Tea and cinnamon polyphenols improve the metabolic syndrome

Polyphenols
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Tea and cinnamon
polyphenols improve the
metabolic syndrome
HEPING CAO, BOLIN QIN, KIRAN S. PANICKAR, RICHARD A. ANDERSON*
*Corresponding author
Diet, Genomics and Immunology Laboratory
Beltsville Human Nutrition Research Center
United States Department of Agriculture, Agricultural Research Service
Beltsville, Maryland 20705, USA
INTRODUCTION
The metabolic syndrome is often a precursor of chronic
diseases including type 2 diabetes, cardiovascular diseases
and neurodegenerative diseases including Alzheimer’s
disease (AD). Factors that improve insulin sensitivity
usually lead to improvements in risk factors associated with
the metabolic syndrome and related diseases. According to
the Third Report of the National Cholesterol Education
Program Expert Panel on Detection, Evaluation and
Treatment of High Blood
Cholesterol in Adults (1),
people with three or more of
the following have the
metabolic syndrome: fasting
plasma glucose level of >6.1
mmol/L (110 mg/dL),
triglycerides > 1.69 mmol/L
(150 mg/dL), HDL cholesterol
for men of 130/85 mm Hg and
waist circumference for men >102 cm (40 inches) and
women >88 cm (35 inches). The incidence of the metabolic
syndrome varies from under 20 percent among Chinese
and Korean people to over 50 percent among Maori and
Pacific Islanders in New Zealand (2). Approximately one in
four Americans has the metabolic syndrome. It is
progressive and often culminates with type 2 diabetes
which increases the incidence of cardiovascular and
neurodegenerative diseases. In patients with
the metabolic syndrome, the relative risk
for atherosclerotic cardiovascular disease
ranges from 1.5 to 3.0 depending upon
the stage of progression. The risk for
developing diabetes is five-fold higher for
people with the metabolic syndrome
compared with those without the syndrome
(3). Accumulating evidence also indicates
an association between the metabolic
syndrome and an increased risk of
developing AD (4). Since the metabolic
syndrome is multi-factorial, strategies for
reducing the incidence and consequences
of the metabolic syndrome must also be multifactorial
to yield the greatest benefits. Polyphenols from
cinnamon and tea are multifactorial with antioxidant, antiinflammatory,
and neuroprotective effects and also enhance
insulin function (5-9) (Figure 1).
Richard A.
Anderson
ABSTRACT: The metabolic syndrome is often a precursor of chronic diseases including type 2 diabetes, cardiovascular
diseases and neurodegenerative diseases including Alzheimer’s disease. Since the metabolic syndrome is multifactorial,
strategies for reducing its incidence and consequences must also be multi-factorial. Green tea and cinnamon
polyphenols improve glucose, insulin, lipids and related variables, and are anti-inflammatory, function as antioxidants
and decrease neurodegeneration. In vitro, animal and human studies support the beneficial roles of cinnamon and tea
polyphenols on the metabolic syndrome and risk factors associated with it.
Since the metabolic syndrome is
multi-factorial, strategies for reducing
the incidence and consequences of the
metabolic syndrome must also be multifactorial
to yield the greatest benefits
Polyphenols
from cinnamon and
tea are multifactorial
with antioxidant,
anti-inflammatory,
and neuroprotective
effects and also
enhance insulin
function
Cinnamon and its components improve blood
glucose, lipids, and insulin function in animals
Rats fed a high fructose diet (HFD) develop elevated
blood glucose and insulin resistance that can be
alleviated or reversed by whole cinnamon or an aqueous
extract of cinnamon. The active components of cinnamon
include type A polymers (10). One tetramer and four type
A trimers have been isolated from cinnamon and all were
shown to have in vitro insulin-potentiating activity. The
dimer, trimer, tetramer and pentamer of similar
compounds from apples have
all been shown to be
absorbed (11). Cinnamontreated
rats show
significantly higher glucose
infusion rates compared
with controls. A cinnamon
polyphenol extract (CPE)
also improved the glucose
utilization of normal male rats fed
a HFD to induce insulin resistance (12). The decreased
glucose infusion rate was improved by CPE administration
to the same level of controls. HbA1c was also improved.
The decreases in the muscular insulin-stimulated insulinreceptor
β (IRβ) and insulin receptor substrate -1 (IRS1)
tyrosine phosphorylation levels and IRS1 associated with
phosphoinositide 3-kinase (PI3K) in HFD-fed rats were
significantly improved by CPE treatment. Homeostasis
model assessment-estimated insulin resistance (HOMA-
IR) was elevated in HFD-fed rats, but
returned to normal in cinnamon extract
HFD-fed rats (12). In a genetic diabetic
mouse model (13), serum insulin levels
were significantly higher in the group
given cinnamon than the control group.
The authors suggested that the possible
mechanism by which cinnamon extract
brings about its hypoglycemic action in
diabetic mice may be by potentiating the
effect of insulin in serum or by increasing
either the pancreatic secretion of insulin
from the existing beta cells or its release.
The metabolic syndrome is commonly
associated with an atherogenic dyslipidemia
which accounts for a high risk of atherothrombosis and
cardiovascular events. Cinnamon shows lipid lowering
properties in animal (13) (14) and human studies (15). In
CPE-treated genetic diabetic mice, the serum triglycerides

Figure 1. Model of actions of green tea and cinnamom polyphenols in the insulin signal transduction pathway leading to potential beneficial effects on
chronic diseases. (“+” represents a positive effect and “-” represents a negative effect). AD, Alzheimer’s disease; Cox-2, cyclooxygenase-2; FAT, fat; G-6-P,
glucose 6-phosphate; GLUT4, glucose transporter 4; GM-CSF, granulocyte-macrophage colony-stimulating factor; GS, glycogen synthetase; GSK3β,
glycogen synthetase kinase 3β, IR, insulin receptor; IRS, insulin receptor substrate; PI3K, 1-phosphoinositol 3-kinase; PIP2, phosphoinositol 4,5bisphosphate;
PIP3, phosphoinositol 3,4,5-triphosphate; PTP-1, protein tyrosine phosphatase-1; PDK1, phosphatidylinositol-dependent protein kinase 1;
PKB, protein kinase B; TTP, tristetraprolin; UDPG, uridine diphosphoglucose; VEGF, vascular endothelial growth factor. Source: modified from (25).
decreased and the level of HDL-cholesterol increased
compared with the controls (13). Recently, we
investigated the effects of a commercial water extract of
cinnamon on the postprandial lipid metabolism in HFDfed
rats, in an olive oil loading study. Aqueous extract of
cinnamon inhibited serum triglyceride levels and the over
production of triglycerides and triglyceride rich lipoproteinapoB48
(14). Cinnamon extract also inhibited the
inflammatory factor, tumour necrosis factor-α (TNFα),
which is associated with increased cardiovascular disease
risks that are particularly atherogenic.
CPE increases anti-inflammatory gene expression
The anti-inflammatory protein, tristetraprolin (TTP), binds
to some mRNAs and destabilizes transcripts coding for
proteins such as TNFα. The mRNA binding activity of
TTP is zinc-dependent and is regulated by posttranslational
phosphorylation. TTP mRNA and/or TTP
protein levels are increased in mammalian cells by a wide
range of agents including insulin (Figure 1). Like insulin,
CPE increases TTP mRNA levels in 3T3-L1 adipocytes
(16). CPE induction of TTP mRNA is sustained in
adipocytes, which is in contrast with the transient
increases by insulin (16). Treatment of adipocytes with
purified type A polyphenols from the cinnamon fraction of
CPE also increases the amount of TTP protein in the
adipocytes. Since TTP gene expression is reduced
several-fold in adipose tissue of obese subjects with the
metabolic syndrome, the induction of TTP by CPE could
reduce the inflammatory effects of obesity and related
diseases similar to its effects in autoimmune disorders.
Unlike insulin, CPE also increases TTP gene expression
in mouse macrophages (17). These results indicate that
while CPE has insulin potentiating effects, its effects on
some of the inflammatory markers differ from those of
insulin.
Green tea improves antioxidant markers and
oxidative stress
Green tea extracts have the potential for large-scale
application as natural antioxidants. Animal studies show
that green tea catechins increase total plasma antioxidant
activity, as well as increase the activity of antioxidants
including super oxide dismutase and catalase. Antioxidant
effects of tea are well-documented and have been
reviewed recently (18).
Green tea increases anti-inflammatory and decreases
pro-inflammatory gene expression
Tea has a wide range of preventive effects on diabetes
and obesity (19, 20). A number of studies have suggested
that GTE mimics insulin action (5, 21-22). Since TTP
expression is increased by insulin (17, 23), it is possible
that TTP expression is also increased by GTE. GTE
increases TTP mRNA levels in liver and muscle of rats
fed a high fructose diet to induce the metabolic syndrome
(24). Green tea also decreases TNF mRNA levels but
does not have significant effects on cyclooxygenase 2
(COX2) mRNA (24). The model shown in Figure 1 links
tea and cinnamon polyphenols, insulin, TTP, and
cytokines to inflammatory diseases including arthritis,
diabetes, obesity and Alzheimer’s disease.
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Green tea regulates the expression of genes involved
in glucose uptake and insulin signalling
Green tea extract increases GLUT1 and GLUT4 mRNA
levels in the liver and increases GLUT2 and GLUT4 mRNA
levels in the muscle. Green tea extract also increases
glycogen synthase kinase 3 beta (GSK3B) and insulin
receptor substrate 2 (IRS2) mRNA levels in the liver (25)
(Figure 1). Green tea also increases GSK3B and
phosphatidylinositol 3-kinase, catalytic, beta mRNA levels
and decreases Src homology 2 domain-containing
transforming protein 1 (SHC1) mRNA levels in the liver. In
the muscle, GTE increases IRS1, SHC1 and Son of
sevenless 1 mRNA levels (25).
Metabolic syndrome and the brain
Since the central nervous system (CNS) is intimately
involved in energy homeostasis via autonomic and
neuroendocrine pathways and by regulation of diet, the
brain is an important organ in the development of the
metabolic syndrome. For instance, hyperleptinemia,
induced by a high fat diet, inhibits leptin transport across
the blood-brain barrier and thereby produces leptin
insufficiency in the hypothalamus. Such insufficiency may
result in loss of hypothalamic control on pancreatic insulin
secretion as well as diminished glucose metabolism and
energy expenditure with the eventual development of
hyperinsulinemia, hyperglycaemia, and diabetes (4).
Metabolic syndrome increases incidences of
Alzheimer’s disease
Accumulating evidence indicates an association between
the metabolic syndrome and an increased risk of
developing AD (4). Insulin resistance, a major component
of the metabolic syndrome, may contribute to the
neuropathology observed in AD. Experimentally induced
perturbation of glucose metabolism by means of
intracerebroventricular administration of streptozotocin, a
toxin that kills insulin receptors, leads to abnormalities in
glucose breakdown and energy formation which closely
resemble the disturbances found in sporadic AD.
Desensitization of the neuronal insulin receptors seems to
be an early event in the pathogenesis or even etiology of
AD causing disturbances in oxidative glucose metabolism
and energy failure in insulin-sensitive brain structures.
Furthermore, purified insulin-degrading enzyme (IDE) from
rats also degrades amyloid β in cultures and in vivo and
neurons regulate extra cellular levels of amyloid betaprotein
via proteolysis by IDE as observed in cultures.
Reduced CNS expression of genes encoding insulin, insulin
growth factor (IGF)I, and IGFII, as well as insulin and IGFI
receptors, suggests that AD may represent a
neuroendocrine disorder that is similar to, yet distinct from,
diabetes mellitus and is now referred to as “Type 3
Diabetes” to reflect the pathogenic mechanism of
neurodegeneration linked to AD (26). Beneficial neural
effects of green tea or its catechin components have
generally been attributed to their anti-oxidant and antiinflammatory
properties in neurotoxicity in cultures or
animal models of neurodegenerative disease (see (27) for
review). EGCG attenuates amyloid
β-induced hippocampal neuronal
death in cultures and reduces
cerebral amyloidosis as well as
cognitive deficits (28) in a
transgenic mouse model of AD.
Likewise, green tea also exerts
neuroprotective effects in cell
cultures. Our preliminary data
indicate a protective effect of
green tea polyphenols,
Cinnamon and the aqueous
extract of cinnamon have also been
shown to improve blood glucose
of people with type 2 diabetes (25)
and in women with polycystic ovary
syndrome (26) which is closely
associated with the MS
cinnamon polyphenols, as well as insulin, on amyloid
β-induced cell death in PC12 neuronal cells and such
protective effects may be through their action on the
mitochondria (unpublished data).
Protective effects of cinnamon and tea polyphenols in
brain
Increasing evidence points to an association between
metabolic syndrome and first or recurrent stroke (29). In
addition, clinical and experimental data suggest that
hyperglycemia, a key feature of metabolic syndrome, worsens
the functional outcome in the presence of neurological injury
from stroke (30). Neuroprotective effects of polyphenols
have been reported in animal models of ischemic stroke.
Polyphenol-rich green tea extract is neuroprotective when
administered in drinking water prior to middle cerebral
artery occlusion in rats or common carotid artery occlusion
in gerbils. In addition, neuroprotective effects have been
reported in rats, mice, and gerbils after middle cerebral
artery occlusion or common carotid artery occlusion when
treated with individual polyphenol components of tea
including catechin, epicatechin and epigallocatechin gallate
(EGCG) (31). Such protective effects are also observed in
cell culture models of ischemic injury with cinnamon
polyphenols. CPE attenuates neuronal death in an in vitro
model of ischemic injury (32). In addition, CPE and green
tea polyphenols also diminish glial damage in culture by
attenuating cell swelling, a key feature of cytotoxic brain
edema in ischemia (33). While the precise mechanisms
underlying the protective effects of cinnamon and green tea
polyphenols in ischemic injury are not clear, and likely
involve multiple intracellular signalling pathways, some of
their protective effects are possibly due to their effects on
mitochondria (33). These studies indicate that cinnamon
and green tea polyphenols may
have promise in attenuating
neural damage associated with
ischemic injury as well as AD.
Human studies
In a study involving 22 subjects
with the metabolic syndrome,
subjects in the group receiving
the capsules containing the
aqueous extract of cinnamon

displayed decreases in fasting
blood glucose and systolic
blood pressure, and increases
in lean mass, compared with
the placebo group. There were
also significant decreases in
body fat in the cinnamon group
(34). The improvement of impaired fasting glucose due to
cinnamon was correlated with the antioxidant effects of
cinnamon supplementation assessed by plasma
malondialdehyde, sulfhydryl groups and plasma antioxidant
status (35). In subjects with the metabolic syndrome,
plasma malondialdehyde levels were reduced by the
aqueous extract of cinnamon, indicating decreased lipid
peroxidation, while plasma sulfhydryl groups were
increased, indicating a protection of antioxidant sulfhydryl
groups against oxidation (35). In the group receiving
cinnamon, plasma sulfhydryl groups were increased after
twelve weeks of supplementation, suggesting that
cinnamon acts in protecting both lipids and proteins against
oxidation.
Cinnamon and the aqueous extract of cinnamon have also
been shown to improve blood glucose of people with type 2
diabetes (15) and in women with polycystic ovary syndrome
(36) which is closely associated with the metabolic
syndrome. The cinnamon extract improved insulin
resistance in the women with polycystic ovary syndrome to
that in the control group. Polyphenols from cinnamon also
have beneficial effects on subjects with good glucose
tolerance (seven healthy males, 26 ± 1 years, with BMI of
24.5 ± 0.3 kg/m 2 ) (37). Cinnamon ingestion led to reduced
total plasma glucose responses to oral glucose ingestion
as well as improving insulin sensitivity. Effects were
significant when the cinnamon was taken with the glucose
and if taken 12 hours before glucose ingestion (37).
Hlebowicz et al. (38) also reported beneficial effects of
cinnamon on postprandial blood glucose of healthy normal
subjects. There were also effects on gastric emptying that
could partially explain the results. Not all of the clinical trials
regarding whole cinnamon or extracts of cinnamon have
reported significant effects and a summary of the human
studies involving cinnamon and possible reasons for the
lack of a response have been reviewed (7).
The effects of tea on people with the metabolic syndrome
are not as clear as those from animal studies. Most human
studies have failed to show significant beneficial effects
associated with tea consumption but the effects appear to
The cinnamon extract improved
insulin resistance in the women
with polycystic ovary syndrome to
that in the control group
be related to the amount of tea
consumed. There is an inverse
relationship of green tea and
diabetes in women, but only in
those consuming more than six
cups of green tea per day (39).
However, a recent study
demonstrated that as little as one cup of black tea, but not
green tea, per day was associated with a lower risk of type
2 diabetes (40). While animal studies clearly show
beneficial effects of tea solids on the variables associated
with the metabolic syndrome, the results for humans with
insulin resistance require further study.
CONCLUSIONS
Green tea and cinnamon polyphenol extracts have insulinlike
and unique effects on the regulation of gene
expression. In vitro, animal and human studies support a
beneficial role of cinnamon and its components on the
metabolic syndrome and risk factors associated with it.
Similarly, in vitro and animal studies support the role of tea
polyphenols on insulin resistance and related factors.
However, human studies are limited for the documentation
of the role of tea polyphenols in the prevention and
alleviation of the metabolic syndrome.
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