of these compounds or
related congeners in MS is attractive.83 Additional experi-
ments have suggested that cinnamon polyphenols can: (a)
increase glucose transport protein (GLUT) expression in
certain cell types and (b) exhibit immunomodulatory effects
that create a less inflammatory cytokine profile in in vitro
models by acting as a transcription factor.84
Results of clinical trials investigating the impact of
cinnamon extract on elements of MS have been mixed. In
a study of 60 people with type 2 diabetes given 1, 3, or 6
g of cinnamon daily or placebo for 40 days, cinnamon
reduced the mean fasting serum glucose by 18%-29%,
serum triglycerides by 23%-30%, LDL cholesterol by
7%-27%, and total cholesterol by 12%-26% in a dose-
independent manner compared with placebo.85 However,
a recent meta-analysis, which included the above positive
study along with 4 other studies, did not show any net
effect on fasting glucose, hemoglobin A1c, or serum lip-
ids.86 This meta-analysis included a study of 72 adoles-
cents with type 1 diabetes, in which 1 g of cinnamon
extract showed no benefit in glycemic control over pla-
cebo.87 This particular study should not have been
included as the mechanism of cinnamon action is to
improve insulin resistance, which is not a primary patho-
genic mechanism in type 1 diabetes. Thus, the effects of
the positive studies in the meta-analysis may have been
blunted by this inclusion.88 Another negative study look-
ing at postmenopausal women was also included in the
analysis, but this study used a whole cinnamon prepara-
tion and not the more bioavailable aqueous extract.89
A crossover study of 14 healthy nondiabetic individu-
als, not included in the above meta-analysis, looked at the
effect of ingestion of 6 g of cinnamon daily on fasting
blood glucose and gastric emptying with positive results.90
Another placebo-controlled study not in the meta-analysis
looked at the effect of 500 mg of cinnamon on body com-
position in 22 individuals with the MS over 12 weeks.91
The treated group had statistically significant increases in
lean mass by 1.1% and decreases in fat by –0.8%. The
treated group also had lower systolic blood pressure
(–3.8%) and lower fasting blood glucose (–8.4%; P < .05).
The use of cinnamon to improve insulin resistance
and other elements of MS should be further studied in
larger trials. Cinnamon extract does not seem to have any
adverse effects. If patients are interested in a trial of cin-
namon extract in addition to conventional therapy, there
are some data to support its use.
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The Metabolic Syndrome / Potenza, Mechanick   567
Soy Protein
Proponents of soy-based diets argue that there are favor-
able effects on MS. Depending on the source of soy, soy-
based diets could be high in isoflavones (phytoestrogens),
as are food sources in the Mediterranean diet. Conflicting
data in the literature showing both favorable92-94 and no95-97
effects are likely because of the inconsistencies in soy prepa-
rations (ie, differing amounts of isoflavone content) and
differing dosing of soy from study to study (20-61 g/day).
Also, some studies replace animal protein with soy protein
in the diet, which could confound the studies by simulta-
neously limiting animal fat when limiting animal protein.
For example, one study replaced 2 meals with a low-calo-
rie soy-based drink and showed improvements in insulin
resistance, waist circumference, and lipid profile over a
group that simply reduced their calories.98 The beneficial
effect in the treatment group could have been due to an
increase in soy protein intake or decreased animal fat
intake, as both were different than in the control group.
To determine whether isoflavone concentration is an
important part of the metabolic effects of soy, a diet
enriched with soy nuts (high in isoflavones) vs soy protein
(low in isoflavones) was compared. The soy nut diet dem-
onstrated decreased HOMA-IR and a more favorable
effect on lipids compared with soy protein.99 A study by the
same group looked at postmenopausal women with MS
and found a decrease in the proinflammatory cytokine
profile in those women given a short-term soy nut–rich
diet (30 g/d).100 A meta-analysis of 11 studies attempted to
further clarify the importance of isoflavones vs soy protein
in its lipid effects.101 The analysis included 11 studies that
used matched amounts of isoflavone-enriched soy and
isoflavone-depleted soy protein and found that the benefi-
cial effect on lipids was lost without isoflavones. The
mechanism of the cholesterol-lowering effect of isofla-
vones is not well understood. Some attribute the effect to
the biologic similarity of isoflavones to mammalian estro-
gens, which have known cholesterol-lowering effects.102
Several meta-analyses have been published in attempt
to summarize the overall effects of soy preparations on
lipids and glucose homeostasis given the above controver-
sies. A recent meta-analysis of 41 prospective, randomized
controlled trials representing a total of 1756 participants
showed an overall benefit of soy preparations on lipid pro-
file.103 The studies were conducted from 1982 to 2004,
varied in participants ranging from 4 to 179, varied in
amount of soy content from 20 to 60 g, lasted a mean of
6 weeks, and participants were mostly women. The overall
pooled net effect of soy protein supplementation on serum
lipids was –5.26 mg/dL (95% CI = –7.14 to –3.38) for
total cholesterol, –4.25 mg/dL (95% CI = –6.00 to –2.50)
for LDL cholesterol, 0.77 mg/dL (95% CI = 0.20 to 1.34)
for HDL cholesterol, and –6.26 mg/dL (95% CI = –9.14
to 3.38) for triglycerides. The authors reported an inverse
relationship to amount of soy protein and isoflavones used
568   Nutrition in Clinical Practice / Vol. 24, No. 5, October/November 2009
and levels of serum total cholesterol, LDL cholesterol, and
triglycerides. A positive relationship was reported with
HDL cholesterol. These trends were statistically signifi-
cant in very few of the trials independently. The authors
concluded that replacing saturated fat with soy protein
had a positive effect on lipid profile. However, this still
leaves the question of whether it is soy protein that affects
the lipid profile, limiting saturated fat, or a combination of
both. Another meta-analysis of 23 studies comprising 1281
participants looked specifically at soy-containing isofla-
vones.104 Studies were selected based on diets that con-
trolled for total and saturated fats. Isoflavone concentration
varied from 3 to 185 mg with an average of 80 mg. Soy
protein with isoflavones was associated with significant
decreases in serum levels of cholesterol (by 8.5 mg/dL, or
3.77%), LDL cholesterol (by 8.1 mg/dL, or 5.25%), and
triglycerides (by 8.85 mg/dL, or 7.27%), and significant
increases in serum HDL cholesterol level (by 1.57 mg/dL,
or 3.03%). The effects were greatest in studies using >80
mg of isoflavones and in men. While isoflavone-depleted
soy proteins were indistinguishable from controls in their
effect on lipids, isolated isoflavones also had no effect on
lipids, suggesting that the isoflavones need to be in their
natural form to maintain their lipid effect.
The data from these 2 meta-analyses are consistent
with 2 other large meta-analyses.105,106 Optimal dosing is
between 20 and 40 g of soy with 50 to 80 mg of isofla-
vones. The effects on lipids are modest but would be
more profound in those individuals with a greater extent
of dyslipidemia (like in those with MS), as the majority of
the participants in the above analyses were healthy adults.
Replacing animal protein (which contains saturated fats,
such as red meat) with soy protein seems like reasonable
advice for patients motivated to try soy protein.
Dietary Fiber
Both the Mediterranean diet and the DASH diet are high
in fiber content. High intake of dietary fiber is associated
with improved insulin sensitivity, improved lipid profile,
and weight loss, making it an ideal supplement for MS.
Dietary fiber is defined as nondigestible carbohydrates
and lignins derived from plants that are not degraded in
the upper gut. Fiber can be subdivided into soluble or
insoluble forms. Insoluble fiber does not dissolve in
water, increases stool bulk, and slows gastric transit time.
This delay in transit time has metabolic consequences, as
secretion of incretin hormones and other signals for sati-
ety are altered with high intake of insoluble fiber.107,108
Soluble fiber passes to the colon and is fermented by
commensal gut bacteria into short-chain fatty acids
(SCFA) such as acetate, propionate, and butyrate.109
SCFAs enter the portal system directly rather than the
lymph system like other fatty acids and are thereby able
to suppress both liver glucose and lipid production.110
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The lipid-lowering potential of soluble fiber has
been confirmed by many high-quality studies and meta-
analyses.111-118 A randomized crossover study evaluated
the effects of a high-fiber diet (8 g/day) vs a low-fat, con-
trol diet in 68 participants with hyperlipidemia.116 The
high-fiber diet reduced serum total cholesterol by 2.1%
(P = .003), reduced serum apolipoprotein B concentration
(a surrogate marker for LDL particle number) by 2.9% (P =
.001), and reduced serum triglyceride levels by 5.2% (P =
.005), all compared with a control diet. These findings were
then confirmed in a large multicenter, randomized con-
trolled trial.112 A total of 248 patients with a serum LDL
cholesterol level between 130 and 160 mg/dL were rand-
omized to receive 5.1 g of psyllium (a form of soluble fiber
derived from the husks of the seeds of Plantago ovate) or
placebo. After 24 weeks, serum total and LDL cholesterol
levels were 4.7% and 6.7% lower, respectively, in the treat-
ment group compared with controls (P < .001). Another
study looked at differing doses of psyllium (3.4, 6.8, and
10.2 g/day) compared with placebo in 286 individuals
with LDL cholesterol levels ranging from 130 to 220
mg/dL.115 After 24 weeks, only the highest-dose group had
a significant reduction in serum LDL cholesterol level
(5.3%, P < .05), with the lower groups trending toward a
reduction. In all of these studies, the psyllium was well
tolerated, with only 3 participants withdrawing in the latter
study in the high-dose group because of GI side effects.
An inverse association with the incidence of type 2
diabetes and intake of dietary fiber has been confirmed by
prospective trials and meta-analyses.119,120 In a prospective
cohort study of 9702 mean and 15,365 women aged 35 to
65 years, dietary intake was compared with incidence of
type 2 diabetes.119 Higher cereal-fiber diets decreased the
risk of developing type 2 diabetes by 28% (95% CI = 0.56-
0.93), while fruit fiber reduced the risk by 11% (95% CI =
0.70-1.13), and vegetable fiber reduced the risk by only 7%
(95% CI = 0.74-1.17). In the same publication, the authors
performed a meta-analysis of 9 cohort studies looking at
fiber intake and incident diabetes, which confirmed their
findings showing a risk reduction of 33% in the high
cereal-fiber cohort (95% CI = 0.62-0.72) with no risk
reduction in the fruit or vegetable group. Further confirm-
ing these data, an analysis of the data from the NHS
showed a risk reduction of developing type 2 diabetes of
37% in the highest fiber intake group compared with the
lowest intake group (P < .001), after adjustments for
potential confounders, including body mass index (BMI).120
To explain the physiology behind these findings, many
studies have shown that fiber supplementation increases
insulin sensitivity in people with and without type 2 diabe-
tes.121-124 One such study used a euglycemic hyperinsuline-
mic clamp technique to determine whole-body glucose
disposal in obese participants before and after a diet of
31.2 g/day of insoluble fiber was given.123 While neuroreg-
ulatory hormones like ghrelin and adiponectin were not
changed, insulin sensitivity significantly increased. Other

studies have reproduced these data, but the precise mech-
anism of improved sensitivity is unclear.
Studies on the relationship between fiber and weight
loss have yielded mixed results.125-134 Initial epidemiologic
data support the notion that soluble fiber can contribute
to weight loss. A prospective trial looking at 27,082 U.S.
men related their dietary habits to the chance of weight
gain.133 In a multivariate analysis, an increase in whole
grain was associated with a decrease in weight gain over
8 years (P < .001). For every 20 g/day of bran fiber intake,
weight gain was reduced by 0.36 kg. In an analysis of the
NHS, 74,091 women were followed over 12 years for cor-
relations between fiber intake and weight gain.132 Those
women with the greatest intake of dietary fiber gained an
average of 1.52 kg less than those with the smallest intake
of dietary fiber (P < .0001). In the Coronary Artery Risk
Development in Young Adults study, a young cohort of
2909 patients was followed over 10 years to assess the influ-
ence of fiber intake on cardiac risk factors.129 Again, those
with the highest intake of fiber had on average 3.3 kg less
weight gain compared with the lowest intake group (P <
.001). One negative epidemiologic study out of Europe
found no association of dietary intake and weight gain in
862 men and 900 women followed for 5 years, though
weight change overall in this study was small.127
Randomized controlled trials in general have not sup-
ported the positive epidemiologic observations. A meta-
analysis of 11 trials using guar gum (insoluble fiber, dose
range 9-30 g) could find no statistically significant weight
loss compared with placebo.131 In a recent large rand-
omized controlled trial, 200 overweight or obese partici-
pants were given 4 g of insoluble fiber 2 or 3 times per
day or placebo for 16 weeks.134 Although postprandial
satiety increased in both treatment groups compared with
placebo, there was no significant difference in weight
loss. To examine the effect of supplemental soluble fiber,
another study gave women either a standard breakfast or
a breakfast supplemented with barley flour and then
recorded their food intake for the rest of the day. The
women supplemented with dietary fiber had an overall
increase in food intake compared with the controls. The
satiety mechanism seen in high-fiber food was lost in
these women merely given a supplement.128 Another ran-
domized controlled study confirmed that supplemental
fiber had no effect on hunger, satiety, and weight gain.125
Some researchers explain the difference between the epi-
demiologic studies and the clinical trials by suggesting
that fiber supplements do not have the same metabolic
effects as consuming foods rich in soluble fiber. In sup-
port of this notion, that only fiber in its natural form
confers satiety, a group of 411 women were randomized
to receive an apple, a pear, or a fiber-supplemented
cookie 3 times per day.135 After 12 weeks of follow-up, the
fruit group lost 1.22 kg (95% CI = 0.44-1.85), while the
cookie group lost a nonsignificant 0.88 kg (difference
between groups P < .001).
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The Metabolic Syndrome / Potenza, Mechanick   569
Overall, increasing fiber content in the diet has ben-
eficial effects on MS. Adding fiber supplements can lower
cholesterol and improve insulin resistance. Fiber can also
have salutary effects on achieving weight loss, but only
when consumed in its natural form as fruits, vegetables,
and whole grains.
Chromium
Chromium deficiency was initially described in 1977 in
patients receiving parenteral nutrition (PN) without sup-
plemental chromium and is characterized by the follow-
ing elements of MS: elevated fasting glucose, low serum
HDL level, hypertriglyceridemia, hypertension, and vis-
ceral obesity. Furthermore, early studies show improve-
ment in these parameters once chromium deficiency is
corrected.136 Chromium is now included in all standard
PN formulas; however, this supplement may not be
enough to correct deficiency and may only prevent defi-
ciency. Patients with protein-energy malnutrition at high
risk for nutrition deficiencies can quickly have severe
insulin resistance reversed with administration of intrave-
nous chromium.137 Chromium influences insulin sensitiv-
ity by improving insulin receptor binding, increasing
insulin receptor number, and enhancing internalization
of the receptor for further signaling.138 It exerts these
effects by binding to a now well-described low molecular
weight oligiopeptide termed chromium-binding substance
or chromodulin.139 In spite of the observations and the
trials discussed below, the American Diabetes Association
advises that “the existence of a relationship between chro-
mium picolinate and either insulin resistance or type 2
diabetes is highly uncertain.”140
Several studies have investigated supplemental chro-
mium to reverse MS. One study looked at 155 individuals
with type 2 diabetes in China (part of the world that is at
risk for chromium deficiency) and revealed a dose-
dependent fall in glucose with increasing chromium sup-
plementation, which was also reflected in longer-term
follow-up with decreases in hemoglobin A1c.141 In a study
of elderly rehabilitation patients (who are at risk for nutri-
tion deficiencies such as chromium), chromium (200
mcg twice daily) or placebo was given to 78 patients with
diabetes over 3 weeks.142 Fasting blood glucose was 150
mg/dL in the chromium group and 190 mg/dL in the con-
trol group (P < .001). Hemoglobin A1c level improved
from 8.2% to 7.6% (P < .01). Mean serum cholesterol
level also modestly decreased from 235 mg/dL to 213 mg/
dL (P < .02). A subsequent meta-analysis looked only at
healthy Western participants with type 2 diabetes (and
therefore excluded trials including populations at risk for
chromium deficiency) and found no benefit from supple-
mental chromium.143 These studies dated from 1980 to
2000 and varied differently in dosing and duration. Since
that publication, 3 more randomized controlled trials
570   Nutrition in Clinical Practice / Vol. 24, No. 5, October/November 2009
have been published looking at chromium and glucose
control—3 showing reduction of fasting glucose and 2
showing no effects.142,144-146 The positive studies were
larger, of longer duration, and included populations that
were at higher risk for deficiency.
Weight gain in individuals with type 2 diabetes may
also be affected by chromium deficiency. In a randomized
controlled study of 37 participants with type 2 diabetes
treated with sulfonylurea therapy for 3 months followed by
either 1000 mcg of chromium or placebo for 6 months,
chromium attenuated the weight gain with sulfonylurea
therapy (2.2 kg compared with 0.9 kg, P < .001).146 The
excess weight found in the control group was indeed an
increase in body fat and not lean body mass, with increases
in waist circumference of 32.5 cm in the untreated group
compared with 12.2 cm in the treated group (P < .05). A
meta-analysis of 10 trials, prior to the one described
above, studied female athletes and attempted to assess the
efficacy of chromium supplementation on body composi-
tion.147 The authors concluded that chromium supple-
mentation caused a modest weight reduction of 1.2 kg but
cautioned that 2 studies by the same author contributed
to most of the power in the analysis that showed such a
benefit. The mechanism behind chromium’s effect on fat
mass is unclear but is probably related to improved insulin
sensitivity, which results in lower circulating levels of insu-
lin and greater levels of glucagon. These alterations in
metabolism would promote lipolysis in the adipoctye,
thereby decreasing fat stores.148
Chromium supplementation is beneficial in those
people with, or at risk for, chromium deficiency. Even
though it may improve insulin action and have a favorable
effect on body composition in people with MS, its routine
use is not supported by the evidence.
Magnesium
Magnesium is present in high levels in the DASH diet and
is a vasodilator as well as a cofactor in enzymes involved
in glucose and insulin metabolism.149 Magnesium is found
in green vegetables, legumes, and whole grains. In indi-
viduals with type 2 diabetes and magnesium deficiency,
supplemental magnesium was shown to increase glycemic
control in a randomized controlled study.150 Magnesium
deficiency has also been linked to development of MS. In
a study of 535 community-living adults, those with the
highest intake of magnesium (by calculations from self-
reported food diaries) were 67% less likely to develop MS
compared with the lowest intake group (P < .001) after
adjustments for possible confounders.151 A meta-analysis
involving 286,668 people found that the relative risk of
developing type 2 diabetes with a 100 mg/day increase in
dietary magnesium intake was 0.85 (95% CI = 0.79-
0.92).152 Epidemiologic data also support the association
of magnesium deficiency with cardiovascular disease.153
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Supplementing magnesium in individuals with MS who
do not have true deficiency may not be beneficial. Analyses of
trials giving magnesium to treat hypertension have had mixed
results. One Cochrane review looked at 12 prospective, rand-
omized controlled trials of 8 weeks duration looking at the
effect of an average of 17 mmol of magnesium on blood pres-
sure in individuals with hypertension and found no effect on
systolic blood pressure.154 The authors commented that the
studies in general were of poor quality. On the other hand, a
meta-analysis of 20 trials and 1220 individuals with and with-
out hypertension found a dose-dependent relationship
between magnesium (doses between 10 and 40 mmol/day)
supplementation and reduction in blood pressure. For each
10 mmol/day increase in magnesium intake, systolic blood
pressure fell by 4.3 mm Hg (95% CI = 6.3-2.2; P < .001) and
diastolic blood pressure fell by 2.3 mm Hg (95% CI = 4.9 to
0; P = .09).155
Overall, the evidence supporting the use of magnesium
supplementation for hypertension is weak, and its use for
MS is primarily helpful in deficient states, though more
studies looking at glycemic control and magnesium supple-
mentation are warranted based on the above observations.
Traditional Chinese Medicine: Ginseng, Bitter
Melon, Green Tea, and Acupuncture
Though much of what is known about dietary inter-
ventions for MS is based on Western experiences, tradi-
tional Chinese medicine also offers putative interventions.
Traditional Chinese medicine is based on Taoist philoso-
phy and proposes that the human body contains 5 ele-
ments (metal, earth, wood, water, and fire), which are not
balanced in disease states. Herbal medications, acupunc-
ture, and massage are used to restore balance in the clini-
cal practice of Chinese medicine.156 Although a large body
of literature exists that investigates the benefits of various
Chinese herbs on MS, this part of the review will focus on
the most popular interventions used in the United States.
Saponins or ginsenosides represent some of the bio-
active substances in ginseng. These substances have clear
effects on blood pressure and blood glucose, which were
reported as early as 1921 by Chinese scientists.157 Any
given ginseng preparation may have varying amounts of
the active compound, though the most popular prepara-
tions in the United States come from Panax quinquefo-
lium (American ginseng). Experiments in the both the ob/
ob mouse (a leptin-deficient mouse model of type 2 dia-
betes) and the db/db mouse (a leptin-insensitive mouse
model of type 2 diabetes) have shown that root and berry
extract from American ginseng can increase insulin-
mediated glucose disposal as much as 2-fold, with berry
extract being more potent than root extract.157-159
Furthermore, db/db mice treated with ginseng extract
reduce their adipocyte mass by 50%.160 In a randomized
controlled study, 36 patients with diabetes were treated
with 200 mg of ginseng extract or placebo.157 There were

significant improvements in mood and physical performance
by questionnaire in the treatment group, along with small
but significant improvements in fasting glucose.161
Another study showed no effect on postprandial hypergly-
cemia in nondiabetic patients, but a 17% reduction of the
same parameter in diabetic patients treated with ginseng
extract compared with placebo (P < .05), suggesting a
more profound effect on those with underlying disease.162
A more recent small randomized controlled trial repli-
cated these data and showed that treatment with ginseng
extract for 12 weeks decreased both fasting and postpran-
dial glucose indices by 33% compared with placebo (P <
.05).163 These trials showed no effect on blood pressure or
renal function. Another trial looked at the same parame-
ters in hypertensive patients over 3 months and found no
effect.164 Ginseng seems to directly affect the pancreatic
β-cell with increases in insulin biosynthesis and preven-
tion of apoptosis in in vitro experiments.165,166
Animal models of lipid metabolism suggest that gin-
senosides may play a role in regulation of lipid metabo-
lism and weight gain. Obese animals fed a high-fat diet,
and also given ginseng extract, were able to reduce food
intake with corresponding rising leptin levels and attenu-
ate weight gain compared with those animals not given
ginseng.167,168 The mechanism of these effects is not clear,
though some suggest it is via ginseng’s ability to inhibit
the peroxisome proliferator-activated receptor-α.169 No
human studies support this assertion.
Bitter melon (Momordica charantia) is a popular herb
in China that has been used for more than 600 years to
treat various diseases. Bitter melon is known for its so-
called “plant insulin,” a polypeptide with 166 residues that
exerts a potent hypoglycemic effect on injection (which is
lost on oral administration).170 Other substances in bitter
melon are likely responsible for its hypoglycemic effect on
oral administration in a variety of animal models.171-173
Bitter melon extract has antioxidant effects and has been
shown to prevent β-cell apoptosis in streptozotocin-treated
mice (which then develop diabetes).174 Additionally, the
extract may act though inhibition of glucose absorption in
the brush border of the jejunum.175 Clinical experience
with the extract is limited and has conflicting results. A
10-year-old study of 100 people with type 2 diabetes
looked at the effect of bitter melon juice on fasting and
postprandial blood sugars. A positive effect was seen in 86
cases, which confirmed a similar study done more than 20
years ago.176,177 A more recent randomized controlled trial
using a capsule preparation looked at 40 people with type
2 diabetes and found no statistical differences in glucose
control, although the authors comment that their study
was underpowered.178 There are insufficient human data
to recommend ginseng or bitter melon use to treat any
aspect of MS so far, but because of positive animal studies
and some initial positive findings in small clinical trials,
more investigation is warranted.
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The Metabolic Syndrome / Potenza, Mechanick   571
Green tea, made from the leaves of Cammellia sinen-
sis, contains many bioactive components that could
potentially affect elements of MS, the most significant of
which are catechin polyphenols and caffeine.179 These 2
main constituents in green tea act in concert to enhance
the stimulatory effect of norepinephrine. Tea catechins
inhibit catechol-o-methyl-transferase, an enzyme that
degrades epinephrine.180 Caffeine inhibits phosphodieste-
rase, increasing cyclic adenosine monophosphate, and
thereby enhancing the activity of certain excitatory neu-
rotransmitters. It also works primarily as an antagonist at
the adenosine receptor, impairing the presynaptic inhibi-
tory function of adenosine and increasing excitatory neu-
rotransmitter release.180 In an attempt to prove that both
caffeine and tea catechins are important bioactive mole-
cules in green tea, one study randomized participants to
receive green tea (50 mg of caffeine, 90 mg epigallocate-
chin gallate), caffeine, or placebo. Green tea promoted fat
oxidation and thermogenesis beyond that explained by
caffeine alone.181
Clinical trials have investigated green tea for possible
weight loss and glucose-lowering effects with limited suc-
cess. In a retrospective cohort study of 17,413 Japanese
adults, those who drank more than 6 cups of green tea
per day were 33% less likely to develop type 2 diabetes
than those who drank no green tea.182 In a randomized
crossover trial, 60 participants with impaired glucose tol-
erance were given 456 mg of catechins or placebo for 2
months. Hemoglobin A1c values fell by 0.4% (P < .03)
with no effects on weight or blood pressure.183 Another
randomized controlled trial did not replicate these results
when 49 individuals with type 2 diabetes were given 0,
375, or 750 mg of green tea extract. Hemoglobin A1c
values increased across all of the groups by 0.3 to 0.5.184
Another negative study showed no change in blood glu-
cose levels, levels of inflammatory cytokines, or changes
in arterial wall stiffness after individuals with diabetes
were treated with green tea extract.185 To look at green
tea’s effects on weight, moderately obese participants
were treated with green tea extract (caffeine 150 mg/day,
and catechins 375 mg/day). Participants experienced
decreases in body weight (4.6%) and waist circumference
(4.5%).186 A randomized controlled trial replicated these
findings. Healthy men were randomized to receive 690
mg catechins from green tea or 22 mg of catechins for
control. After 12 weeks, BMI, waist circumference, and
subcutaneous fat deposits were significantly lower
in the treatment group compared with the control.187
Another study looked at green tea’s effect at preventing
weight gain after 7.5% body weight loss.188 Not only did
green tea fail to prevent regain of weight, but those indi-
viduals with the highest levels of caffeine intake prior to
the study actually had the highest amount of weight
regain during treatment with green tea. Perhaps chronic
caffeine use blunts the weight-loss potential of green tea.
572   Nutrition in Clinical Practice / Vol. 24, No. 5, October/November 2009
Overall, the data are stronger supporting green tea for
weight loss than for improving glycemic control, though
green tea cannot be recommended to patients until fur-
ther evidence is available.
Acupuncture has been proven effective in a variety of
different clinical scenarios. Several randomized control-
led trials have been published looking at acupuncture’s
efficacy in weight loss in recent years.189 In a recent meta-
analysis that included 31 of these trials, with 3013 indi-
vidual represented, the efficacy of acupuncture for weight
loss was examined by separating those trials with diet
alone as control and those trials with sham acupuncture
as control.189 Compared with lifestyle, acupuncture was
associated with an additional average weight loss of 1.72 kg.
Acupuncture reduced body weight of 1.56 kg on average
compared with sham procedures. The authors commented
that many of the trials included had poor methodologies
and were often not completely blinded. Although the
results were promising, more well-designed long-term
studies are necessary to confirm those results.
Conclusion
MS is an inflammatory state described clinically by the
presence of several metabolic disturbances and accounts
for much of the cardiovascular disease seen in the general
population. It is common in the United States, and its
impact on public health is profound. Researchers are just
beginning to understand the impact of dietary interven-
tion in reversing the syndrome, and many treatments with
dietary origins that once were considered CAM, such as
fiber, ω-3 fatty acids, resveratrol, and soy products, are
becoming mainstream because of the emergence of qual-
ity evidence. Though much of the data behind the more
unconventional CAM treatments such as traditional
Chinese medicine, cinnamon, and trace elements are
often conflicting and of lower quality, all clinicians must
be aware of the potential of these treatments. These sub-
stances exert their actions on MS by virtue of their anti-
inflammatory properties and effects on the β-cell and
insulin signaling. Many of these substances have been
shown to modulate intermediary metabolism and alter
visceral “sick fat,” which is considered the primary cause
of MS. As more CAM therapies become conventional
with the emergence of additional quality evidence, the
clinician must be ready to understand and incorporate
into practice these new treatment modalities.
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