Phytomedicine 23 (2016) 11341144

Contents lists available at ScienceDirect

Phytomedicine
journal homepage: www.elsevier.com/locate/phymed

Role of phytochemicals in the management of metabolic syndrome

Arrigo F.G. Cicero, Alessandro Colletti
Diseases Research Center, Medicine & Surgery Dept., Alma Mater Studiorum Atherosclerosis and Metabolic University of Bologna, Bologna, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Background: The World Health Organization (WHO) for some years has been focusing on what is now com-
Received 10 August 2015 monly referred to as an "epidemic of obesity and diabetes" ("diabesity"): behind this outbreak, there are
Revised 14 November 2015
several risk factors grouped in what is called "metabolic syndrome" (MetS). The basis of this "epidemic" is
Accepted 19 November 2015
either a diet too often characterized by excessive consumption of saturated and trans-esteried fatty acids,
simple sugars and salt, either a sedentary lifestyle.
Keywords: Purpose: The aim of this review is to focus on the phytochemicals that have a more positive effect on the
Metabolic syndrome treatment and/or prevention of MetS.
Hypertension Chapters: Treatment strategies for MetS include pharmacologic and non-pharmacologic options, with vary-
Dyslipidaemia
ing degrees of success rate. The rst is indicated for patients with high cardiovascular risk, while the second
Nutraceuticals
one is the most cost-effective preventive approach for subjects with borderline parameters and for patients
Insulin resistance
Obesity intolerant to pharmacological therapy. MetS non-pharmacological treatments could involve the use of nu-
traceuticals, most of which has plant origins (phytochemicals), associated with lifestyle improvement. The
chapter will discuss the available evidence on soluble bres from psyllium and other sources, cinnamalde-
hyde, cinnamic acid and other cinnamon phytochemicals, berberine, corosolic acid from banaba, charantin
from bitter gourd, catechins and avonols from green tea and cocoa. Vegetable omega-3 polyunsaturated
fatty acids, alliin from garlic, soy peptides, and curcumin from curcuma longa.
Conclusion: Some nutraceuticals, when adequately dosed, should improve a number of the MetS components.
2015 Elsevier GmbH. All rights reserved.

Introduction The most commonly accepted denition of MetS includes three

Metabolic syndrome (MetS) is a clinical entity substantially het-
erogeneous, represented by the coexistence of multiple alterations,
in particular abdominal obesity, insulin-resistance, hypertension and
dyslipidaemia (high TG and low HDL-C values), associated with an in-
creased risk to develop cardiovascular diseases, type 2 diabetes and
for all-cause mortality (Wu et al. 2010).
Abbreviations: ACE, angiotensin converting enzyme; ALA, alpha-linoleic acid;
AMPK, AMP-activated protein kinase; DHA, docosahexaenoic acid; EPA, eicosapen-
taenoic acid; FPG, fasting plasma glucose; GLP-1, glucagon like peptide-1; GLUT, glu-
cose transporter; HbA1c, glycated haemoglobin; HBF-4-alpha, hepatic nuclear factor
4-alpha, HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein
cholesterol; MAPK, mitogen-activated protein kinase; MetS, metabolic syndrome; NF-
kB, nuclear factor Kappa-B; NO, nitric oxide; OGTT, 75-g glucose tolerance test; PCSK9,
proprotein convertase subtilisin/kexin type 9; PGG, penta-O-galloyl-glucopyranose;
PPAR, peroxisome proliferator-activated receptor; PUFAs, polyunsaturated fatty acids;
RBP-4, retinol binding protein-4; TG, triglcyerides; TGF-beta, transforming growth
factor-beta; WMD, weighted mean difference.
Corresponding author at SantOrsola-Malpighi University Hospital, Building 2 IV
Floor, Via Albertoni 15, 40138 Bologna, Italy. Tel.: +39 512142224; fax: +39 51390646.
E-mail address: arrigo.cicero@unibo.it, afgcicero@gmail.com (A.F.G. Cicero).
or more of the following signs: waist circumference > 102 cm (male)
or > 88 cm (female), TG > 1.7 mmol/l, HDL cholesterol < 1.0 mmol/l
(male) or <1.3 mmol/l (female), blood pressure > 135/85 mmHg on
medication, fasting plasma glucose (FPG) > 6.1 mmol/l (Malik et al.
2004; Grundy et al. 2005).
The cornerstone in the treatment of MetS is based on an improve-
ment of lifestyle, promoting physical activity and a balanced low-
energy diet, which is also the most cost-effective approach to this
condition. When life-style modication has improved the MetS fea-
tures, but further improvement is required, before to begin a (often
multiple) pharmacological therapy, some phytochemicals could be
also useful tools in the treatment of one or more MetS components
(Table 1) (Graf et al. 2010). In some cases, the use of nutraceuticals
could also be considered in already pharmacologically treated pa-
tients in support to drugs when the therapeutic target has not been
reached (Grundy et al. 2005; NCEP expert panel 2001).
Giving the large number of phytochemicals with proposed pos-
itive effects on Mets, the purpose of this review is to analyse
those that have had a demonstrated impact on more than one
MetS components in clinical trials, and in particular those having
an effect on insulin-resistance, the pathophysiological background
of MetS.

http://dx.doi.org/10.1016/j.phymed.2015.11.009
0944-7113/ 2015 Elsevier GmbH. All rights reserved.
Table 1
Clinical studies on nutraceuticals in diabetes mellitus and metabolic syndrome.
Reference Intervention
Vitamin C (ascorbic acid)
Chen et al. (2006) Vitamin C (800 mg/day)
Dakhale et al. (2011) Vitamin C (1 g/day) with metformin or
placebo with metformin
Vitamin E ( -tocopherol)
The Heart Outcomes Prevention Vitamin E (400 IU daily) or placebo and
Evaluation Study Investigators (20 0 0) an angiotensin-convertingenzyme
inhibitor (ramipril) or placebo
Sesso et al. (2008) Vitamin E (400 IU every other day) vs.
placebo or Vitamin C (500 mg daily)
vs. placebo
Vitamin D
Pittas et al. (2007) Calcium citrate (500 mg) + vitamin D3
(700 IU daily)
Pilz et al. (2015) Vitamin D3 (2800 IU daily as oily drops)
or placebo
Zhou et al. (2014) Vitamin D3 ( 0.50 g daily)
Flavonoids
Dower et al. (2015) Epicatechin (100 mg/d),
quercetin-3-glucoside (160 mg/d) or
placebo
West et al. (2014) Active group: 37 g/d of dark chocolate
and a sugar-free cocoa beverage (total
cocoa = 22 g/d, total avanols (TF) =
814 mg/d); control group:
low-avanol chocolate bar and a
cocoa-free beverage with no added
sugar (TF = 3 mg/d)
Mink et al. (2007) Total avonoids intake: 0.6133.1
mg/day 133.2201.8 mg/day
201.9281.9 mg/day 282.0425.2
mg/day 425.33524.4 mg/day
Omega-3 fatty acids
Tsitouras et al. (2008) Fatty sh (720 g/week) + sardine oil (15
mL/day; 45 g n-3) or olive and corn
oil
Participants (n)
Subjects with T2DM with
low plasma vitamin C
(<40 M) (32)
Type 2 DM subjects (70)
Subjects with high risk for
cardiovascular disease, in
particular with
cardiovascular disease or
diabetes in addition to
one other risk factor.
(9541)
Male physicians (14,641)
Non diabetic Caucasian
adults aged > 65 years
(314)
Subjects with arterial
hypertension and
25-hydroxyvitamin D
levels below 30 ng/mL
(200)
Subjects with T2DM (164) 12 weeks
Subjects with BP between
125-160 mm Hg (37)
Overweight adults(30)
Postmenopausal women 16 years
(34,489)
Healthy men and women 8 weeks
(12)
Duration of intervention Outcome measures Main results
4 weeks FPG, FPI, Forearm blood No signicant effect
ow
12 weeks FPG, PPBG, HBA1c Signicant reduction in all parameters
4,5 years Major CV events No apparent effect on cardiovascular
outcomes.
A.F.G. Cicero, A. Colletti / Phytomedicine 23 (2016) 11341144
10 years CV events The supplementation doesnt reduce the
risk of major CV events
3 years FPG, IS The supplementation attenuates the
increases in glycemia and IR
8 weeks BP, Cardiovascular risk No signicant effects on blood pressure
factors and CV risk factors
BMI, WC, FPG, FPI, HbA1C, Signicant improvement in all
HOMA-IR, IR parameters
4 weeks Vascular function and Epicatechin improved FPI and IR. There
cardiometabolic health were not other signicant results
neither with the supplementation
with epicatechin either with
quercetin-3-glucoside.
4 weeks CVD risk Endothelial Enhanced vasodilation and signicant
function reductions in arterial stiffness in
women.
CV and all-cause mortality Reduced risk in death due to CV and all
causes
FPG, Insulin concentration No change in FPG and insulin Improved
IR in 3 h OGTT
(continued on next page)
1135
 1136
Table 1 (continued)

Reference Intervention Participants (n) Duration of intervention Outcome measures Main results

Oh et al. (2014) n-3 fatty acids (1, 2 or 4 g daily) or Healthy subjects and 2 months Tryglicerides, Insulin Signicantly decreased triglycerides and
placebo. patients with metabolic sensitivity improved ow-mediated dilation. No
syndrome, T2DM (44) improvements of acute-phase
reactants and insulin sensitivity
Farsi et al. (2014) n-3 fatty acids (4 g daily) or placebo Patients with T2DM (44) 10 weeks Non-esteried fatty acid Improved insulin sensitivity, decreased
concentration, insulin non-esteried fatty acid
sensitivity and concentrations.
resistance, glucose and
lipid metabolism
Chromium
Kleefstra et al. (2006) Chromium picolinate (500 or 1000 Type 2 DM subjects with 6 months Weight, BP, HbA1c lipid No differences between the three groups
g/day) or placebo HbA1C8%, and age <75 prole
years (46)
Magnesium
Rodrguez-Moran (2014) MgCl2 5% solution (equivalent to 382 mg Metabolically obese, 4 months BP, HOMA-IR, FG, Improved the metabolic prole and

A.F.G. Cicero, A. Colletti / Phytomedicine 23 (2016) 11341144

of magnesium) or placebo normal-weight triglycerides blood pressure
individuals (47)
Zinc plus antioxidants formulation
Evans and Henshaw (2008) Zinc sulfate 200 mg daily Subjects from the general Risk of progression to Modest benet
population with AMD at advanced AMD
different stages (969)
-Lipoic acid
Jacob et al. (1999) 600 mg/day 1200 mg/day 1800 mg/day Subjects with T2DM (72) 4 weeks FPG, IS Increase in IS with 600 mg/day may be
the maximum effective dose
Huerta et al. (2015) EPA (1.3 g/d), -lipoic acid (0.3 g/d), Overweight/obese women 10 weeks Body weight, Promote body weight loss
EPA+ -lipoic acid (1.3 g/d+0.3 g/d (174) anthropometric
measurements, body
composition,
Phytoestrogens
Ikeda et al. (2006) Fermented Soy Bean (40 g of natto) Pre- and postmenopausal 3 years Weight BMI No effects
women (944)
Acharjee (2015) Active group: diet with 0.5 cup of soy Postmenopausal women 8 weeks BP, lipid levels, adhesion In women with MetS signicant
nuts (25 g of soy protein and 101 mg (60) molecules and reductions in diastolic BP, TG,
of aglycone isoavones) that replaced inammatory markers C-reactive protein and sICAM
25 g of nonsoy protein daily. Control
group: diet alone.
Dietary ber supplements (soluble)
Wolf et al. (2003) OGTT (50 g of available carbohydrate Healthy subjects (30) Baseline-adjusted peak The peak of glucose response is reduced
from maltodextrin and white bread) glucose response with guar gum and increased with
or the same meal with either 5 g of fructose
guar gum (3.6 g galactomannan), 5 g
of fructose, or 5 g guar gum + 5 g of
fructose
DallAlba (2013) Partially hydrolysed guar gum (10 g Patients with T2DM (44) 6 weeks CV risk factors Reduced WC, HbA1c, UAE and serum
daily) trans-fatty acids (FA)
Dietary ber supplements (insoluble)
Gruendel et al. (2007) 200 mL water w/50 g glucose and 5, 10, Healthy subjects (20) Plasma glucose Serum Increase in PPBG and insulin response
or 20 g carob ber insulin with 10 g of carob ber (no further
increase with 20 g)
BMI, body mass index; BP, blood pressure; FPG, fasting plasma glucose; FPI, fasting plasma insulin, OGTT, oral glucose tolerance test; , PPBG, post prandial plasma glucose, DM, diabetes mellitus; CV, cardiovascular; IR, insulin
resistance; IS, insulin sensitivity; AMI, acute myocardial infarction; AMD, age-related macular degeneration, UAE= 24 h urinary albumin excretion, WC, waist circumference.
 A.F.G. Cicero, A. Colletti / Phytomedicine 23 (2016) 11341144
Data selection
A systematic search strategy was developed to identify trials in
both MEDLINE (National Library of Medicine, Bethesda, MD; January
1970 to May 2015) and the Cochrane Register of Controlled Trials (The
Cochrane Collaboration, Oxford, UK). The terms nutraceuticals di-
etary supplements, herbal drug, insulin-resistance, metabolic syn-
drome, diabetes, dyslipidaemia, hypertension and obesity were
incorporated into an electronic search strategy. The bibliographies of
all identied studies and review articles were reviewed to look for ad-
ditional studies of interest. The authors reviewed all of the citations
retrieved from the electronic search to identify potentially relevant
articles for this review. We excluded in vitro data and animal studies
because focusing on human data, in order to limit our report to phy-
tochemicals and nutraceutical for which safety and tolerability in hu-
mans are already known. So, we preferably selected papers reporting
recent comprehensive reviews or meta-analyses, or original clinical
trials on substance with action on at least two or more components
of MetS at the same time.
Soluble bres from psyllium and other sources
Dietary bres with signicant metabolic effect are the soluble
ones (NCEP expert panel 2001). Psyllium husk has maybe the largest
scientic evidence of ecacy. Although true psyllium comes from
Plantago psyllium, the husks and seeds of Plantago ovata (Plantagi-
naceae) are commonly referred to as psyllium (Petchetti et al. 2007).
Psyllium is one of the most widely used bre supplements because
it is reasonably cheap and is better tolerated than other bre sup-
plements (Pal and Radavelli-Bagatini 2012). Psyllium has mild lipid-
lowering, anti-obesity, anti-diabetic and anti-hypertensive effects in
humans (Cicero et al. 2010).
In humans, soluble bres, and in particular psyllium husk, reduce
the plasma LDL-cholesterol level by decreasing bowel cholesterol ab-
sorption and increasing the fractional turnover of both chenodeoxy-
cholic acid and cholic acids (Everson et al. 1992). Animal studies also
suggest that psyllium increases activity of cholesterol 7-alpha hy-
droxylase, the rate-limiting enzyme for bile acid synthesis, more than
twice than cellulose or oat bran and pectin (Vergara-Jimenez et al.
1998), but this effect has never been adequately investigated in hu-
mans.
Different meta-analyses suggest that psyllium supplementation
has a mild but signicant dose- and time-dependent cholesterol-
lowering effect in hypercholesterolemic patients, with a mean de-
crease in LDL-cholesterolemia of 7% for 10 g/d of supplemented bre,
without signicant effect on other lipid fractions (Wei et al. 2009).
Psyllium also increases the lipid-lowering ecacy of bile acid se-
questrant drugs (even reducing their bowel side effects), phytosterols
(Cicero et al. 2014), and statins (Agrawal et al. 2007).
Psyllium husk and other soluble bres have also a positive global
impact on post-prandial glycaemia and other insulin-resistance re-
lated parameters (Bajorek and Morello 2010).
Randomized clinical studies also showed that psyllium has signif-
icant benecial effects on both systolic and diastolic blood pressures
with doses of 3.5 g t.i.d. taken 20 mins before two main meals (Cicero
et al. 2007). It was also shown to improve vascular function measured
through augmentation index (Pal et al. 2012). Its effect on weight re-
duction is encouraging, probably because of its positive effect on sati-
ety and decreased intestinal absorption, but more conrming clinical
data are needed (Pittler and Ernst 2004).
All the available trials and meta-analysis conclude for an overall
safety of psyllium supplements. However, it could have transient gas-
trointestinal side effects which are usually not severe and only mildly
decrease compliance to treatment, especially when micronized bre
is used (Cicero et al. 2012). Entire seeds, used for the treatment of
constipation, did not demonstrate a lipid-lowering action and they
1137
could exacerbate diverticulitis in patients affected by chronic diver-
ticulosis.
A main safety concern about soluble bres use as cholesterol-
lowering agents is the risk of drug interaction that regards oral antidi-
abetic drug, digoxin, warfarin, lithium, iron, oral steroids, tricyclic an-
tidepressants, carbamazepine and other molecules (Mechanick et al.
2003).
Other soluble bres with positive effects on more than one MetS
component are guar gum, fenugreek, chitosan and glucomannan.
The dietary bre guar gum has benecial effects on dyslipidaemia,
insulino-resistance and obesity in both humans and animals (Den
Besten et al. 2015). In mice, the intake of guar gum with the diet de-
creased the markers of MetS (body weight, adipose weight, triglyc-
erides, glucose and insulin levels and HOMA-IR) in a dose-dependent
manner. An important role have been suggested to be played by the
short-chain fatty acids, that act through a signalling cascade that in-
hibits the peroxisome proliferator-activated receptor and that ac-
tivates AMP-activated protein kinase (Den Besten et al. 2014). In hu-
mans, diets enriched suciently in guar gum may improve overall
glycaemic control in type 2 diabetes mellitus and increase satiety
(Mello and Laaksonen 2009). Furthermore, a randomized controlled
clinical trial demonstrated that guar gum has an anti-hypertensive,
lipid-lowering and hypoglycaemic effect, supporting a role for guar
in the treatment of the MetS (Landin et al. 1992).
Dietary bre from fenugreek (Trigonella foenum-graecum) blunts
glucose and lipids after a meal and regulates the production of
cholesterol in the liver, but some interesting central metabolic effects
are also under study (Roberts 2011). Chitosan, a deacetylated chitin,
is associated to a short-term improvement in body weight and blood
pressure (Jull et al. 2008), plasma lipids (Choi et al. 2012) and insulin-
resistance (Hernndez-Gonzlez et al. 2010), as well. Moreover, the
intake of glucomannan, in a meta-analysis of randomized clinical tri-
als, signicantly lowered TG (weighted mean difference (WMD):
11.08 mg/dl; 95% CI: 22.07, 0.09), body weight (WMD: 0.79 kg;
95% CI: 1.53, 0.05), and fasting plasma glucose (WMD: 7.44 mg/dl;
95% CI: 14.16, 0.72), but not blood pressure (Sood et al. 2008).
Cinnamaldehyde, cinnamic acid and other cinnamon
phytochemicals
Cinnamon (Cinnamon zeylanicum) is a very old spice and several
cultural practices have been using it for centuries. In addition to
its culinary uses, cinnamon has a rising popularity due to its stated
health benets (Varker et al. 2012). Out of the large number of cin-
namon species available, Cinnamomum aromaticum (Cassia) and Cin-
namomum zeylanicum have been subjected to extensive research.
Cinnamon primarily contains vital oils and other derivatives, such
as cinnamaldehyde, cinnamic acid and cinnamate (Rao and Gan
2014).
In vitro and in vivo available evidence indicates that cinnamon
may have multiple health benets, mainly in relation to glucose-
and lipid-lowering activity. Furthermore, the therapeutic potential of
cinnamon is brought about by its anti-microbial, anti-fungal, antivi-
ral, anti-oxidant, anti-tumour, blood pressure-lowering, and gastro-
protective properties (Bandara et al. 2012).
Studies carried out on streptozotocin-induced diabetic rats show
that oral intake of cinnamon reversibly and competitively inhibits
alpha-glucosidase enzyme and improves postprandial hypergly-
caemia (Mohamed Sham Shihabudeen et al. 2011). Cinnamaldehyde
administration to diabetic rats for 2 months signicantly improves
muscle and hepatic glycogen content; moreover it increases glucose
uptake through GLUT-4 translocation in peripheral tissues (Anand
et al. 2010). Cinnamic acid also reduces bloodglucose levels in
a dose-dependent manner in non-obese type 2 diabetic rats: the
improvement by 10 mg/kg of cinnamic acid has been comparable to
that of the sulphonylurea glibenclamide (5 mg/kg); furthermore, in
1138 A.F.G. Cicero, A. Colletti / Phytomedicine 23 (2016) 11341144
vitro it signicantly enhances glucose-stimulated insulin secretion in
isolated pancreas islets (Hazur et al. 2015).
Cinnamon may also improve insulin resistance by preventing
and reversing impairments in insulin signalling in skeletal mus-
cle and adipose tissue, such as increasing the expression of perox-
isome proliferator-activated receptor (PPAR)-gamma, genes coding
for adipokines, increased glucose transporter (GLUT) -1 mRNA lev-
els, meanwhile decreasing the expression of further genes encoding
insulin-signalling pathway proteins (Kim and Choung 2010;Cao et al.
2010). Moreover it can act as a dual activator of PPAR-gamma and
alpha, and may be an alternative to PPAR-gamma activator in manag-
ing obesity-related diabetes and hyperlipidaemia (Sheng et al. 2008).
PPAR-related mechanisms account for antiadipogenic effects of cin-
namaldehyde, as well (Huang et al. 2011).
Moreover, together with cinnamaldehyde, cinnamon polyphenols
are active in increasing GLUT-4 levels, insulin receptor- (IR) beta and
tristetraprolin (Cao et al. 2007).
Several phenolic compounds, such as catechin, epicatechin, and
procyanidin B2, and phenol polymers identied from the subfrac-
tions of aqueous cinnamon extract has shown signicant inhibitory
effects on the formation of advanced glycation end-products, sug-
gesting a potential in the prevention of diabetes complications (Peng
et al. 2008).
However, it is not yet clear which cinnamon active components
have the higher bioavailability in humans.
In a recent meta-analysis of randomized clinical trials including
435 patients enrolled in trials with follow-up between 40 days and
4 months and doses ranging from 1 g to 6 g per day, a signicant
decrease in mean HbA1c (0.09%; 95% CI was 0.040.14) and mean
FPG (0.84 mmol/l; 95% CI 0.661.02) has been observed (Akilen et al.
2012). Similar data have been conrmed also in prediabetic subjects
(Davis and Yokoyama 2011).
Positive effects of cinnamon on fasting TG and HDL cholesterol,
and postprandial hypertriglyceridemia have also been conrmed in
animal models (Qin et al. 2009) and diabetic patients (Khan et al.
2003).
Blood pressure has been also reduced by cinnamon treatment
in diabetic patients (Akilen et al. 2010;Wainstein et al. 2011). Cin-
namaldehyde also averts the progress of hypertension in types 1 and
2 diabetes by abridging vascular contractility (El-Bassossy et al. 2011).
In animal studies the median lethal dose (LD50) of cinnamalde-
hyde could not be obtained even at 20 times (0.4 g/kg bw) of its ef-
fective dose, showing a high margin of safety (Ranasinghe et al. 2012),
conrmed by the high tolerability shown in the available clinical tri-
als (Akilen et al. 2012; Davis and Yokoyama 2011).
Berberine
Berberine is a quaternary plant ammonium salt extract, which
has lipid-lowering, hypoglycaemic, anti-inammatory and anti-
hypertensive effects, beyond a low systemic bioavailability (Cicero
and Ertek 2009).
Berberine stabilizes the mRNA of liver LDL receptor (by the ac-
tivation of AMP-activated protein kinase (AMPK), the inhibition of
mitogen-activated protein kinase MAPK) and modulatory effects on
PPAR-gamma and alpha (Brusq et al. 2006). The most relevant mecha-
nism of action of berberine is however the inhibition of the transcrip-
tion of the mRNA encoding the proprotein convertase subtilisin/kexin
type 9 (PCSK9): it is an enzyme which facilitates the detachment of
the hepatic LDL receptor from the cell surface to the lysosomes where
it is degraded(Cameron et al. 2008).
Patients with mixed hyperlipidaemia treated with berberine ex-
perienced a mean reduction of 25% in LDL and TG levels, by using
doses of 50 0150 0 mg daily (Zhang et al. 2008; Yin et al. 2008a).
Berberine has also an insulin-sensitizer effect comparable to
that of metformin, through a mechanism involving retinol binding
protein-4 (RBP-4) (Zhang et al. 2008) and GLUT-1(Kim et al. 2007)
and an insulinotropic effect different from sulfonylureas by increas-
ing both mRNA expression of hepatic nuclear factor 4-alpha (HNF-4-
alpha) and glucokinase activity (Wang et al. 2008). Moreover it in-
creases the levels of glucagon like peptide-1 (GLP-1), acting directly
on pancreas (Yin et al. 2008b).
A recent meta-analysis conrmed the lipid-lowering power
of berberine, with an average reduction in total cholesterol of
0.61 mmol/l, TG of 0.50 mmol/l and LDL cholesterol of 0.65 mmol/l
(Dong et al. 2013).
Standard doses of berberine (50 010 0 0 mg/day) are usually well
tolerated and adverse reactions are rare and mild (mainly gas-
trointestinal discomfort). On the contrary, high doses (more than
10 0 0 mg/day) have been associated to arterial hypotension, dys-
pnoea, u-like symptoms, gastrointestinal discomfort, constipation
and cardiac damage (Derosa et al. 2012; Vuddanda et al. 2010).
The main concerns are about berberine interactions: berberine
displaces bilirubin from albumin about ten-fold more than phenylbu-
tazone, thus it should be avoided in jaundiced infants and pregnant
women (Chan 1993). Berberine also displaces warfarin, thiopental
and tolbutamide from their protein binding sites, increasing their
plasma levels (Tan et al. 2002). Meanwhile, it can markedly increase
the blood levels of cyclosporine A by the inhibition of the cytochrome
P450 3A4 in the liver and of the P-glycoprotein in the gut wall and
by increasing the gastric emptying time, thus causing its increased
bioavailability and reduced metabolism (Xin et al. 2006).Therefore,
berberine should not be used in patients assuming drugs with nar-
row therapeutic range.
Corosolic acid from banaba
Lagerstroemia speciosa, in Philippines folk medicine known as ba-
naba, seems to have anti-diabetic and anti-obesity effects (Klein
et al. 2007). Although its mechanism of action is still not clear, the
increase of cellular uptake of glucose, the inhibition of the hydrol-
ysis of sucrose and starches, the decreased gluconeogenesis and the
regulation of lipid metabolism, mediated by PPAR, MAPK, nuclear fac-
tor kappa-B (NF- B) and other transduction signal factors, could be
responsible for its effects (Stohs et al. 2012). The main active com-
ponents of banaba extract may be corosolic acid, ellagitannins, tan-
nic acid and penta-O-galloyl-glucopyranose (PGG) (Liu et al. 2005;
Saumya and Basha 2011). The bioavailability of corosolic acid in hu-
mans has not yet investigated.
In mice, banaba suppresses blood glucose elevation and plasma
total cholesterol (Kakuda et al. 1996), decreases hepatic lipid content
and body weight (Suzuki et al. 1999). Moreover, banaba extract in-
hibits adipocyte differentiation in preadipocytes in a dose-dependent
manner (Liu et al. 2001).
In humans, the antidiabetic activity of a banaba extract (Kouzi
et al. 2015), standardized to 1% corosolic acid, has been examined
and a 30% decrease in blood glucose levels has been reported after 2
weeks administration (Judy et al. 2003). In another study, 31 subjects
has taken 10 mg of corosolic acid or placebo, 5 mins before an oral
75-g glucose tolerance test (OGTT) in a double-blind and cross-over
design: corosolic acid treatment subjects has shown lower glucose
levels from 60 min until 120 min and have reached statistical signif-
icance at 90 min (Fukushima et al. 2006). Overall, controlled human
studies and animal data reported no adverse effects when using this
compound, even if effects on other components of the MetS than FPG
and post-prandial glycaemia have yet to be assessed in humans.
There is strong evidence that these effects are determined by
both corosolic acid and ellagitannins of banaba and also valoneic
and oleanolic acids have anti-hyperglycaemic properties (Miura et al.
2012). However further clinical trials are needed to evaluate their ef-
fectiveness and tolerability in humans, in particular focusing on dose-
dependent effects of corosolic acid and banaba.
 A.F.G. Cicero, A. Colletti / Phytomedicine 23 (2016) 11341144
Charantin from bitter gourd
Bitter gourd (Momordica charantia L.) is a common tropical veg-
etable that has been used in traditional or folk medicine to treat dia-
betes (Chaturvedi 2012).
In mice, M. charantia (200 mg/kg/day of charantin-rich extract of
M. charantia for 8 weeks) has potential for increasing insulin sensi-
tivity in animals with type 2 diabetes mellitus more than protecting
the ones with type 1 diabetes against -cell dysfunction (Wang et al.
2014).
A study considering subjects with MetS has shown that the 12%
of them no more responded to the diagnostic criteria after 7 weeks
treatment with 4.8 g/d of lyophilized bitter gourd, mainly because of
an improving effect on FPG and waist circumference (Tsai et al. 2012).
Bitter gourd 2 g/day had a modest hypoglycaemic effect among
patients with newly diagnosed type 2 diabetes when compared to
that of metformin 10 0 0 mg/day (Fuangchan et al. 2011), but more
ecacious than rosiglitazone in the global management of type 2 di-
abetes (Huang et al. 2011).
A clinical trial controlled with placebo has examined the effects of
the association of bitter gourd with other nutraceuticals, in particular
red yeast rice, chlorella, soy protein, and licorice, and have evaluated
their effectiveness in subjects with MetS, which have received the
active treatment or placebo for 12 weeks: the plant extractives has
shown to be effective in reducing low-density lipoprotein (3.4 0.7
to 2.7 0.5 mmol/l, P < 0.001) and triglyceride (0.5 0.8 versus
0.2 1.0 mmol/l, P = 0.039), improving blood pressure level, as well
(Lee et al. 2012).
Bitter gourd supplementation appears to be safe, since it did not
induce acute hypoglycaemias or other negative metabolic effects in
non-diabetic subjects (Kasbia et al. 2009).
Catechins and avonols from green tea and cocoa
Consumption of green tea as well as cocoa can be benecial in pa-
tients with MetS. In fact these nutraceuticals are rich in phytochemi-
cals, including catechins and phenols, which have signicant antiox-
idant properties with clear benets for cardiovascular health (USDA
database for the avonoid content of selected foods 2011; Grassi et al.
2012). Animal studies have shown that green tea lowers blood pres-
sure by suppressing the activity of NADPH oxidase and reducing the
reactive oxygen species (Ihm et al. 2012).
The green tea extract has demonstrated lipid-lowering activity in
hypercholesterolemic rats, with a reduction of 21% in LDL-C and 13%
in TG. In hyperglycaemic rats the reduction in blood glucose has been
of 13%: if conrmed in humans, these results would be a further evi-
dence of the effectiveness of green tea in subjects with MetS (Yousaf
et al. 2014).
A meta-analysis of 20 randomized clinical trials, with a total of
1536 participants who received green tea regularly, has shown a
slight decrease in systolic blood pressure (MD: 1.94 mmHg; 95% CI:
2.95 to 0.93; I2 = 8%; p = 0.0 0 02), as well as a moderate reduction
of LDL cholesterol (MD: 0.19 mmol/l; 95% CI: 0.3 to 0.09; I2 = 70%;
p = 0.0 0 04) (Onakpoya et al. 2014).
Moreover, green tea extracts reduces adipogenesis in patients
with MetS by decreasing expression of transcription factors C/EBP
and PPAR-gamma (Yang et al. 2014).
The avonoids of cocoa are the most studied in the clinical eld: in
particular it has been shown that the avonols content in some types
of cocoa, improves the endothelial function in healthy subjects and
in hyperglycaemic or hypertensive patients with or without glucose
intolerance, increasing the ow-mediated vasodilation (Grassi et al.
2008).
A recent meta-analysis of 20 randomized, double-blind, placebo-
controlled, which involved a total of 856 participants mostly healthy,
has revealed a statistically signicant decrease in blood pressure in
1139
patients taking products made from cocoa rich in avonoids (average
value of avonoids 545 mg/day) for a period from 2 to 18 weeks: the
average decrease in systolic blood pressure has been of 2.77 mmHg
(95%CI: 4.72, 0.82; p = 0.005), while the average decrease in dias-
tolic blood pressure has been of 2.20 mmHg (95% CI: 3.46, 0.93;
p = 0.006) (Ried et al. 2012).
In addition to the hypotensive effects, cocoa avonols could stim-
ulate thermogenesis, lipolysis and consequently reduce the adipose
tissue, with a reduction of body weight, especially in response to high
fat intake diets (Osakabe et al. 2014).
Vegetable omega-3 polyunsaturated fatty acids
Lipid-lowering action of omega-3 polyunsaturated fatty acids (PU-
FAs) has been clearly demonstrated in several clinical trials and meta-
analyses (Wei and Jacobson 2011), however the most part of available
clinical data have been obtained through the use of marine omega-3
PUFAs.
Nuts, vegetables with green leaves, linseed, axseed, walnuts
and vegetable oils, including canola, soybean and hemp oil, are
rich in alpha-linoleic acid (ALA), which is the principle vegetable
omega-3 fatty acid. Moreover, some microalgae are rich in docosa-
hexaenoic acid (DHA) and in particular the diatom Odontella au-
rita (Mimouni et al. 2012). Omega-3 PUFAs enhance prostaglandins
formation, suppress angiotensin converting enzyme (ACE) activity,
reduce angiotensin II formation, enhance nitric oxide (NO) forma-
tion and suppress transforming growth factor (TGF)-beta expression
(Mohan and Das 2001). Its probable that ALA has a hypotensive effect
acting as a precursor for eicosanoids that can generate the production
of prostaglandins and leukotrienes and reduce vascular tone (Salonen
et al. 1988; Djouss et al. 2005).
Alpha-linolenic acid seems to have benecial effects on MetS and
type 2 diabetes, because of its action on dyslipidaemia, inamma-
tion, hypertension, platelet aggregation and prothrombotic effects
(Douglas 2007) and to reduce the risk factors of cardiovascular dis-
ease (Poudyal et al. 2011). The cardioprotective effects of ALA have
been attributed to its precursor role in converting to EPA in the
body (Rajaram 2014). A clinical trial that evaluated the ecacy of a
6-months hypoenergetic diet enriched with a high MUFA content and
an ALA intake of 3.5 g/die in patients with metabolic syndrome: sys-
tolic blood pressure, insulin levels, total and LDL cholesterol and also
body weight were reduced in both groups (P < 0.05), while diastolic
blood pressure and serum TAG were signicantly reduced after the
high ALA intake, but not in the control group (P < 0.05) (Baxheinrich
et al. 2012).
Effective lipid-lowering doses of omega-3 PUFAs range from 2 to
4 g/die, which can only be obtained consistently by supplementation.
At present, it seems that both eicosapentaenoic acid (EPA) and DHA
have similar triglyceride (TG)-lowering properties, but in compara-
tive studies DHA caused greater reduction in TG and increase in LDL-
C and HDL-C than EPA (Wei and Jacobson 2011). Also ALA has modest
but short lived LDL-C lowering effect, reduces Lp(a) and improves in-
sulin sensitivity in hyperlipidaemic adults (Bloedon et al. 2008). An
intake of 4 g/die of ALA seems to have biological effects similar to
those of 0.3 g/die of long-chain -3 PUFA: comparatively, EPA and
DHA produce more rapid effects than ALA, but the role of ALA could
be more effective in terms of long-term dietary intake (Simopoulos
20 0 0).
Moreover, omega-3 PUFAs seem to have a small, dose-dependent
hypotensive effect, the extent of which seems to be dependent on the
degree of hypertension, as shown in some animal and clinical studies
(Cicero et al. 2009a).
These results suggest that a diet with a high intake of ALA can be
an effective strategy in the therapy of subjects with MetS, but data
about appropriate dosage and evidence for PUFAs protective role are
still insucient to suggest them as effective antihypertensive drug
1140 A.F.G. Cicero, A. Colletti / Phytomedicine 23 (2016) 11341144

Fig. 1. Target of action of nutraceuticals potentially improving metabolic syndrome components.

and further clinical trial are needed to conrm these results(Sanders Soy proteins lower the insulin/glucagon ratio, reducing the syn-
et al. 2006). thesis of LDL by liver (Davidson 2008) and increasing the expression
of the receptors for the Apolipoprotein B100 (Jones et al. 2009). The
reduction of LDL in response to soy intake is expected to be between
Alliin from garlic
7.9% and 10.3% (Jenkins et al. 2010).
Soy proteins presents also a hypotensive effect, in addition to in-
Allium sativum (garlic), and in particular alliin, is well known for
duce weight-loss, due to their low caloric value and their ability to
its anti-diabetic, hypotensive, anti-inammatory and lipid-lowering
induce satiety (Singh et al. 2014). Moreover, they contain isoavones
properties suggesting a signicant role in the management of MetS
that have a regulating action on glucose metabolism (Nanri et al.
(Hosseini and Hosseinzadeh 2015).
2010).
Garlic extracts have mainly a signicant blood pressure lowering
These multiple effects of soy proteins make them a potential tool
effect (Ried and Fakler 2014).The dry aged garlic extract has an in-
to prevent MetS, to treat the rst alterations in patients with border-
hibitory activity on ACE and acts as calcium channel blocker, which
line values or to increase the effectiveness of medical therapies.
reduces the sensitivity to catecholamines; it also increases the lev-
The intake of 25 g/day of lupine proteins has shown a marked lipid
els of bradykinin and nitric oxide and consequently improves arterial
lowering activity (Bhr et al. 2015), due to a presumed inhibition of
compliance (Butt et al. 2009).A recent meta-analysis of randomized
Hydroxy-methyl-glutaryl-coenzyme A reductase and to an increased
clinical trials controlled with placebo has shown an average reduc-
expression of hepatic LDL receptor and SREBP2, through the activa-
tion in systolic blood pressure of 4.6 2.8 mmHg in the group of
tion of different pathways. (Lammi et al. 2014)
patients treated with garlic (p = 0.001); moreover, in the subgroup
of patients with hypertension it has been found a mean reduction in
Curcumin from curcuma longa
systolic blood pressure of 8.4 2.8 mmHg (p < 0.001) and diastolic
pressure of 7.3 1.5 mmHg (p < 0.001). These effects seems to be
Studies on extracts of Curcuma longa and their lipid-lowering ef-
additive to the ones of the antihypertensive drugs (Reid et al. 2010).
fects have had mixed results and require further studies (Ghorbani
Data from different trials suggest that garlic extract could also ex-
et al. 2014).
ert variable effects on human lipid metabolism, reducing the serum
Turmeric is obtained from the C. longa L. plant; its main con-
level of apolipoprotein B and increasing the one of HDL-cholesterol
stituent, curcumin, is a polyphenol with multiple effects that can
(Jung et al. 2014).
modulate several signalling pathways.
In a recent study of 43 subjects (Gmez-Arbelez et al. 2013), the
Curcumin contained in the rhizome, could favourably act on all
intake of aged garlic extract for 12 weeks has proved to be effective
the main components of the MetS including insulin resistance, obe-
in increasing the levels of adiponectin, an adipokine secreted by adi-
sity, hypertriglyceridemia, decreased HDL-C and high blood pressure,
pose tissue, whose serum level is inversely associated to both body
and prevent the worst complications of MetS, including diabetes and
weight and cardiovascular disease risk (Kumada et al. 2003). This ef-
cardiovascular events. Due to its anti-oxidant and anti-inammatory
fect is probably related to a kind of insulin-sensitizing effects exerted
activity, curcumin can also exert several pleiotropic effects and im-
by garlic extract that, in diabetic patients, reduce fasting plasma glu-
prove endothelial dysfunction, adipokines and hyperuricemia imbal-
cose, fructosamine and TG levels (Sobenin et al. 2008).
ances, that usually accompany MetS (Sahebkar 2013).
Curcumin has hypoglycaemic and insulin sensitizing effects: in
Soy peptides fact it can lower plasmatic glycaemia, reducing hepatic glucose pro-
duction and inammation-induced hyperglycaemia, stimulating glu-
Soy have received international recognition about its preventive cose uptake by the up-regulation of GLUT4, GLUT2 and genes GLUT3
and therapeutic activity on cardiovascular risk and there is a consen- expressions and the activation of AMP kinase, promoting the activity
sus document drawn up in 2006 by the American Heart Association of PPAR ligand, stimulating insulin secretion from pancreatic tissues,
Nutrition Committee on the benets of soy on cardiovascular health improving the functionality of pancreatic cells and reducing insulin
(Sacks et al. 2006). resistance (Panahi et al. 2014; Yao et al. 2014).
Torres et al. highlighted the normalizing effect of soy on lipid pro- Therefore, Curcumin has proven to inhibit 11 -hydroxysteroid de-
le, with decreased synthesis of LDL also in subjects with MetS, and hydrogenase type 1, with an increase blood levels of cortisol (Hu et al.
its preventive role in diabetes (Villegas et al. 2008). 2013).
 A.F.G. Cicero, A. Colletti / Phytomedicine 23 (2016) 11341144 1141

Table 2
Phytochemicals and their effect on MetS.

Phytochemicals Effects on MetS Level of evidence

Psyllium husk Lipid-lowering, anti-obesity, anti-diabetic, anti-hypertensive Meta-analyses of RCT in humans

Guar gum Lipid-lowering, insulino-resistance, anti-diabetic, anti-hypertensive RCT in humans
Fibres from fenugreek Lipid-lowering, hypoglycaemic RCT in humans
Chitosan Lipid-lowering, anti-obesity, anti-diabetic, anti-hypertensive RCT in humans
Glucomannan Lipid-lowering, anti-obesity, anti-diabetic Meta-analyses of RCT in humans
Cinnamon Lipid-lowering, anti-diabetic, anti-hypertensive Meta-analyses RCT in humans
Berberine Lipid-lowering, insulin-sensitizer, anti-hypertensive Meta-analyses of RCT in humans
Corosolic Acid Lipid-lowering, anti-diabetic, anti-obesity RCT in humans
Charantin Insulin-sensitizer, hypoglycaemic, anti-obesity, RCT in humans
Catechins and avonols Lipid-lowering, anti-hypertensive, anti-obesity Meta-analyses of RCT in humans
Omega-3 PUFA Lipid-lowering, anti-hypertensive, insulin-sensitizer, anti-obesity Meta-analyses of RCT in humans
Alliin Lipid-lowering, anti-diabetic, insulin-sensitizer, anti-obesity, anti-hypertensive Meta-analyses of RCT in humans
Soy peptides Lipid-lowering, anti-diabetic, anti-hypertensive, anti-obesity RCT in humans
Curcumin Lipid-lowering, insulin-sensitizer, hypoglycaemic, anti-obesity, anti-hypertensive RCT in humans

RCT, randomized clinical trials.

Discussion nutraceuticals. Moreover these compounds, usually easily available

Even if cardiovascular diseases are today the leading cause of mor-
tality and one of the rst causes of disability in developed countries,
we seems to be far from reaching the treatment goals, especially in
the setting of primary prevention (Banegas et al. 2011).
A change in lifestyle, increasing physical activity and improving
dietary habits, is the most important step in term of prevention
and cost/effectiveness (Saha et al. 2010; King et al. 2011). Weight
loss (reduction of 710% of weight) and moderate intensity exer-
cise, such as walking, 57 days per week) could be useful tools to
help blood pressure, LDL cholesterol, and blood glucose control. Quit-
ting smoking habit is recommended, as well. However, life-style pro-
grams are often dicult to follow for long periods and some risk pa-
rameters, such as cholesterolemia, are relatively resistant to changes
in dietary habits and physical activity (Cicero et al. 2009b). On the
other hand, a large number of dietary supplements and nutraceu-
ticals have been studied for their supposed or demonstrated ability
to safely improve MetS components in humans (Table 1) (Dav et al.
2010). We have above highlighted the possibility that some of them
could act simultaneously improving more than one MetS component,
such as omega-3 fatty acids, berberine, psyllium and other soluble -
bres, cinnamon, banaba, green tea and cocoa, garlic and bitter gourd
(Fig. 1).
Other natural compounds like Gymnema sylvestre, Crataegus
monogyna, Panax quinquefolium and Eugenia jambolana were demon-
strated to have positive effects on glucose metabolism in small clin-
ical trials (Kouzi et al. 2015), but the effects on MetS components
havent been denitively investigated yet.
The consumption of beetroot juice is suitable in hypertensive pa-
tients with MetS. In fact beetroot is known for its proven antihyper-
tensive properties (Cicero and Colletti 2015), mainly due to the pres-
ence of inorganic nitrates, that in vivo are converted into nitric oxide
(NO), which is responsible for vasodilatation of large arteries and re-
sistance vessels (Coles and Clifton 2012). However it is important to
evaluate the effects of beetroot on all components of the MetS; in fact
are starting new clinical trial to assess its effects on insulin sensitivity.
The largest part of the most widely marketed nutraceuticals was
not clearly demonstrated to have positive cardiometabolic effects.
The reasons could be different, among the others low bioavailabil-
ity (also often not tested, thus unknown), scarce tolerability of eca-
cious dosages, short duration of the studies, low methodology quality
of the available clinical trials. The low interest of industries to invest
large amounts of money in outcome study on products that could not
be exclusive is probably an important reason, as well. In the future,
the increased availability and reduced cost of validated and standard-
ized laboratory and instrumental CVD risk biomarkers could improve
the possibility to discover new pleiotropic effects of lipid-lowering
in the market, need to be long-term tested and evaluated on larger
patient samples in clinical practice setting.
Clinicians should be informed about nutraceuticals ecacy and
safety, in order to use them as preventive tools in non-complicated
MetS patients or as additive tools to potentiate more conventional
treatments in high-risk subjects. They should also be able to give the
consumer full information about the product that he is assuming.
Solutions and polypills of nutraceuticals, associated with a healthy
lifestyle, can be the future of the prevention of Mets and the next
step is to evaluate its cost/effectiveness, appropriate dosages and side
effects in the long term.
Conclusions
MetS is a medical priority worldwide that requires better pre-
ventive and therapeutic strategies. In addition to a pharmacological
treatment for patients with severe MetS, the use of phytochemicals
in the prevention and treatment of subjects with borderline parame-
ters can be useful to avoid the progression of the disease as well as to
limit the side effects of drug intake.
MetSs risk factors, i.e. hypertension, dyslipidaemia, obesity and
insulin-resistance, are biologically interrelated in the development of
the pathology and it is consequently necessary to treat all of them to
increase the effectiveness of the therapy. Furthermore, patients with
MetS can present different patterns of this syndrome and the need of
a tailored therapy based on the individuals pathologies and a specic
combination of phytochemicals is very important.
Although there are many studies on single nutraceuticals com-
ponents (Table 2), only a few describe the use of phytochemicals on
multiple components of MetS and they have often short duration or
low methodology quality. Consequently, further well-designed and
suciently powered randomized clinical trials with a large and het-
erogeneous sample of people at risk for MetS are needed to eval-
uate which are the best nutraceuticals available and to better un-
derstand their mechanism of action both alone and in compounds
(possible synergistic effects). It is also necessary to evaluate their
cost/effectiveness ratio and to conrm their ecacy and safety in the
middle-long term.
Conict of interest
We wish to conrm that there are no known conicts of inter-
est associated with this publication and there has been no signif-
icant nancial support for this work that could have inuenced its
outcome.
1142 A.F.G. Cicero, A. Colletti / Phytomedicine 23 (2016) 11341144
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