molecules

Review
Antidiabetic Effects of Tea
Qiu-Yue Fu 1,† , Qing-Sheng Li 1,† , Xiao-Ming Lin 1 , Ru-Ying Qiao 1 , Rui Yang 1 , Xu-Min Li 1 ,
Zhan-Bo Dong 2 , Li-Ping Xiang 3 , Xin-Qiang Zheng 1 , Jian-Liang Lu 1 , Cong-Bo Yuan 4 ,
Jian-Hui Ye 1, * and Yue-Rong Liang 1, *
1 Tea Research Institute, Zhejiang University, Hangzhou 310058, China; 21516103@zju.edu.cn (Q.-Y.F.);
qsli@zju.edu.cn (Q.-S.L.); 21516097@zju.edu.cn (X.-M.L.); ryqiao@zju.edu.cn (R.-Y.Q.);
kexiaonao@163.com (R.Y.); 21616096@zju.edu.cn (X.-M.L.); xqzheng@zju.edu.cn (X.-Q.Z.);
jllu@zju.edu.cn (J.-L.L.)
2 Wenzhou Vocational College of Science and Technology, Wenzhou 325035, China; dozhanbo@gmail.com
3 National Tea and Tea product Quality Supervision and Inspection Center (Guizhou), Zunyi 563100, China;
gzzyzj_2009@vip.sina.com
4 Yuyuanchun Tea Limited, Jufeng Town, Rizhao 276812, China; yuyuanchun@126.com
* Correspondence: jianhuiye@zju.edu.cn (J.-H.Y.); yrliang@zju.edu.cn (Y.-R.L.);
Tel.: +86-571-8898-2704 (J.-H.Y.); +86-571-8898-2704 (Y.-R.L.)
† These authors contributed equally to this work.

Academic Editors: Solomon Habtemariam and Giovanni Lentini

Received: 18 April 2017; Accepted: 18 May 2017; Published: 20 May 2017

Abstract: Diabetes mellitus (DM) is a chronic endocrine disease resulted from insulin secretory
defect or insulin resistance and it is a leading cause of death around the world. The care of DM
patients consumes a huge budget due to the high frequency of consultations and long hospitalizations,
making DM a serious threat to both human health and global economies. Tea contains abundant
polyphenols and caffeine which showed antidiabetic activity, so the development of antidiabetic
medications from tea and its extracts is increasingly receiving attention. However, the results claiming
an association between tea consumption and reduced DM risk are inconsistent. The advances in
the epidemiologic evidence and the underlying antidiabetic mechanisms of tea are reviewed in this
paper. The inconsistent results and the possible causes behind them are also discussed.

Keywords: Camellia sinensis; tea catechins; tea polysaccharides; caffeine; diabetes mellitus;
epidemiological analysis

1. Introduction
Diabetes mellitus (DM) is a threat to human health and it was the 6th leading cause of death in
the world in 2015 [1] and the 7th leading cause of death in the USA in 2011 [2]. The number of people
with DM was estimated to be 382 million in 2013, and it was predicted that by 2035 around 600 million
people could develop DM [3], causing disabilities, economic hardship and even death. There are two
types of DM. Type 1 DM (T1DM) is a metabolic disease characterized by an insulin secretory defect
due to the autoimmune destruction of the beta cells in the pancreas [4] and type 2 DM (T2DM) is a
long term metabolic disorder characterized by high blood sugar (hyperglycemia), insulin resistance,
and relative lack of insulin [5]. T2DM is the most common form and it accounts for 90–95% of all
DM cases [6–8]. A national survey conducted in 2010 showed that the weighted prevalence of T2DM
among Chinese adults aged 18 years and above was 9.7% [9]. Three out of four people with DM live
in low- and middle-income countries and they can’t afford necessary drugs such as insulin and/or
other medicaments [10]. As both a serious threat to human health and global economies DM is at crisis
levels and one of the biggest public health challenges in the 21st century.

Molecules 2017, 22, 849; doi:10.3390/molecules22050849 www.mdpi.com/journal/molecules

Molecules 2017, 22, 849 2 of 19

Tea is a common beverage consumed daily in many parts of the world. It is classified into
unfermented tea (green tea, white tea), semi-fermented tea (oolong tea) and fully fermented tea (black
tea and pu’erh tea). The predominant chemical components in unfermented tea are catechins and
caffeine, while in semi-fermented and fully fermented tea teatheaflavins, thearubigins and caffeine
predominate. Catechins, caffeine and theaflavins have been confirmed to possess a broad range of
biological activities [11,12]. Tea has been suggested to decrease blood glucose levels and to protect
pancreatic β cells in diabetic mice. As a result the development of antidiabetic medications from tea
and its extracts is increasingly receiving attention. However, human epidemiological studies linking
tea consumption and DM risk have shown inconsistent results. In this review, we examine the possible
role of tea consumption in modulating the risk of DM, as well as the possible mechanisms behind the
observed associations and inconsistencies.

2. Epidemiologic Evidences
A series of population-based cohort studies have showed that tea consumption was associated
with reduced risk of DM. A survey involving 8821 adults (51.4% female) conducted in Krakow
(Poland) showed that higher tea consumption were negatively associated with metabolic syndrome,
with an odds ratio (OR) of 0.79 (95% confidence intervals (CI) 0.67–0.92), after adjusting for potential
confounding factors. Among specific components of metabolic syndrome, tea consumption was
negatively associated with central obesity and fasting plasma glucose [13]. A 10-year follow-up
study in The Netherlands involving 918 incident T2DM cases which were documented from among
40,011 participants showed that tea consumption was inversely associated with the hazard of T2DM,
with an OR of 0.63 (95% CI: 0.47–0.86) for >5.0 cups of tea per day (p = 0.002). Total daily consumption
of at least three cups of tea reduced the risk of T2DM by approximately 42% [14]. An 11.7-year
follow-up survey in the UK involving 5823 British people (4055 men and 1768 women) showed that
there was an association between tea intake and reduced risk of T2DM, with a hazard ratio (HR) of
0·66 (95% CI: 0.61–1.22; p < 0.05) after adjustment for age, gender, ethnicity and social status [15].
A 5-year follow-up study involving 17,413 Japanese people (6727 men and 10,686 women) from 40 to
65 years of age showed that consumption of green tea was inversely associated with risk of T2DM
after adjustment for age, sex, body mass index, and other risk factors. Multivariable OR for DM
among participants who frequently drank six cups of green tea per day were 0.67 (95% Cl: 0.47–0.94),
compared with those who drank less than one cup per week [16]. A study involving 71,239 Danish
women revealed that moderate first trimester tea intake was not associated with increased risk of
gestational DM and may possibly have a protective effect [17]. A cross-sectional study involving
452 T2DM participants conducted in a community-based specialized care center in Pakistan showed
that prevalence of uncontrolled DM was approximately 39% and higher consumption of tea was
independently associated with uncontrolled DM, with an OR: 1.5 (95% CI: 1.0–2.2) [18].
Many meta-analysis studies have revealed the effects of tea consumption on the reduced risk of
DM. A study including 608 T2DM patients carried in China showed that tea drinking could alleviate
the decrease of fasting blood insulin (1.30 U/L, 95% CI: 0.36–2.24) and reduced waist circumference
in more than 8-week intervention [19]. Data from 18 studies including 457,922 participants showed
that high intakes of decaffeinated tea were significantly associated with reduced risk of incident
diabetes [20]. Daily tea consumption (≥3 cups/day) is associated with a lower T2DM risk. However,
further studies are needed to enrich related evidence, especially with regard to types of tea or sex [21].
Various kinds of tea showed different effects on DM. Consumption of unfermented green tea or
semi-fermented oolong tea was considered to protect against the development of T2DM in Chinese
men and women. Green tea consumption was associated with a lower risk of impaired fasting glucose
(IFG), while oolong tea consumption was associated with a lower risk of impaired glucose tolerance
(IGT). A U-shaped association was observed, subjects who consumed 16–30 cups of green and oolong
tea per week had the lowest ORs for IFG and IGT, respectively [22], suggesting that green tea and
oolong tea showed antidiabetic effects through different mechanisms. The chemical composition of
Molecules 2017, 22, 849 3 of 19

teas varies with the degree of fermentation. The major bioactive component in unfermented green
tea is epigallocatechin gallate (EGCG), but in the fully fermented black tea and the semi-fermented
oolong tea the major active ingredients are the theaflavins and thearubigins [23,24]. IFG and IGT are
two different states in insulin secretion and insulin resistance [25]. IFG involves severe hepatic insulin
resistance with near-normal or normal muscle insulin resistance, while IGT has marked muscle insulin
resistance with mild hepatic insulin resistance. Both IFG and IGT are characterized by a decrease
in early-phase insulin secretion, while subjects with IGT also have an impaired late-phase insulin
secretion. Both conditions contribute to the development of T2DM [26]. Green tea consumption was
particularly associated with a lower risk of IFG, probably as a result of its high level EGCG, which had
insulin mimetic effects. First, EGCG inhibits the hepatic glucose production, and promotes tyrosine
phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1). Second, EGCG controls
gluconeogenesis by suppressing the expression of genes phosphoenolpyruvate carboxykinase (PEPCK)
and glucose-6-phosphatase (G6Pase), ameliorates cytokine-induced β-cell damage and improves
insulin sensitivity [27]. Third, EGCG regulates the expression of genes involved in the insulin signal
transduction pathways and glucose uptake [28]. Oolong tea in particular lowered the risk of IGT, in
which theaflavins may be the contributor. First, theaflavins inhibit α-glucosidase activity, resulting in
decrease in glucose production at the intestine [29]. Second, compared to green tea, oolong tea contains
higher levels of caffeine which increases glucose transporter IV expression [30]. An ecological study
using a systematic data-mining approach to investigate the potential statistical relationship between
consumption of fully fermented black tea and epidemiological indicators around the world showed
that high black tea consumption was significantly correlated to low DM prevalence [31]. A single dose
of black tea decreased peripheral vascular resistance across upper and lower limbs after a glucose load,
accompanying by a lower insulin response (p < 0.05). Postprandial insulin response was attenuated by
~29% after tea intake (p < 0.0005) [32]. Chronic administration of the Rauvolfia-Citrus tea to overweight
T2DM patients on oral anti-diabetic agents significantly improved the markers of glycaemic control
and modified the fatty acid profile of skeletal muscle, without adverse effects or hypoglycaemia [33].

3. Protective Effects of Tea Against DM

3.1. Alleviation of Oxidative Stress

Oxidative stress is implicated in the pathogenesis of DM which is associated with distribution
of cognitive functioning. Hyperglycemia-induced oxidative stress has been proposed as a cause of
memory complications of DM including cognitive impairment. GTE showed antioxidant effects [34–36]
and improved cognitive impairment in streptozotocin (STZ)-induced DM rats [37]. Daily intake of one
cup (150 mL) to four cups (600 mL) of black tea improved oxidative stress biomarkers and decreased
serum C-reactive protein level in DM patients [38].
Tea and tea extracts exhibit antioxidative effects through various pathways. First, antioxidants
in tea can scavenge free radicals by directly acting on active oxygen species [35,39–41]. Second,
tea components, especially the abundant tea polyphenols, chelate metal ions such as liver iron,
preventing their participation in Fenton and Haber–Weiss reactions [41,42], a hydroxyl radical- forming
process. Third, tea antioxidants increase the level of plasma antioxidants such as glutathione [36,38].
Fourth, tea bioactives suppress the activity of superoxidase by chelating plasma zinc and copper,
the important cofactors of superoxidase [43]. Fifth, tea bioactives increase the biological activity of
antioxidases including catalase (CAT), superoxide dismutase (SOD) [39], and glutathione peroxidase
(GSH-Px) [36]. Sixth, tea catechins inhibit plasma protein carbonylation induced by hyperglycemia.
Protein oxidative modifications are a major class of protein post-translational changes and contribute
to cell dysfunction and human disease including T2DM. Carbonylation is an irreversible modification
in oxidized proteins [36]. This explains why tea catechins showed beneficial effects against the redox
impairment linked to hyperglycemic conditions.
Molecules 2017, 22, 849 4 of 19

There are many bioactive components in tea showing antioxidant activity, including catechins [23],
gallic acid [44] and polysaccharides [45]. EGCG, the most abundant catechin compound, is a
potent antioxidant in GTE [46]. Tea polysaccharides are another group of antioxidants in tea,
and their antioxidant activities depend on monosaccharide composition and molecular weight [47].
The polysaccharides extracted from fully fermented black tea consisted of a higher proportion of low
molecular weight fractions than those extracted from green tea and oolong tea, resulting in higher
bioactivities [45]. Gallic acid concentration in tea increases with fermentation during tea processing,
with 1.67 ± 0.06 mg/g in the unfermented green tea and 21.98 ± 1.03 mg/g in the fully fermented
pu’erh tea [44].

3.2. Inhibition of α-Amylase and α-Glucosidase Activity

Controlling the sharp increase in postprandial blood glucose resulted from rapidly digesting and
absorbing dietary carbohydrates is a challenge for DM patients. Dietary supplement of α-amylase and
α-glucosidase inhibitors is an accepted clinical method for controlling the increase in postprandial
blood glucose. Tea was confirmed to contain many natural products showing obvious inhibitory
effects on α-glucosidase and α-amylase [48]. In vivo study on a starch 13 C breath test on 28 healthy
volunteers showed that GTE intake inhibited α-amylase activity, resulting in decreased absorption and
digestion of starch [49]. The 50% inhibitory concentration (IC50) of green tea, black tea and oolong tea
for inhibiting α-glucosidase was 2.82, 2.25 and 1.38 µg/mL equivalent polyphenols, respectively [50].
The bioactive components in tea such as catehcins, chlorogenic acid, caffeine and theaflavins
show inhibitory effects on α-glucosidase and α-amylase activity, resulting in decreased plasma levels
of glucose, lipid metabolites, and albuminuria [29,51,52], among which tea polyphenols showed major
inhibitory potential [53–55]. Both α-amylase and a-glucosidase can be restrained in a non-competitive
way. Structure-activity relationships of polyphenols by computational ligand docking showed that
their inhibitory activity depends on the hydrogen bonds between the enzyme and hydroxyl groups
in ring B or the condensate AC-ring, and the formation of a conjugated π-system that stabilizes the
interaction with the active site [56]. A docking study showed green tea epicatechin gallate (ECG)
presented stronger affinity than EGCG, with more number of amino acid residues involved in amylase
binding with hydrogen bonds and Van der Waals forces [57].
The number of hydroxyl groups on the bioactive compounds is important for α-glucosidase
inhibition. The structure of gallate group esterified at the 3-position of the C-ring of catechins is
important and so the gallated catechins such as catechin gallate (CG), gaallocatechin gallate (GCG),
ECG, and EGCG showed stronger inhibitory activity than their corresponding ungallated compounds
catechin (C), gallocatechin (GC), epicatechin (EC) and epigallocatechin (EGC), respectively [55,58].
Black tea theaflavins constitute a group of pigments which are formed from the condensation of
catechins during fermentation of black tea and they could strongly suppress the α-glucosidase
activity. The α-glucosidase inhibitory effects of theaflavins decreased in the order of potency of
theaflavin-3-O-gallate, theaflavin-3,30 -di-O-gallate, theaflavin-30 -O-gallate and theaflavin [29].

3.3. Improvement of Endothelial Disfunction

Endothelial dysfunction (ED) is considered to be the initial lesion of atherosclerosis which is the
main etiology for mortality and a great percent of morbidity in DM patients. The ED is associated with
the changes in the concentration of the chemical messengers produced by the endothelial cell and/or by
blunting of the nitric oxide (NO)-dependent vasodilatory response to acetylcholine or hyperemia [59].
Factors associated with ED in DM patients include activation of protein kinase C, over expression of
growth factors and/or cytokines, and oxidative stress. Green tea catechins (0.3–3.0 mg/mL) suppressed
the decrease in nicotinamide adenine dinucleotide phosphate and NO in endothelial cells induced by
high glucose (HG) [60], and so green tea EGCG acutely improved ED in patients with coronary artery
disease [61].
Molecules 2017, 22, 849 5 of 19

The underlying mechanisms of endothelial improvement may be related to phosphatidyl inositol

3 kinase (PI3K)/protein kinase B (Akt) and mitogen-activated protein kinases (MAPK) signaling
pathways. Catechin hydrate treatment prevents DM-induced vascular endothelial abnormalities
through activation of PI3K signal and subsequent activation of endothelial nitric oxide synthase (eNOS)
and generation of NO [62]. Tea EGCG induced endothelium-dependent vasodilation by a PI3K and
Akt-dependent increase in eNOS activity [63]. Enhancing p38 MAPK could improve phosphorylation
of the estrogen receptor α (ERα) on Ser-118, and stimulate eNOS activity. Polyphenol-induced
eNOS activation required cotransfection with ERα subject to phosphorylation at Ser-118. Black
tea polyphenols enhanced eNOS activity through p38 MAPK activation [64].

3.4. Modulation of Cytokines Expression

Cytokines are small-secreted proteins expressed mainly by immunocompetent cells, which
contribute to inflammation as inflammatory mediators [65]. Inflammation induces and amplifies
the immune assault against pancreatic β cells at early stages, then stabilizes and maintains insulitis at
later stages. Inflammatory mediators suppress β cells function and subsequent apoptosis, even inhibit
β cells regeneration and cause peripheral insulin resistance [66]. B-Cell dysfunction and insulitis are
key pathological events in DM, thus the modulation of cytokine expression is highly related to DM.
Interleukin (IL), a tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) are normally
used in research as typical cytokines.
Tea and tea extracts may have protective effects against cytokine-induced injuries in β cells
and insulin-producing cells. There was study showing that three cups (600 mL with 7.5 g) of black
tea intake reduced pro-inflammatory cytokines as TNF-α in human, while the expressions of the
anti-inflammatory cytokines such as IL-4, IL-5 and IL-10 were increased [67]. An in vitro study
showed that black tea infusion (150 mL with 2.5 g) suppressed expression of the inflammatory
cytokines TNF-α, IL-1β and IL-6, while it increased IFN-γ, suggesting black tea had a selective
pro-inflammatory cytokine that can also reduce IL-1β and IFN-γ in insulinoma cell and inducible
NO synthase (iNOS) gene expression suppressive effect [68]. EGCG, as an important component of
tea catechins, inhibited the pro-inflammatory effects induced by cytokine that lead to a reduction of
glucose-induced insulin secretion [69] through inhibiting NF-κB activation [27]. Furthermore, green
tea can modulate cytokine expression in the periodontium and attenuate alveolar bone resorption
in which the expression of pro-inflammatory cytokine TNF-α is reduced and the anti-inflammatory
cytokine IL-10 is increased [70].
Pro-inflammatory cytokines can reduce glucose-induced insulin secretion and mitochondrial
activity in cells. EGCG pretreatment of cells has an effect on mitochondrial electron transfer and energy
production, and thus protects the insulin-producing cells through the mitochondrial pathway [69].
Recent studies have further indicated that green tea EGCG inhibits DNA methyltransferase activity
by reactivating methylation-silenced genes and, consequently, IL-10 expression [71]. Most of the
epidemiology and in vivo studies have showed that tea or tea extracts could reduce cytokines or have
a selective effect. The concentration of EGCG is vital to its biofunction, as excessive concentration of
EGCG may trigger other pathways leading to an invalid result.

3.5. Ameliorating Insulin Resistance

Insulin resistance, a key characteristic of T2DM, is characterized by impaired insulin-mediated
glucose disposal in skeletal muscle, hepatic cells or adipose cells. Epidemiological studies have
suggested that tea or tea extracts can decrease insulin resistance, with homeostasis model assessment
of insulin resistance or insulin sensitivity, TG, glycemic, cholesterol, and lipid profiles as index [72–74].
DM decreases the acetylcholinesterase (AChE) activity on brain or erythrocytes membrane, which
is a potential cause of insulin resistance. EGCG restored AChE activity to normal levels like insulin
treatment [75].
Molecules 2017, 22, 849 6 of 19

The function of insulin is to induce PI3K sensitive phosphorylation of transcription factor FOXO1a
that is sensitive to scavengers of free radicals. EGCG mimics insulin actions [76] and promotes
nuclear efflux of FOXO1 in skeletal muscle, resulting in increase in insulin receptor (IR) sensitivity
and decrease in insulin resistance [77]. Dysfunction of IR substrate, a family of docking molecules
attaching to IR, may be the predominant molecular lesion signature of insulin resistance in liver [78].
EGCG can reduce Ser307 phosphorylation of IRS-1 to attenuate insulin signaling blockade through
5’-AMP-activated protein kinase (AMPK) activation pathway, eventually leading to reduction of
insulin resistance [79,80]. Green tea GC, a kind of tea catechins, can stimulate Akt phosphorylation,
instead of AMPK phosphorylation, to promote skeletal muscle glucose transport [81]. An in vivo study
indicated that tea may ameliorate insulin resistance by increasing expression of glucose transporters
IV [82], or alleviating oxidative stress by scavenging reactive oxygen species [83].

3.6. Antihyperglycemic Activity

As a hallmark of DM, chronic hyperglycemia could initiate impairment in diverse cell types [84]
and were considered to be a main cause of diabetic complications like microvascular complications,
neuropathy, retinopathy, stroke, nephropathy and peripheral vascular disease [85]. Intake of 1500 mL
of the oolong tea (15 g brewed in 1500 mL boiling water) by T2DM patients for 1–2 weeks decreased
the concentrations of plasma glucose and fructosamine [86]. The hypoglycemic effect of green tea is
mainly due to its abundant polyphenols, especially catechins, which play a beneficial role in improving
the glucose metabolism of DM, in which EGCG is the predominant antidiabetic active ingredient [87].
First, EGCG can regulate the expression of genes involving in insulin resistance. The sirtuin family
of proteins is downregulated in cells with high insulin resistance, resulting in an increase in insulin
sensitivity. A catechin-enriched GTE prevented glucose-induced survival reduction in Caenorhabditis
elegans through activating adaptive responses mediated by gene SIR-2.1 [88], a gene encoding one of
the sirtuin proteins.
Second, tea extracts regulate enzymes contributing to absorption of glucose. The α-glucosidase
activity was inhibited by oral administration of black tea brew in both normoglycaemic and
STZ-induced DM adult male Wistar rats, resulting in the impairment of glucose absorption from
small intestine and the improvement of glucose tolerance [89]. Maltase was suppressed by oral
administration of extract of LG tea (a co-fermented tea using green tea leaf and loquat leaf, 50 mg/kg)
in maltose-loaded SD rats, showing a strong antihyperglycemic effect [90].
Third, EGCG stimulate glucose-induced insulin secretion. Dietary supplementation with EGCG
at dosages of 2.5–10.0 g/kg of diet for 5–10 weeks in diabetic db/db mice or diabetic Zucker Diabetic
Fatty rats increased blood insulin concentration in a dose-dependent manner [91], resulting in boost
of oral glucose tolerance and reduction of plasma glucose levels. EGCG also improved pancreatic
function and glucose-stimulated insulin secretion [91].

3.7. Improving Complications Associated with Hyperglycemia

DM is often accompanied by many hyperglycemia-associated complications, including
dyslipidemia, cardiovascular diseases (CVD), albuminuria and nephropathy as well as liver damage.
Bioactive components in tea can improve the diabetes complications.
Dyslipidemia is common in DM patients, which is associated with cardiovascular and
atherosclerosis diseases and characterized by overweight and high levels of triglycerides (TG),
total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and low levels of high-density
lipoprotein cholesterol (HDL-C) [92–95]. Animal tests and clinic studies showed that tea and its extract
can alleviate the dyslipidemia. Tests on mice and SD rats revealed that dietary supplementation with
green tea EGCG (1% feed weight) significantly reduced the weight gain and the adipose tissue weight
caused by high fat diet. EGCG supplementation prevented diet-induced increases in body weight
and in state plasma levels of glucose, TG, and leptin by decreasing fatty acid synthase (FAS) and
acetyl-CoA carboxylase-1 mRNA levels in adipose tissue [96]. Furthermore, caffeine in tea might
Molecules 2017, 22, 849 7 of 19

play a role in controlling body weight and dyslipidemia, because caffeine supplement (2.5–8.0%
feed weight) could reduce the body weight and hepatosteatosis in mice overfed with zebrafish [97].
Test on T2DM patients showed that intake of chamomile tea (3 g/150 mL hot water) three times
a day after meals for 8 weeks resulted in a considerable decrease in serum TG, TC, and LDL-C,
compared to control group drinking water [98]. Tea consumption improves DM-induced CVD. The
development of DM is a complex process, in which there is an intermediate state known as prediabetes
characterized by a higher level of blood glucose than normal but below the level identified as DM [99].
Prediabetes is associated with CVD. White tea consumption ameliorated overall metabolic status of
prediabetic rats and prevented most of heart-related deleterious effects by improving glucose tolerance
and insulin sensitivity, increasing the level of cardiac lactate and acetate, decreasing the glucose
transporters (GLUT1 and GLUT3) mRNA expression in cardiac tissue [100,101]. In addition to tea
polyphenols, geraniol, a compound of tea aromatic volatiles, was confirmed to ameliorate impaired
vascular reactivity in STZ-induced DM rats [102].
Tea and its extract ameliorate DM-associated albuminuria which is strongly associated with the
increased risk of diabetic nephropathy. Oral administration of green tea or green tea poplyphenols
reduced albuminuria in DM patients by decreasing podocyte apoptosis through activation of the WNT
pathway [103]. Test on STZ-induced DM rats showed that that (+)-catechin and EGCG in green tea had
renoprotective properties comparable with angiotensin-converting enzyme inhibitor (ACEi), which is
the primary treatment option for patients with diabetic nephropathy [104].
GTE showed hepatoprotective properties in STZ-induced DM rats. Treatment with GTE (1.5%,
w/v) improved histopathological and serum biomarkers in liver tissue in STZ-induced rats, including
hepatic glucose, TG and TC levels as well as antioxidant activities [105].

3.8. Regulation of Gene Expression

Bioactive compounds in tea or tea extract play a role in controlling BG levels by regulating the
expression of genes involving in glycometabolism and the insulin signaling (Irs) pathway. EGCG
downregulated the genes involving in gluconeogenesis. Studies on H4IIE cells and db/db mice showed
that EGCG downregulated the mRNA expression of gluconeogenic enzyme phosphoenolpyruvate
carboxykinase, but upregulated the mRNA expression of glucokinase, an enzyme that facilitates
phosphorylation of glucose to glucose-6-phosphate [91]. GTE at 1 g per kg diet increased the levels of
glucose transporter family (Glut) genes Glut1, Glut4, Gsk3b, and Irs pathway gene Irs2 mRNA by 110,
160, 30, and 60% in the liver, respectively, and increased Irs1 by 80% in the muscle. GTE at 2 g per kg
diet increased levels of Glut4, Gsk3b, and Pik3cb mRNA by 90, 30, and 30% in the liver and increased
Glut2, Glut4, Shc1, and Sos1 by 80, 40, 60, and 50% in the muscle [28]. Dietary supplement of GTE or
EGCG has the potential for beneficially modifying glucose and markedly enhancing glucose tolerance
by regulating the expression of genes involving in the glucose uptake and Irs pathway.
EGCG or green tea regulate the expression of genes involving in the lipid metabolism and the
pathways associated with ageing diseases. EGCG downregulated the genes involving in synthesis
of fatty acids, triacylgycerol and cholesterol [91], resulting in reducing weight and alleviating DM
complications. Advanced glycation end products (AGEs) are believed to play a causative role in
the vascular complications of DM [106,107]. Nuclear factor erythroid-2-related-factor-2 (Nrf2) is
a transcription factor that is encoded by the NFE2L2 gene in humans [108], which regulates the
expression of antioxidant proteins which protect against oxidative damage triggered by inflammation
and injury. Receptor activator of nuclear factor kappa-B ligand (RANKL) is a type II membrane
protein and a member of the tumor necrosis factor (TNF) superfamily. RANKL can affect the immune
system and control the bone regeneration and remodeling. RANKL is an apoptosis regulator gene
which controls cell proliferation by modifying protein levels of Id4, Id2 and cyclin D1 [109]. Dietary
supplement of EGCG attenuated the formation of AGEs in both plasma and liver, activated Nrf2, but
inhibited the expression of receptor for AGE, compared to control mice without dietary supplement of
EGCG [110]. Dietary green tea treatment decreased the expression of the osteoclastogenic mediator
Molecules 2017, 22, 849 8 of 19

RANKL and pro-inflammatory cytokine TNF-α in STZ-induced DM rats, compared with the control
group treated with water. Green tea also increased the expression of osteoprotegerin (a member
of the TNF receptor superfamily), runt-related transcription factor 2 (RUNX-2, a key transcription
factor associated with osteoblast differentiation) and anti-inflammatory cytokine IL-10 [70]. Dietary
supplementation with green tea or EGCG could potentially contribute to nutritional strategies for the
prevention of DM.

3.9. Alleviating Diabetes-Induced Damages of Neural Cells

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder. Increasing evidences
implicate that DM is a risk factor for AD. Tea consumption has been associated with low prevalence of
AD and severe cognitive impairment [111].
The brain is susceptible to glucose fluctuations and hyperglycemia-induced oxidative
stress. Phytochemicals, such as polyphenols, L-theanine, polysaccharides and methylxanthines
were considered to be responsible for the antidiabetic and neuroprotective properties of tea.
Daily administration of tea in prediabetic Wistar rats improved the cerebral cortex neurons by
inhibiting glucose metabolism in the cerebral cortex and reducing the cerebral cortex alanine content
and the expression level of brain glucose transporters. Furthermore, regular consumption of tea has
positive effects on DM-caused complications and restored the cerebral cortex antioxidant capacity
and protein synthesis to normal levels in the cerebral cortex of prediabetic rats [112], contributing to
an improvement of the cognitive function. GABA tea prevented the diabetic-induced cerebral cortex
apoptosis by inhibiting the activity of FAS and by blocking the expression of mitochondrial apoptotic
pathway components, such as FAS, pro-apoptotic t-Bid, Bax, cytosolic cytochrome c, and caspase-3,
caspase-8 and caspase-9. GABA tea also reduced the diabetic-induced autophagy [113]. The formation
of amyloid is associated with the development of diseases such as Huntington’s chorea, Parkinson’s
disease and AD [114,115]. EGCG can effectively inhibit the formation of islet amyloid polypeptide
(IAPP) and break down the amyloid formed by IPPA, which is closely related to the formation of
T2DM [116].
GTE can modulate the analgesic effect of morphine in DM mice [117]. STZ can induce
regurgitation, thermal hyperalgesia and abnormal pain [118–120] and DM decreased the analgesic
effect of morphine [121]. However, co-administration of GTE (50 mg/kg·BW) and morphine
(5 mg/kg·BW) enhanced the analgesic effect of morphine. A possible mechanism is considered
to be the inhibitory effect of GTE on iNOS, resulting in a decrease in NO free radical levels [122]. Green
tea EGCG also inhibited the expression of iNOS by suppressing the inhibitor of nuclear factor kappa B
(NF-κB) and cytokines IL-1, resulting in activation of the NF-κB and inhibition of the IL-1β induced
iNOS [123,124]. These experiments suggest that GTE enhanced the analgesic effect of morphine via
its inhibitory effects on cytokines and iNOS. Furthermore, GTE alleviated the DM-induced vision
disorder. The expression levels of glial fibrillary acidic protein, glutamine synthetase and oxidative
retinal markers were increased in DM rats, resulting in vision disorder. However, green tea protected
the retina against glutamate toxicity via an antioxidant mechanism [125].

3.10. Immunity Improvement and Anti-Inflammation

Inflammation is an important reaction associated with T2DM. GTE had suppressive effects on
inflammatory transcription factors in STZ-induced DM rats. The expression of proinflammatory
in retinae was significantly inhibited by oral administration of GTE (200 mg/kg·BW), as compared
to control (p < 0.05) [40]. Dietary supplementation with EGCG at concentration 0.1% for 25 weeks
in T2DM Goto-Kakizaki rats suppressed the expression of genes encoding proteins involved in
inflammation such as IL-1β, TNF-α, IL-6, CD11s, CD18 and MCP-1 in adipose tissue [126]. Multiple
low doses of STZ (MLD-STZ) induced diabetes via local and systemic pro-inflammatory cytokines [127].
GTE suppressed the expression of MLD-STZ-induced iNOS, in which EGCG was considered to play a
protective role via blocking the cytokine-oxygen radical NF-κB (nuclear factor κB)-iNOS pathway [128].
Molecules 2017, 22, 849 9 of 19

It is considered that the anti-inflammatory activity of EGCG might be associated with decreased
expression of inflammatory transcription factors including NF-κB, signal transducer and transcription
activator, as well as suppressed pro-inflammatory factors such as IL-1β, TNF-α, iNOS, toll-like receptor
4, cyclooxygenase-2 and interferon γ [69,129–133].

4. Inconsistent Results
Although there were many in vitro studies showing that tea and tea extracts had antidiabetic
effects, inconsistent results were also reported from in vivo and clinic studies. A double-blind, placebo
controlled, randomized multiple-dose (0, 375, or 750 mg GTE or black tea extract per day for 3 months)
study in adults with T2DM not taking insulin revealed that green tea or black tea extracts showed no
hypoglycemic effect inT2DM adults [134]. A prospective cohort study including 4975 male workers
over a median of 3.4 years of follow-up in Japan revealed that long-term consumption of oolong tea
may be a predictive factor for new onset diabetes. Compared with those not consuming oolong tea,
multivariable adjusted HR for developing diabetes were 1.00 (95% CI: 0.67–1.49) for those who drank
one cup of oolong tea per day and 1.64 (95% CI: 1.11–2.40) for those drinking two or more cups per
day. Fasting blood glucose increment per year was 0.11 mmol/L (95% CI: 0.09–0.12 mmol/L) for those
who did not drink oolong tea, 0.12 mmol/L (95% CI: 0.09–0.15 mmol/L) for those who drank one cup
per day and 0.15 mmol/L (95% CI: 0.11–0.18 mmol /L) for those who drank two cups per day, with
a significant linear trend (p < 0.0001) [135]. A case-control study involved 600 newly diagnosed DM
children and 536 randomly selected population-based children showed that the risk for T1DM was
increased in the children who consumed one cup of tea (OR: 1.69, 95% CI: 1.21–2.37) or at least two
cups daily (OR 2.59, 95% CI: 1.60–4.18) when adjusted for mother’s education, child’s age and child’s
sex [136].
DM is not a single diseases but a complex syndrome characterized by hyperglycemia resulting
from altered carbohydrate, fat and protein metabolism. There were many factors leading to the
inconsistent results on association of the tea consumption and the decreased DM risk.
First, dosage difference between animal test and clinic test resulted in great variation in
hypoglycaemic effect between animal and clinic tests. When Xiaoke tea was consumed by STZ-induced
DM mice at 20–50 times of the recommended clinical dose (per unit body weight), it produced a slowly
generated antihyperglycaemic effect, without affecting insulin concentrations [137,138]. However,
no significant effects on blood glucose and insulin concentrations were observed in T2DM patients
who drank four cups (2.72 g tea bag infused in 250 mL freshly boiled water) of Xiaoke tea or green tea
daily for four weeks [139].
Second, the antidiabetic effects of tea and tea extract were differentiated among the tested
individuals. Tests on non-obese diabetic mice using water-soluble tea polysaccharide conjugates
(TPC-W) and alkali-soluble tea polysaccharide conjugates (TPC-A) extracted from green tea showed
that two out of 10 mice in non-obese diabetic groups treated with TPC-W or TPC-A exhibited diabetic
symptoms compared with model control group, in which seven of 10 mice developed diabetes [140].
Analysis also showed a difference between men and women. High tea consumption was negatively
associated with central obesity and fasting plasma glucose in women, but not in men [13]. The RR
was 0.92 (95% CI: 0.84 to 1.00) for men, and 1.00 (95% CI: 0.96 to 1.05) for women. For Asians, the RR
was 0.84 (95% CI: 0.71–1.00); but for Americans and Europeans, the RR was 1.00 (95% CI: 0.97–1.04).
Tea consumption of more than three cups per day was associated with decreased T2DM risk in women,
but not in men [21].
Molecules 2017, 22, 849 10 of 19

Third, changes in chemical composition of teas used in experiments lead to variation of test results.
Partial removal of tea components might lead to changes in efficacy. There was test showing that total
caffeine was associated with a reduced risk for T2DM [16]. Decaffeinated tea was prepared by partial
removal of caffeine from tea leaf [141]. Although daily consumption of more than three cups of full tea
could reduce risk of T2DM [14], intake of decaffeinated tea was not associated with the reduced T2DM
risk [142]. The effect of non-fermented green tea on DM was differentiated from that of fully fermented
black tea. It was shown that green tea consumption was associated with increased prevalence of DM
(p = 0.0001), but black tea consumption showed no association with DM [143].
Fourth, many indicators can be used to assess antidiabetic effects of medicines, but individual
medicine might play an antidiabetic effect through different pathways. PGC-1α, a key regulator
of mitochondrial biogenesis and function, plays an important role in the improvement of insulin
sensitivity by increasing fatty acids β-oxidation. Palmitate induced insulin resistance in C2C12 cells by
decreasing PGC-1α protein expression. Rosiglitazone (RGZ), an anti-diabetic drug, could alleviate the
palmitate-induced PGC-1α expression inhibition, while green tea EGCG had no significant effect on
the expression of this gene. However, both RGZ and EGCG significantly improved glucose uptake in
the C2C12 cells treated with palmitate, suggesting that RGZ and EGCG both exert their anti-diabetic
activity by increasing insulin sensitivity, but with different molecular mechanisms. The effect of RGZ
is mediated, at least partly, by increasing PGC-1α protein expression [144], while EGCG played its role
through different pathway.

5. Conclusions and Future Expectations

Both in vitro and in vivo tests have confirmed that green tea catechins, black tea theaflavins and
polysaccharides and caffeine in both green tea and black tea showed antidiabetic effects on T2DM.
Most of the epidemiologic studies showed daily consumption of green tea, black tea and oolong
tea and dietary supplements of EGCG have beneficial effects on T2DM. Table 1 summarizes the
epidemiological evidence for the association between tea drinking and the risk of T2DM.
Tea and its extract play an antidiabetes role by alleviating oxidative stress, inhibiting α-amylase
and α-glucosidase activity, improving endothelial disfunction, modulating cytokine expression,
ameliorating insulin resistance, suppressing hyperglycemia, improving hyperglycemic complications,
regulating signaling pathway involving in DM, enhancing immunity and alleviating diabetes-induced
damages of neural cells.
The antidiabetic effect of tea depends on the bioactive compounds in tea. The chemical
composition of teas varies with the tea cultivars and degree fermentation during tea processing,
which lead to inconsistent antidiabetic results between various tests using teas from various sources.
It is important to isolate purified individual bioactive compounds so as to test their antidiabetic effect
individually. This will help to clarify the principal antidiabetic components in tea, and be interesting
for improvement of tea processing.
Bioavailability is an important factor influencing the pharmaceutical effects of tea on diabetes [11].
The inconsistent antidiabetic effect of tea from tests on various individuals and populations might
be related to the variation in bioavailability of tea components owing to differences in physiological
status between tested individuals and populations. Encapsulating tea extract in chitosan nanoparticles
was reported to be beneficial to stabilize tea bioactive components such as catechins in vivo, and to
improve intestinal absorption [145]. Furthermore, co-administration of green tea EGCG with foods
such as strawberry sorbet will reduce plasma EGCG [146]. Studies on in vivo adsorption mechanism
of antidiabetic components in tea and development of methods to improve their bioavailability will be
an important research topic in the future.
Molecules 2017, 22, 849 11 of 19

Table 1. Epidemiological evidence for the association between tea drinking and the risk of T2DM.

Type of Study Location Tea Type Number of Subjects Main Results References
Population Tea consumption was negatively associated with central obesity and
Krakow, Poland Black tea 8821 adults (51.4% female) [13]
based study fasting plasma glucose
Population
Amsterdam, Black tea 10-year follow-up
based cohort Daily consumption of ≥3 cups of tea reduced the risk of T2DM by 42% [14]
The Netherlands green tea (40,011 participants)
study
Tea intake was associated with the reduced risk of T2DM, with a hazard
Prospective 11.7 years follow-up (4055 men
London, UK Black tea ratio (HR): 0·66 (95% CI: 0.61–1.22; p < 0.05) after adjustment for age, [15]
cohort study and 1768 women)
gender, ethnicity and social status
Retrospective 5-year follow-up (6727 men and Drinking six cups of green tea per day was significantly associated with
Osaka, Japan Green tea [16]
cohort study 10,686 women) a lower risk for T2DM (OR = 0.67, 95% CI: 0.47–0.94)
Case-control Moderate first trimester tea intake were not associated with increased
Denmark Black tea Cases: 912, control: 70,327 [17]
study risk of gestational diabetes mellitus, but may have a protective effect
Prevalence of uncontrolled DM (UDM) was about 39% and higher
Community
Karachi, Pakistan Black tea 452 T2DM participants consumption of tea was independently associated with UDM, with an [18]
based study
OR: 1.5 (95% CI: 1.0–2.2)
Tea drinking could alleviate the decrease of fasting blood insulin
China, South Korea, USA, Black tea, green
Meta-analysis 608 participants (1.30 U/L, 95% CI: 0.36–2.24) and reduced waist circumference in more [19]
Japan, Iran tea, oolong tea
than 8-week intervention
USA, Japan, Singapore, Black tea, High intakes of decaffeinated tea were significantly associated with
Meta-analysis 457,922 participants [20]
Puerto Rico, UK, Finland green tea reduced risk of incident diabetes
12 countries including
Oolong tea, Daily tea consumption (≥3 cups/day) was associated with a lower
Meta-analysis USA, Finland, Japan, UK, 761,949 participants [21]
green tea T2DM risk
and etc.
Consumption of green or oolong tea may protect against the
Cross-sectional Oolong tea, green
Fujian, China 4808 participants development of T2DM in Chinese men and women, particularly in those [22]
study tea, black tea
who drink 16–30 cups per week
A World Health Survey High black tea consumption was significantly correlated to low DM
Meta-analysis Black tea More than 38,562 participants [31]
involving 50 countries prevalence
A single dose of black tea decreased peripheral vascular resistance (VR)
Cross-sectional Nijmegen, across upper and lower limbs after a glucose load which was
Black tea 16 men [32]
study The Netherlands accompanied by a lower insulin response (p < 0.05). Postprandial insulin
response was attenuated by ~29% after tea consumption (p < 0.0005)
Chronic administration of the Rauvolfia-Citrus tea to overweight T2DM
Case control Rauvolfia-Citrus on OADs caused significant improvements in markers of glycaemic
Denmark Cases: 11, control: 7 [33]
study tea control and modifications to the fatty acid profile of skeletal muscle,
without adverse effects or hypoglycaemia
Molecules 2017, 22, 849 12 of 19

Acknowledgments: This work was financially supported by the Agricultural Science and Technology
Development Foundation of Shandong Province.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. World Health Organization. The Top 10 Causes of Death. 2015. Available online: http://www.who.int/
mediacentre/factsheets/fs310/en/ (accessed on 19 May 2017).
2. Hoyert, D.L.; Xu, J. Deaths. Preliminary Data for 2011. Natl. Vital Stat. Rep. 2012, 61, 1–51. [PubMed]
3. Zhu, B.; Wu, X.M.; Bi, Y.F.; Yang, Y. Effect of bilirubin concentration on the risk of diabetic complications:
A meta-analysis of epidemiologic studies. Sci. Rep. 2017, 7, 41681. [CrossRef] [PubMed]
4. Aathira, R.; Jain, V. Advances in management of type 1 diabetes mellitus. World J. Diabetes 2014, 5, 68–96.
[CrossRef] [PubMed]
5. American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care 2014, 37, S14–S80.
6. American Diabetes Association. Clinical practice recommendations 2007. Diabetes Care 2007, 30, S3.
7. Lopes, G.; Andrade, P.B.; Valentao, P. Phlorotannins: Towards New Pharmacological Interventions for
Diabetes Mellitus Type 2. Molecules 2017, 22, 56. [CrossRef] [PubMed]
8. De Souza, G.F.P.; Novaes, L.F.T.; Avila, C.M.; Nascimento, L.F.R.; Velloso, L.A.; Pilli, R.A.
(−)-Tarchonanthuslactone Exerts a Blood Glucose-Increasing Effect in Experimental Type 2 Diabetes Mellitus.
Molecules 2015, 20, 5038–5049. [CrossRef] [PubMed]
9. Hong, X.; Xu, F.; Wang, Z.; Liang, Y.; Li, J. Dietary patterns and the incidence of hyperglyacemia in China.
Public Health Nutr. 2015, 19, 131–141. [CrossRef] [PubMed]
10. Jankun, J.; Al-Senaidy, A.; Skrzypczak-Jankun, E. Can drinking black tea fight diabetes: Literature review
and theoretical indication. Cent. Eur. J. Immunol. 2012, 37, 167–172.
11. Xiang, L.P.; Wang, A.; Ye, J.H.; Zheng, X.Q.; Polito, C.A.; Lu, J.L.; Li, Q.S.; Liang, Y.R. Suppressive effects of
tea catechins on breast cancer. Nutrients 2016, 8, 458. [CrossRef] [PubMed]
12. Du, L.L.; Fu, Q.Y.; Xiang, L.P.; Zheng, X.Q.; Lu, J.L.; Ye, J.H.; Li, Q.S.; Polito, C.A.; Liang, Y.R.
Tea Polysaccharides and Their Bioactivities. Molecules 2016, 21, 1449. [CrossRef] [PubMed]
13. Grosso, G.; Stepaniak, U.; Micek, A.; Topor-Madry, R.; Pikhart, H.; Szafraniec, K.; Pajak, A. Association of
daily coffee and tea consumption and metabolic syndrome: Results from the Polish arm of the HAPIEE
study. Eur. J. Nutr. 2015, 54, 1129–1137. [CrossRef] [PubMed]
14. Van Dieren, S.; Uiterwaal, C.S.; van der Schouw, Y.T.; van der Schouw, D.L.; Boer, J.M.; Spijkerman, A.;
Grobbee, D.E.; Beulens, J.W. Coffee and tea consumption and risk of type 2 diabetes. Diabetologia 2009, 52,
2561–2569. [CrossRef] [PubMed]
15. Hamer, M.; Witte, D.R.; Mosdøl, A.; Marmot, M.G.; Brunner, E.J. Prospective study of coffee and tea
consumption in relation to risk of type 2 diabetes mellitus among men and women: The Whitehall II study.
Br. J. Nutr. 2008, 100, 1046–1053. [CrossRef] [PubMed]
16. Iso, H.; Date, C.; Wakai, K.; Fukui, M.; Tamakoshi, A. The relationship between green tea and total caffeine
intake and risk for self-reported type 2 diabetes among Japanese adults. Ann. Intern. Med. 2006, 144, 554–562.
[CrossRef] [PubMed]
17. Hinkle, S.N.; Laughon, S.K.; Catov, J.M.; Olsen, J.; Bech, B.H. First trimester coffee and tea intake and risk
of gestational diabetes mellitus: A study within a national birth cohort. Bjog-Int. J. Obstet. Gy. 2015, 122,
420–428. [CrossRef] [PubMed]
18. Siddiquia, F.J.; Avanc, B.I.; Mahmudd, S.; Nananf, D.J.; Jabbarh, A.; Assama, P.N. Uncontrolled diabetes
mellitus: Prevalence and risk factors among people with type 2 diabetes mellitus in an Urban District of
Karachi, Pakistan. Diabetes Res. Clin. Pract. 2015, 107, 148–156. [CrossRef] [PubMed]
19. Li, Y.; Wang, C.; Huai, Q.; Guo, F.; Liu, L.; Feng, R.; Sun, C. Effects of tea or tea extract on metabolic profiles
in patients with type 2 diabetes mellitus: A meta analysis of ten randomized controlled trials. Diabetes Metab.
Res. Rev. 2016, 32, 2–10. [CrossRef] [PubMed]
20. Huxley, R.R.; Lee, C.; Barzi, F.; Timmermeister, L.; Czernichow, S.; Perkovic, V.; Grobbee, D.E.; Batty, D.;
Woodward, M. Coffee, decaffeinated coffee, and tea consumption in relation to incident type-II diabetes
mellitus: A systematic review with meta-analysis. Arch. Intern. Med. 2009, 169, 2053–2063. [CrossRef]
[PubMed]
Molecules 2017, 22, 849 13 of 19

21. Yang, J.; Mao, Q.X.; Xu, H.X.; Ma, X.; Zeng, C.Y. Tea consumption and risk of type 2 diabetes mellitus: A
systematic review and meta-analysis update. BMJ Open 2014, 4, e005632. [CrossRef] [PubMed]
22. Huang, H.; Guo, Q.; Qiu, C.; Huang, B.; Fu, X.; Yao, J.; Liang, J.; Li, L.; Chen, L.; Tang, K.; et al. Associations
of green tea and rock tea consumption with risk of impaired fasting glucose and impaired glucose tolerance
in Chinese men and women. PLoS ONE 2013, 8, e79214. [CrossRef] [PubMed]
23. Liang, Y.R.; Ye, Q.; Jin, J.; Liang, H.; Lu, J.L.; Du, Y.Y.; Dong, J.J. Chemical and instrumental assessment of
green tea sensory preference. Int. J. Food Prop. 2008, 11, 258–272. [CrossRef]
24. Liang, Y.R.; Lu, J.L.; Zhang, L.Y.; Wu, S.; Wu, Y. Estimation of black tea quality by analysis of chemical
composition and colour difference of tea infusions. Food Chem. 2003, 80, 283–290. [CrossRef]
25. Abdul-Ghani, M.A.; Jenkinson, C.P.; Richardson, D.K.; Tripathy, D.; DeFronzo, R.A. Insulin secretion and
action in subjects with impaired fasting glucose and impaired glucose tolerance: Results from the veterans
administration genetic epidemiology study. Diabetes 2006, 55, 1430–1435. [CrossRef] [PubMed]
26. Abdul-Ghani, M.A.; Tripathy, D.; Defronzo, R.A. Contributions of β-cell dysfunction and insulin resistance
to the pathogenesis of impaired glucose tolerance and impaired fasting glucose. Diabetes Care 2006, 29,
1130–1139. [CrossRef] [PubMed]
27. Han, M.K. Epigallocatechin gallate, a constituent of green tea, suppresses cytokine-induced pancreatic β-cell
damage. Exp. Mol. Med. 2003, 35, 136–139. [CrossRef] [PubMed]
28. Cao, H.; Hininger-Favier, I.; Kelly, M.A.; Benaraba, R.; Dawson, H.D.; Coves, S.; Roussel, A.M.; Anderson, R.A.
Green tea polyphenol extract regulates the expression of genes involved in glucose uptake and insulin
signaling in rats fed a high fructose diet. J. Agric. Food Chem. 2007, 55, 6372–6378. [CrossRef] [PubMed]
29. Matsui, T.; Tanaka, T.; Tamura, S.; Toshima, A.; Tamaya, K.; Miyata, Y.; Tanaka, K.; Matsumoto, K.
Alpha-glucosidase inhibitory profile of catechins and theaflavins. J. Agric. Food Chem. 2007, 55, 99–105.
[CrossRef] [PubMed]
30. Mukwevho, E.; Kohn, T.A.; Lang, D.; Nyatia, E.; Smith, J.; Ojuka, E.O. Caffeine induces hyperacetylation
of histones at the MEF2 site on the Glut4promoter and increases MEF2A binding to the site via a
CaMK-dependent mechanism. Am. J. Physiol. Endocrinol. Metab. 2008, 294, E582–E588. [CrossRef] [PubMed]
31. Beresniak, A.; Duru, G.; Berger, G.; Bremond-Gignac, D. Relationships between black tea consumption and
key health indicators in the world: An ecological study. BMJ Open 2012, 2, e000648. [CrossRef] [PubMed]
32. Fuchs, D.; Nyakayiru, J.; Draijer, R.; Mulder, T.P.J.; Hopman, M.T.E.; Eijsvogels, T.M.H.; Thijssen, D.H.
Impact of flavonoid-rich black tea and beetroot juice on postprandial peripheral vascular resistance and
glucose homeostasis in obese, insulin-resistant men: A randomized controlled trial. Nutr. Metab. 2016, 13, 34.
[CrossRef] [PubMed]
33. Campbell-Tofte, J.I.; Mølgaard, P.; Josefsen, K.; Abdallah, Z.; Hansen, S.H.; Cornett, C.; Mu, H.; Richter, E.A.;
Petersen, H.W.; Nørregaard, J.C.; et al. Randomized and double-blinded pilot clinical study of the safety and
anti-diabetic efficacy of the Rauvolfia-Citrus tea, as used in Nigerian traditional medicine. J. Ethnopharmacol.
2011, 133, 402–411. [CrossRef] [PubMed]
34. Babu, P.V.A.; Sabitha, K.E.; Shyamaladevi, C.S. Therapeutic effect of green tea extract on oxidative stress in
aorta and heart of streptozotocin diabetic rats. Chem-Biol Interact. 2006, 162, 114–120. [CrossRef] [PubMed]
35. Kumar, D.; Rizvi, S.I. Black tea extract improves anti-oxidant profile in experimental diabetic rats.
Arch. Physiol. Biochem. 2015, 121, 109–115. [CrossRef] [PubMed]
36. Ozyurt, H.; Luna, C.; Estevez, M. Redox chemistry of the molecular interactions between tea catechins
and human serum proteins under simulated hyperglycemic conditions. Food Funct. 2016, 7, 1390–1400.
[CrossRef] [PubMed]
37. Sharifzadeh, M.; Ranjbar, A.; Hosseini, A.; Khanavi, M. The effect of green tea extract on oxidative stress and
spatial learning in Streptozotocin-diabetic rats. Iran. J. Pharm. Res. 2017, 16, 201–209. [PubMed]
38. Neyestani, T.R.; Shariatzade, N.; Kalayi, A.; Gharavi, A.A.; Khalaji, N.; Dadkhah, M.; Zowghi, T.; Haidari, H.;
Shab-bidar, S. Regular daily intake of black tea improves oxidative stress biomarkers and decreases serum
c-reactive protein levels in type 2 diabetic patients. Ann. Nutr. Metab. 2010, 57, 40–49. [CrossRef] [PubMed]
39. Frei, B.; Higdon, J.V. Antioxidant activity of tea polyphenols in vivo: Evidence from animal studies. J. Nutr.
2003, 133, 3275S–3284S. [PubMed]
40. Kumar, B.; Gupta, S.K.; Nag, T.C.; Srivastava, S.; Saxena, R. Green tea prevents hyperglycemia-induced
retinal oxidative stress and inflammation in streptozotocin-induced diabetic rats. Ophthal Res. 2012, 47,
103–107. [CrossRef] [PubMed]
Molecules 2017, 22, 849 14 of 19

41. Han, H.R.; Bai, X.R.; Zhang, N.; Zhao, D.D.; Wei, K.H.; Zhang, C.H.; Li, M.H. Activities constituents from
yaowang tea (Potentilla glabra Lodd.). Food Sci. Technol. Res. 2016, 22, 371–376. [CrossRef]
42. Dufresne, C.J.; Farnworth, E.R. A review of latest research findings on the health promotion properties of tea.
J. Nutr. Biochem. 2001, 12, 404–421. [CrossRef]
43. Basu, A.; Betts, N.M.; Mulugeta, A.; Tong, C.; Newman, E.; Lyons, T.J. Green tea supplementation increases
glutathione and plasma antioxidant capacity in adults with the metabolic syndrome. Nutr. Res. 2013, 33,
180–187.
44. Kongpichitchoke, T.; Chiu, M.T.; Huang, T.C.; Hsu, J.L. Gallic acid content in taiwanese teas at different
degrees of fermentation and its antioxidant activity by inhibiting PKC delta activation: In vitro and in silico
studies. Molecules 2016, 21, 1346. [CrossRef] [PubMed]
45. Chen, H.X.; Qu, Z.; Fu, L.L.; Dong, P.; Zhang, X. Physicochemical properties and antioxidant capacity of
3 polysaccharides from green tea, oolong tea, and black tea. J. Food Sci. 2009, 74, C469–C474. [CrossRef]
[PubMed]
46. Spadiene, A.; Savickiene, N.; Ivanauskas, L.; Jakstas, V.; Skesters, A.; Silova, A.; Rodovicius, H. Antioxidant
effects of Camellia sinensis L. extract in patients with type 2 diabetes. J. Food Drug Anal. 2014, 22, 505–511.
47. Zhang, M.; Cheung, P.C.; Zhang, L. Evaluation of mushroom dietary fiber (nonstarch polysaccharides) from
sclerotia of pleurotus tuber-regium (fries) singer as a potential antitumor Agent. J. Agric. Food Chem. 2001,
49, 5059–5062. [CrossRef] [PubMed]
48. Ye, X.P.; Song, C.Q.; Yuna, P.; Mao, R.G. α-Glucosidase and α-amylase inhibitory activity of common
constituents from traditional Chinese medicine used for diabetes mellitus. Chin. J. Nat. Med. 2010, 8, 349–352.
[CrossRef]
49. Lochocka, K.; Bajerska, J.; Glapa, A.; Fidler-Witon, E.; Nowak, J.K.; Szczapa, T.; Grebowiec, P.; Lisowska, A.;
Walkowiak, J. Green tea extract decreases starch digestion and absorption from a test meal in humans: A
randomized, placebo-controlled crossover study. Sci. Rep. 2015, 5, 12015. [CrossRef] [PubMed]
50. Yang, X.P.; Kong, F.B. Evaluation of the in vitro alpha-glucosidase inhibitory activity of green tea polyphenols
and different tea types. J. Sci. Food Agr. 2016, 96, 777–782. [CrossRef] [PubMed]
51. Li, T.; Liu, J.; Zhang, X.D.; Ji, G. Antidiabetic activity of lipophilic (−)-epigallocatechin-3-gallate derivative
under its role of α-glucosidase inhibition. Biomed. Pharmacother. 2007, 61, 91–96. [CrossRef] [PubMed]
52. Peixoto, E.B.; Papadimitriou, A.; Teixeira, D.A.T.; Montemurro, C.; Duarte, D.A.; Silva, K.C.; de Faria, J.L.
Reduced LRP6 expression and increase in the interaction of GSK3β with p53 contribute to podocyte apoptosis
in diabetes mellitus and are prevented by green tea. J. Nutr. Biochem. 2015, 26, 416–430. [CrossRef] [PubMed]
53. Oh, J.; Jo, S.; Kim, J.; Ha, K.; Lee, J.; Choi, H.; Yu, S.; Kwon, Y.; Kim, Y. Selected tea and tea pomace extracts
inhibit intestinal α-glucosidase activity in vitro and postprandial hyperglycemia in vivo. Int. J. Mol. Sci.
2015, 16, 8811–8825. [CrossRef] [PubMed]
54. Liu, S.Y.; Yu, Z.; Zhu, H.K.; Zhang, W.; Chen, Y.Q. In vitro alpha-glucosidase inhibitory activity of isolated
fractions from water extract of qingzhuan dark tea. BMC Complem. Altern. M. 2016, 16, 378. [CrossRef]
[PubMed]
55. Kamiyama, O.; Sanae, F.; Ikeda, K.; Higashi, Y.; Minami, Y.; Asano, N.; Adachi, I.; Kato, A. In vitro inhibition
of alpha-glucosidases and glycogen phosphorylase by catechin gallates in green tea. Food Chem. 2010, 122,
1061–1066. [CrossRef]
56. Lo Piparo, E.; Scheib, H.; Frei, N.; Williamson, G.; Grigorov, M.; Chou, C.J. Flavonoids for controlling starch
digestion: Structural requirements for inhibiting human α-amylase. J. Med. Chem. 2008, 51, 3555–3561.
[CrossRef] [PubMed]
57. Miao, M.; Jiang, B.; Jiang, H.; Zhang, T.; Li, X.F. Interaction mechanism between green tea extract and human
alpha-amylase for reducing starch digestion. Food Chem. 2015, 186, 20–25. [CrossRef] [PubMed]
58. Yilmazer-Musa, M.; Griffith, A.M.; Michels, A.J.; Schneider, E.; Frei, B. Grape seed and tea extracts and
catechin 3-gallates are potent inhibitors of alpha-amylase and alpha-glucosidase activity. J. Agric. Food Chem.
2012, 60, 8924–8929. [CrossRef] [PubMed]
59. Calles-Escandon, J.; Cipolla, M. Diabetes and endothelial dysfunction: A clinical perspective. Endocr. Rev.
2001, 22, 36–52. [CrossRef] [PubMed]
60. Peristiowati, Y.; Indasah, I.; Ratnawati, R. The effects of catechin isolated from green tea GMB-4 on NADPH
and nitric oxide levels in endothelial cells exposed to high glucose. J. Intercult. Ethnopharmacol. 2015, 4, 114.
[PubMed]
Molecules 2017, 22, 849 15 of 19

61. Widlansky, M.E.; Hamburg, N.M.; Anter, E.; Holbrook, M.; Kahn, D.F.; Elliott, J.G.; Keaney, J.F.; Vita, J.A.
Acute EGCG supplementation reverses endothelial dysfunction in patients with coronary artery disease.
J. Am. Coll. Nutr. 2007, 26, 95–102. [CrossRef] [PubMed]
62. Bhardwaj, P.; Khanna, D.; Balakumar, P. Catechin averts experimental diabetes mellitus-induced vascular
endothelial structural and functional abnormalities. Cardiovasc. Toxicol. 2014, 14, 41–51. [CrossRef] [PubMed]
63. Lorenz, M.; Wessler, S.; Follmann, E.; Michaelis, W.; Dusterhoft, T.; Baumann, G.; Stangl, K.; Stangl, V.
A constituent of green tea, epigallocatechin-3-gallate, activates endothelial nitric oxide synthase by a
phosphatidylinositol-3-OH-kinase-, cAMP-dependent protein kinase-, and Akt-dependent pathway and
leads to endothelial-dependent vasorelaxation. J. Biol. Chem. 2004, 279, 6190–6195. [CrossRef] [PubMed]
64. Anter, E.; Chen, K.; Shapira, O.M.; Karas, R.H.; Keaney, J.F. P38 mitogen-activated protein kinase activates
eNOS in endothelial cells by an estrogen receptor alpha-dependent pathway in response to black tea
polyphenols. Circ. Res. 2005, 96, 1072–1078. [CrossRef] [PubMed]
65. Wedekind, L.; Belkacemi, L. Altered cytokine network in gestational diabetes mellitus affects maternal
insulin and placental-fetal development. J. Diabetes Complicat. 2016, 30, 1393–1400. [CrossRef] [PubMed]
66. Eizirik, D.L.; Colli, M.L.; Ortis, F. The role of inflammation in insulitis and beta-cell loss in type 1 diabetes.
Nat. Rev. Endocrinol. 2009, 5, 219–226. [CrossRef] [PubMed]
67. Mahmoud, F.; Haines, D.; Al-Ozairi, E.; Dashti, A. Effect of black tea consumption on intracellular cytokines,
regulatory t cells and metabolic biomarkers in type 2 diabetes patients. Phytother. Res. 2016, 30, 454–462.
[CrossRef] [PubMed]
68. Neyestani, T.R.; Gharavi, A.; Kalayi, A. Selective effects of tea extract and its phenolic compounds on human
peripheral blood mononuclear cell cytokine secretions. Intl. J. Food Sci. Nutr. 2009, 60, 79–88. [CrossRef]
[PubMed]
69. Zhang, Z.F.; Ding, Y.; Dai, X.Q.; Wang, J.B.; Li, Y. Epigallocatechin-3-gallate protects pro-inflammatory
cytokine induced injuries in insulin-producing cells through the mitochondrial pathway. Eur. J. Pharmacol.
2011, 670, 311–316. [CrossRef] [PubMed]
70. Gennaro, G.; Claudino, M.; Cestari, T.M.; Ceolin, D.; Germino, P.; Garlet, G.P.; de Assis, G.F. Green tea
modulates cytokine expression in the periodontium and attenuates alveolar bone resorption in type 1 diabetic
rats. PLoS ONE 2015, 10, e0134784. [CrossRef] [PubMed]
71. Wong, C.P.; Nguyen, L.P.; Noh, S.K.; Bray, T.M.; Bruno, R.S.; Ho, E. Induction of regulatory t cells by green
tea polyphenol EGCG. Immunol. Lett. 2011, 139, 7–13. [CrossRef] [PubMed]
72. Liu, C.Y.; Huang, C.J.; Huang, L.H.; Chen, I.J.; Chiu, J.P.; Hsu, C.H. Effects of green tea extract on
insulin resistance and glucagon-like peptide 1 in patients with type 2 diabetes and lipid abnormalities:
A randomized, double-blinded, and placebo-controlled trial. PLoS ONE 2014, 9, e91163. [CrossRef] [PubMed]
73. Chang, C.S.; Chang, Y.F.; Liu, P.Y.; Chen, C.Y.; Tsai, Y.S.; Wu, C.H. Smoking, habitual tea drinking and
metabolic syndrome in elderly men living in rural community: The Tianliao old people (top) study 02.
PLoS ONE 2012, 7, e38874. [CrossRef] [PubMed]
74. Keske, M.A.; Ng, H.L.H.; Premilovac, D.; Rattigan, S.; Kim, J.A.; Munir, K.; Yang, P.X.; Quon, M.J. Vascular
and metabolic actions of the green tea polyphenol epigallocatechin gallate. Curr. Med. Chem. 2015, 22, 59–69.
[CrossRef] [PubMed]
75. Rizvi, S.I.; Zaid, M.A. Insulin-like effect of (−)epicatechin on erythrocyte membrane acetylcholinesterase
activity in type 2 diabetes mellitus. Clin. Exp. Pharmacol. Physiol. 2001, 28, 776–778. [CrossRef] [PubMed]
76. Anton, S.; Melville, L.; Rena, G. Epigallocatechin gallate (EGCG) mimics insulin action on the transcription
factor foxo1a and elicits cellular responses in the presence and absence of insulin. Cell Signal 2007, 19,
378–383. [CrossRef] [PubMed]
77. Wimmer, R.J.; Russell, S.J.; Schneider, M.F. Green tea component EGCG, insulin and IGF-1 promote nuclear
efflux of atrophy-associated transcription factor Foxo1 in skeletal muscle fibers. J. Nutr. Biochem. 2015, 26,
1559–1567. [CrossRef] [PubMed]
78. Thirone, A.C.P.; Huang, C.; Klip, A. Tissue-specific roles of IRS proteins in insulin signaling and glucose
transport. Trends Endocrin. Met. 2006, 17, 70–76. [CrossRef] [PubMed]
79. Lin, C.L.; Lin, J.K. Epigallocatechin gallate (EGCG) attenuates high glucose-induced insulin signaling
blockade in human hepG2 hepatoma cells. Mol. Nutr. Food Res. 2008, 52, 930–939. [CrossRef] [PubMed]
Molecules 2017, 22, 849 16 of 19

80. Collins, Q.F.; Liu, H.Y.; Pi, J.B.; Liu, Z.Q.; Quon, M.J.; Cao, W.H. Epigallocatechin-3-gallate (EGCG), a green
tea polyphenol, suppresses hepatic gluconeogenesis through 50 -AMP-activated protein kinase. J. Biol. Chem.
2007, 282, 30143–30149. [CrossRef] [PubMed]
81. Ma, X.; Tsuda, S.; Yang, X.; Gu, N.; Tanabe, H.; Oshima, R.; Matsushita, T.; Egawa, T.; Dong, A.J.; Zhu, B.W.;
et al. Pu-erh tea hot-water extract activates akt and induces insulin-independent glucose transport in rat
skeletal muscle. J. Med. Food 2013, 16, 259–262. [CrossRef] [PubMed]
82. Wu, L.Y.; Juan, C.C.; Hwang, L.S.; Hsu, Y.P.; Ho, P.H.; Ho, L.T. Green tea supplementation ameliorates insulin
resistance and increases glucose transporter IV content in a fructose-fed rat model. Eur. J. Nutr. 2004, 43,
116–124. [CrossRef] [PubMed]
83. Yan, J.Q.; Zhao, Y.; Suo, S.Q.G.W.; Liu, Y.; Zhao, B.L. Green tea catechins ameliorate adipose insulin resistance
by improving oxidative stress. Free Radical Bio. Med. 2012, 52, 1648–1657. [CrossRef] [PubMed]
84. Preuss, H.G. Effects of glucose/insulin perturbations on aging and chronic disorders of aging: The evidence.
J. Am. Coll. Nutr. 1997, 16, 397–403. [CrossRef] [PubMed]
85. Cade, W.T. Diabetes-Related Microvascular and Macrovascular Diseases in the Physical Therapy Setting.
Phys. Ther. 2008, 88, 1322–1335. [CrossRef] [PubMed]
86. Hosoda, K.; Wang, M.F.; Liao, M.L.; Chuang, C.K.; Iha, M.; Clevidence, B.; Yamamoto, S. Antihyperglycemic
effect of oolong tea in type 2 diabetes. Diabetes Care 2003, 26, 1714–1718. [CrossRef] [PubMed]
87. Anderson, R.A.; Polansky, M.M. Tea Enhances Insulin Activity. J. Agric. Food Chem. 2002, 50, 7182–7186.
[CrossRef] [PubMed]
88. Deusing, D.J.; Winter, S.; Kler, A.; Kriesl, E.; Bonnlander, B.; Wenzel, U.; Fitzenberger, E. A catechin-enriched
green tea extract prevents glucose-induced survival reduction in Caenorhabditis elegans through sir-2.1 and
uba-1 dependent hormesis. Fitoterapia 2015, 102, 163–170. [CrossRef] [PubMed]
89. Jayakody, J.R.A.C.; Ratnasooriya, W.D. Blood glucose level lowering activity of Sri Lankan black tea brew
(Camellia sinensis) in rats. Pharmacogn. Mag. 2008, 4, 341–349.
90. Tamaya, K.; Matsui, T.; Toshima, A.; Noguchi, M.; Ju, Q.; Miyata, Y.; Tanaka, T.; Tanaka, K. Suppression of
blood glucose level by a new fermented tea obtained by tea-rolling processing of loquat (Eriobotrya japonica)
and green tea leaves in disaccharide-loaded Sprague-Dawley rats. J. Sci. Food Agric. 2010, 90, 779–783.
[CrossRef] [PubMed]
91. Wolfram, S.; Raederstorff, D.; Preller, M.; Wang, Y.; Teixeira, S.R.; Riegger, C.; Weber, P. Epigallocatechin
gallate supplementation alleviates diabetes in rodents. J. Nutr. 2006, 136, 2512–2518. [PubMed]
92. Moller, D.E. New drug targets for type 2 diabetes and the metabolic syndrome. Nature 2001, 414, 821–827.
[CrossRef] [PubMed]
93. Saxena, R.; Madhu, S.V.; Shukla, R.; Prabhu, K.M.; Gambhir, J.K. Postprandial hypertriglyceridemia and
oxidative stress in patients of type 2 diabetes mellitus with macrovascular complications. Clin. Chim. Acta
2005, 359, 101–108. [CrossRef] [PubMed]
94. Toth, P.P. High-density lipoprotein as a therapeutic target: Clinical evidence and treatment strategies.
Am. J. Cardiol. 2005, 96, 50K–58K. [CrossRef] [PubMed]
95. Veiraiah, A. Hyperglycemia, lipoprotein glycation, and vascular disease. Angiology 2005, 56, 431–438.
[CrossRef] [PubMed]
96. Wolfram, S.; Raederstorff, D.; Wang, Y.; Teixeira, S.R.; Elste, V.; Weber, P. TEAVIGOTM (Epigallocatechin
gallate) supplementation prevents obesity in rodents by reducing adipose tissue mass. Ann. Nutr. Metab.
2005, 49, 54–63. [CrossRef] [PubMed]
97. Zheng, X.C.; Dai, W.C.; Chen, X.H.; Wang, K.Y.; Zhang, W.Q.; Liu, L.; Hou, J.L. Caffeine reduces hepatic lipid
accumulation through regulation of lipogenesis and ER stress in zebrafish larvae. J. Biomed. Sci. 2015, 22, 105.
[CrossRef] [PubMed]
98. Greenberg, J.A.; Axen, K.V.; Schnoll, R.; Boozer, C.N. Coffee, tea and diabetes: The role of weight loss and
caffeine. Int. J. Obes. (Lond). 2005, 29, 1121–1129. [CrossRef] [PubMed]
99. Hinder, L.M.; O’Brien, P.D.; Hayes, J.M.; Backus, C.; Solway, A.P.; Sims-Robinson, C.; Feldman, E.L. Dietary
reversal of neuropathy in a murine model of prediabetes and the metabolic syndrome. Dis. Model. Mech.
2017. [CrossRef] [PubMed]
100. Alves, M.G.; Martins, A.D.; Teixeira, N.F.; Rato, L.; Oliveira, P.F.; Silva, B.M. White tea consumption improves
cardiac glycolytic and oxidative profile of prediabetic rats. J. Funct. Foods 2015, 14, 102–110. [CrossRef]
Molecules 2017, 22, 849 17 of 19

101. Dias, T.R.; Alves, M.G.; Rato, L.; Casal, S.; Silva, B.M.; Oliveira, P.F. White tea intake prevents
prediabetes-induced metabolic dysfunctions in testis and epididymis preserving sperm quality. J. Nutr.
Biochem. 2016, 37, 83–93. [CrossRef] [PubMed]
102. El-Bassossy, H.M.; Elberry, A.A.; Ghareib, S.A. Geraniol improves the impaired vascular reactivity in diabetes
and metabolic syndrome through calcium channel blocking effect. J. Diabetes Complicat. 2016, 30, 1008–1016.
[CrossRef] [PubMed]
103. Borges, C.M.; Papadimitriou, A.; Duarte, D.A.; Lopes de Faria, J.M.; Lopes de Faria, J.B. The use of green tea
polyphenols for treating residual albuminuria in diabetic nephropathy: A double-blind randomised clinical
trial. Sci. Rep. 2016, 6, 28282. [CrossRef] [PubMed]
104. Yamabe, N.; Kang, K.S.; Hur, J.M.; Yokozawa, T. Matcha, a powdered green tea, ameliorates the progression
of renal and hepatic damage in type 2 diabetic OLETF rats. J. Med. Food. 2009, 12, 714–721. [CrossRef]
[PubMed]
105. Abolfathi, A.A.; Mohajeri, D.; Rezaie, A.; Nazeri, M. Protective effects of green tea extract against hepatic
tissue injury in streptozotocin-induced diabetic rats. J. Evid. Based Complement. Altern. Med. 2012, 2012,
740671. [CrossRef] [PubMed]
106. Ashraf, J.M.; Shahab, U.; Tabrez, S.; Lee, E.J.; Choi, I.; Ahmad, S. Quercetin as a finer substitute to
aminoguanidine in the inhibition of glycation products. Int. J. Biol. Macromol. 2015, 77, 188–192. [CrossRef]
[PubMed]
107. Tabrez, S.; Al-Shali, K.Z.; Ahmad, S. Lycopene powers the inhibition of glycationinduced diabetic
nephropathy: A novel approach to halt the AGE-RAGE axis menace. BioFactors 2015, 41, 372–381. [CrossRef]
[PubMed]
108. Moi, P.; Chan, K.; Asunis, I.; Cao, A.; Kan, Y.W. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic
leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus
control region. Proc. Natl. Acad. Sci. USA 1994, 91, 9926–9930. [CrossRef]
109. Mueller, C.G.; Hess, E. Emerging functions of RANKL in lymphoid tissues. Front. Immunol. 2012, 3, 261.
[CrossRef] [PubMed]
110. Sampath, C.; Rashid, M.R.; Sang, S.M.; Ahmedna, M. Green tea epigallocatechin 3-gallate alleviates
hyperglycemia and reduces advanced glycation end products via nrf2 pathway in mice with high fat
diet-induced obesity. Biomed. Pharmacother. 2017, 87, 73–81. [CrossRef] [PubMed]
111. Yang, L.; Jin, X.Q.; Yan, J.; Jin, Y.; Yu, W.; Wu, H.B.; Xu, S.H. Prevalence of dementia, cognitive status and
associated risk factors among elderly of Zhejiang province, China in 2014. Age Ageing 2016, 45, 707–711.
[CrossRef] [PubMed]
112. Nunes, A.R.; Alves, M.G.; Tomas, G.D.; Conde, V.R.; Cristovao, A.C.; Moreira, P.I.; Oliveira, P.F.; Silva, B.M.
Daily consumption of white tea (Camellia sinensis (L.) improves the cerebral cortex metabolic and oxidative
profile in prediabetic Wistar rats. Brit. J. Nutr. 2015, 113, 832–842. [CrossRef] [PubMed]
113. Huang, C.Y.; Kuo, W.W.; Wang, H.F.; Lin, C.J.; Lin, Y.M.; Chen, J.L.; Kuo, C.H.; Chen, P.K.; Lin, J.Y. GABA tea
ameliorates cerebral cortex apoptosis and autophagy in streptozotocin-induced diabetic rats. J. Funct. Foods
2014, 6, 534–544. [CrossRef]
114. Sipe, J.D. Amyloidosis. Crit. Rev. Clin. Lab. Sci. 1994, 31, 325–354. [CrossRef] [PubMed]
115. Selkoe, D.J. Cell biology of protein misfolding: The examples of Alzheimer’s and Parkinson’s diseases.
Nat. Cell Biol. 2004, 6, 1054–1061. [CrossRef] [PubMed]
116. Meng, F.; Abedini, A.; Plesner, A.; Verchere, C.B.; Raleigh, D.P. The flavanol (−)-epigallocatechin 3-gallate
inhibits amyloid formation by islet amyloid polypeptide, disaggregates amyloid fibrils, and protects cultured
cells against IAPP-induced toxicity. Biochemistry 2010, 49, 8127–8133. [CrossRef] [PubMed]
117. Singal, A.; Anjaneyulu, M.; Chopra, K. Modulatory role of green tea extract on antinociceptive effect of
morphine in diabetic mice. J. Med. Food 2005, 8, 386–391. [CrossRef] [PubMed]
118. Anjaneyulu, M.; Chopra, K. Quercetin, a bioflavonoid, attenuates thermal hyperalgesia in a mouse model of
diabetic neuropathic pain. Prog. Neuro-Psychoph. 2003, 27, 1001–1005. [CrossRef]
119. Kamei, J.; Zushida, K.; Morita, K.; Sasaki, M.; Tanaka, S. Role of vanilloid VR1 receptor in thermal allodynia
and hyperalgesia in diabetic mice. Eur. J. Pharmacol. 2001, 422, 83–86. [CrossRef]
120. Ohsawa, M.; Kamei, J. Possible involvement of spinal protein kinase C in thermal allodynia and hyperalgesia
in diabetic mice. Eur. J. Pharmacol. 1999, 372, 221–228. [CrossRef]
Molecules 2017, 22, 849 18 of 19

121. Courteix, C.; Eschalier, A.; Lavarenne, J. Streptozocin-induced diabetic rats: Behavioural evidence for a
model of chronic pain. Pain 1993, 53, 81–88. [CrossRef]
122. Paquay, J.B.G.; Haenen, G.R.M.M.; Stender, G.; Wiseman, S.A.; Tijburg, L.B.M.; Bast, A. Protection against
nitric oxide toxicity by tea. J. Agric, Food Chem. 2000, 48, 5768–5772. [CrossRef]
123. Singh, R.; Ahmed, S.; Islam, N.; Goldberg, V.M.; Haqqi, T.M. Epigallocatechin-3-gallate inhibits
interleukin-1β–induced expression of nitric oxide synthase and production of nitric oxide in human
chondrocytes: Suppression of nuclear factor κB activation by degradation of the inhibitor of nuclear factor
κB. Arthritis Rheum. 2002, 46, 2079–2086. [CrossRef] [PubMed]
124. Ahmed, S.; Rahman, A.; Hasnain, A.; Lalonde, M.; Goldberg, V.M.; Haqqi, T.M. Green tea polyphenol
epigallocatechin-3-gallate inhibits the IL-1 beta-induced activity and expression of cyclooxygenase-2 and
nitric oxide synthase-2 in human chondrocytes. Free Radic. Biol. Med. 2002, 33, 1097–1105. [CrossRef]
125. Silva, K.C.; Hamassaki, D.E.; Saito, K.C.; Faria, A.M.; Ribeiro, P.A.O.; de Faria, J.B.L.; de Faria, J.M.L. Green
tea is neuroprotective in diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2013, 54, 1325–1336. [CrossRef]
[PubMed]
126. Uchiyama, Y.; Suzuki, T.; Mochizuki, K.; Goda, T. Dietary supplementation with
(−)-epigallocatechin-3-gallate reduces inflammatory response in adipose tissue of non-obese type
2 diabetic Goto-Kakizaki (GK) rats. J. Agric. Food Chem. 2013, 61, 11410–11417. [CrossRef] [PubMed]
127. Stosic-Grujicic, S.; Maksimovic, D.; Badovinac, V.; Samardzic, T.; Trajkovic, V.; Lukic, M.; Mostarica
Stojkovic, M. Antidiabetogenic effect of pentoxifylline is associated with systemic and target tissue
modulation of cytokines and nitric oxide production. J. Autoimmun. 2001, 16, 47–58. [CrossRef] [PubMed]
128. Song, E.K.; Hur, H.; Han, M.K. Epigallocatechin gallate prevents autoimmune diabetes induced by multiple
low doses of streptozotocin in mice. Arch. Pharm Res. 2003, 26, 559–563. [CrossRef] [PubMed]
129. Bao, S.; Cao, Y.; Fan, C.; Fan, Y.; Bai, S.; Teng, W.; Shan, Z. Epigallocatechin gallate improves insulin signaling
by decreasing toll-like receptor 4 (TLR4) activity in adipose tissues of high-fat diet rats. Mol. Nut. Food Res.
2014, 58, 677–686. [CrossRef] [PubMed]
130. Lee, S.J.; Kang, H.W.; Lee, S.Y.; Hur, S.J. Green tea polyphenol epigallocatechin-3-O-gallate attenuates
lipopolysaccharide-induced nitric oxide production in RAW264. 7 cells. J. Food Nutr. Res. 2014, 2, 425–428.
[CrossRef]
131. Pullikotil, P.; Chen, H.; Muniyappa, R.; Greenberg, C.C.; Yang, S.T.; Reiter, C.E.N.; Lee, J.W.; Chung, J.H.;
Quon, M.J. Epigallocatechin gallate induces expression of heme oxygenase-1 in endothelial cells via p38
MAPK and Nrf-2 that suppresses proinflammatory actions of TNF-alpha. J. Nutr. Biochem. 2012, 23,
1134–1145. [CrossRef] [PubMed]
132. Bae, J.Y.; Choi, J.S.; Choi, Y.J.; Shin, S.Y.; Kang, S.W.; Han, S.J.; Kang, Y.H. (−)Epigallocatechin gallate
hampers collagen destruction and collagenase activation in ultraviolet-B-irradiated human dermal fibroblasts:
Involvement of mitogen-activated protein kinase. Food Chem. Toxicol. 2008, 46, 1298–1307. [CrossRef]
[PubMed]
133. Hisanaga, A.; Ishida, H.; Sakao, K.; Sogo, T.; Kumamoto, T.; Hashimoto, F.; Hou, D.X. Anti-inflammatory
activity and molecular mechanism of Oolong tea theasinensin. Food Funct. 2014, 5, 1891–1897. [CrossRef]
[PubMed]
134. MacKenzie, T.; Leary, L.; Brooks, W.B. The effect of an extract of green and black tea on glucose control
in adults with type 2 diabetes mellitus: Double-blind randomized study. Metabolism 2007, 56, 1340–1344.
[CrossRef] [PubMed]
135. Hayashino, Y.; Fukuhara, S.; Okamura, T.; Tanaka, T.; Ueshima, H. High oolong tea consumption predicts
future risk of diabetes among Japanese male workers: A prospective cohort study. Diabet. Med. 2011, 28,
805–810. [CrossRef] [PubMed]
136. Virtanen, S.M.; Rasanen, L.; Ylonen, K.; Lounamaa, R.; Akerblom, H.K.; Tuomilehto, J.; Toivanen, L.;
Kaprio, E.A. Is childrens or parents coffee or tea consumption associated with the risk for type-1
diabetes-mellitus in children. Eur. J. Clin. Nutr. 1994, 48, 279–285. [PubMed]
137. Bailey, C.J. Xiaoke: Effect on glucose homeostasis in normal and streptozotocin diabetic mice. IRCS Med. Sci.
1986, 14, 577–578.
138. Bailey, C.J.; Brown, D.; Smith, W.; Bone, A.J. Xiaoke, a traditional treatment for diabetes. Studies in
streptozotocin diabetic mice and spontaneously diabetic BB/E rats. Diabetes Res. 1987, 4, 15–18. [CrossRef]
Molecules 2017, 22, 849 19 of 19

139. Hale, P.J.; Horrocks, P.M.; Wright, A.D.; Fitzgerald, M.G.; Nattrass, M.; Bailey, C.J. Xiaoke tea, a chinese
herbal treatment for diabetes mellitus. Diabet. Med. 1989, 6, 675–676. [CrossRef] [PubMed]
140. Chen, X.; Lin, Z.; Ye, Y.; Zhang, R.; Yin, J.; Jiang, Y.; Wan, H. Suppression of diabetes in non-obese diabetic
(NOD) mice by oral administration of water-soluble and alkali-soluble polysaccharide conjugates prepared
from green tea. Carbohyd. Polym. 2010, 82, 28–33. [CrossRef]
141. Liang, H.L.; Liang, Y.R.; Dong, J.J.; Lu, J.L.; Xu, H.R.; Wang, H. Decaffeination of fresh green tea leaf
(Camellia sinensis) by hot water treatment. Food Chem. 2007, 101, 1451–1456. [CrossRef]
142. Boggs, D.A.; Rosenberg, L.; Ruiz-Narvaez, E.A.; Palmer, J.R. Coffee, tea, and alcohol intake in relation to risk
of type 2 diabetes in African American women. Am. J. Clin. Nutr. 2010, 92, 960–966. [CrossRef] [PubMed]
143. Golozar, A.; Khademi, H.; Kamangar, F.; Poutschi, H.; Islami, F.; Abnet, C.C.; Freedman, N.D.; Taylor, P.R.;
Pharoah, P.; Boffetta, P.; et al. Diabetes mellitus and its correlates in an Iranian adult population. PLoS ONE
2011, 6, e26725. [CrossRef] [PubMed]
144. Karimfar, M.H.; Haghani, K.; Babakhani, A.; Bakhtiyari, S. Rosiglitazone, but not epigallocatechin-3-gallate,
attenuates the decrease in PGC-1α protein levels in palmitate-induced insulin-resistant C2C12 cells. Lipids
2015, 50, 521–528. [CrossRef] [PubMed]
145. Dube, A.; Nicolazzo, J.A.; Larson, I. Chitosan nanoparticles enhance the intestinal absorption of the green
tea catechins (+)-catechin and (−)-epigallocatechin gallate. Eur. J. Pharm. Sci. 2014, 41, 219–225. [CrossRef]
[PubMed]
146. Garcia, J.P.D.; Hsieh, M.F.; Doma, B.T.; Peruelo, D.C.; Chen, I.H.; Lee, H.M. Synthesis of
gelatin-γ-polyglutamic acid-based hydrogel for the in vitro controlled release of epigallocatechin gallate
(EGCG) from Camellia sinensis. Polymers 2014, 6, 39–58. [CrossRef]

© 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).