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Beneficial effects of green tea on age related diseases

Juan Chen1,Zhi Zhang1,Ping Yu1,Wen-Tao Gan1,Kai-Han Ren1,Fang Zhang1,Feng Chen2,Ming-Wei Wang1,*,Jun-Zhe Bao3,Tengfei Wang4
1
Department of Cardiology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
2
Department of pharmacy, Nanjing Children's Hospital of Nanjing Medical University, Nanjing, China
3
Department of Health Policy and Management, School of Public Health, Sun Yat-sen University, Guangzhou, China
4
Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN, USA
DOI: 10.2741/S541 Volume 12 Issue 1, pp.70-91
Published: 01 January 2020
(This article belongs to the Special Issue New trends in atherosclerosis research)
*Corresponding Author(s):  
Ming-Wei Wang
E-mail:  
wmw990556@163.com
Abstract

Green tea (Camellia sinensis, Theaceace), has been extensively studied for its putative effects in prevention of age related diseases. Here, we discuss the increasing evidence that consumption of green tea has preventative effects in obesity, hypertension, insulin resistance, type II diabetes, atherosclerosis, coronary heart disease and Metabolic Syndrome (MetS). The catechins in green tea has been found to be beneficial in obesity induced by a high-fat diet. These effects are mainly attributable to the gallate esters of catechins, (-)-epicatechin gallate (ECG) and (-)-epigallocatechin-3- gallate (EGCG).

Key words

Green tea; Obesity; Hypertension; Insulin resistance and diabetes; Plasma cholesterol; Atherosclerosis; Metabolic syndrome

2. Introduction

Green tea and tea planting originated in China and have spread throughout the world since the middle of the Tang Dynasty. At present, tea ranks as the second most frequently consumed beverage worldwide, surpassed only by water. As early as 4000 to 5000 years ago, the Chinese were aware that tea could promote health and prevent some human diseases, which was recorded in ancient medical books, such as Shen Nong’s Herbal Classics. In recent years, the health benefits (1) of tea have been under investigation, including prevention of cardiovascular diseases (2) and cancer (3), as well as its antiarthritic (4), anti-inflammatory (5), antioxidative (6), antiangiogenic (7), antibacterial (8), cholesterol-lowering (9), neuroprotective (10), and antiviral (11) effects. Actually, antioxidative, antiinflammatory, antiproliferative, and antithrombotic effects on the vasculature, as well as beneficial effects on endothelial function, at least in part, account for the anti-atherogenic effects of green tea (4-7).

The definition of metabolic syndrome (MetS) was first put forward by the World Health Organization (WHO) in 1999. MetS is defined by a multitude of pathophysiological disorders composed of abdominal obesity, insulin resistance, high blood pressure, and dyslipidemia. MetS has become a significant public health problem, affecting millions of people all over the world (12). The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines highlight the key features of this syndrome and propose a clinical definition to facilitate diagnosis and preventive interventions (13). Major challenges still remain for the integration of the key MetS features into clinical practice in identifying high-risk populations (14). Diagnosing MetS early and taking appropriate treatment can lower the risk of diabetes, atherosclerosis, and cardiovascular disease (Figure 1).

Figure 1. Chemical structures of epigallocatechin gallate (EGCG) and related compounds.

Over the last decades, several epidemiological studies have been carried out to investigate the beneficial effects of green tea ingredients and derivatives in MetS and atherosclerosis. However, the results have not always been consistent. For example, some studies found that EGCG may ameliorate MetS by regulating the rhythmic expression of circadian clock genes (15,16), whereas another study found that green tea extract did not improve MetS significantly (17). Therefore, this review is aimed to provide an overview of the effect of green tea ingredients and derivatives on atherosclerosis and MetS.

3. Effect of green tea on human diseases

3.1. Obesity

Obesity is defined as a body mass index (BMI) equal to or greater than 30, which approximates at least 30 pounds of excess weight (18). It is associated with increased health-care costs, premature death, and reduced quality of life. The data from 195 countries reveal that the prevalence of obesity has doubled in more than 70 countries since 1980, and over 600 million adults were obese in 2015, with a high BMI related to 4 million deaths globally (19).

During the past decade, the effects of green tea and green tea polyphenols have been examined in some animal models of obesity. Fat-rich diets not only induce obesity in humans but also in animals. Therefore, animals that accumulate body fat in response to a high-fat diet (especially rodents) are commonly used in obesity research. To explain the beneficial properties of GTE in obesity, adult zebrafish in one study were allocated to four diet groups, and the results showed that a high-fat diet supplemented with GTE significantly suppressed increases in body weight, body fat volume, and body fat volume ratio in male and female zebrafish as compared with those fed the same diet lacking in GTE (20). In addition, studies of male and female rodents have shown that body weight and body fat accumulation induced by a fat-rich diet were suppressed by dietary GTE supplement (21-24). Meanwhile, studies in mice have shown that tea polyphenol extracts induced weight loss and had anti-inflammatory and angiogenic effects (25).

To investigate the anti-obesity effects of green tea extracts, including polyphenols, polysaccharides, caffeine, and a complex of polysaccharide and polyphenol, a dosage of 400 or 800 mg/kg was given to rats on a 6-week high-fat diet. The results indicated that polyphenols and polysaccharides could reduce rat serum leptin levels, inhibit the absorption of fatty acids, and then suppress body weight increase and fat accumulation (26). Many studies in humans confirm that GTE can cause weight loss. An open study (27) demonstrated the activity of green tea extract AR25 (Exolise) in treating obesity. AR25 exerted a direct inhibition of gastric and pancreatic lipases and stimulated thermogenesis in vitro. Body weight was reduced by 4.6% and waist circumference decreased by 4.48% after using AR25 for 3 months. Catechins (the major component of GTE) reduce body fat through inhibiting the malondialdehyde modified LDL (MDA-LDL).

Functional foods and nutraceuticals have gained extensive acceptability from consumers. Interestingly, one study (28) tested functional drinks containing catechins and EGCG in experimental rat models (Sprague Dawley). Catechins contributed to the prevention of various lifestyle-related diseases, particularly obesity. Functional drinks T2 and T3 were prepared by adding EGCG 550 mg/500 mL and compared with control T1, without an active ingredient. Results showed that the functional drinks with added EGCG can help treat obesity, hypercholesterolemia, and hyperglycemia effectively.

By assessing the impact of GTE on starch digestion and absorption, we found that the use of GTE was a viable alternative to pharmaceutical inhibitors of glycoside hydrolase enzymes (29). GTE is widely available, inexpensive, and well tolerated. It is promising for weight control and diabetes treatment.

In one investigation (30) to see if GTE activates the lipolytic pathway, attenuates obesity, and reduces low-grade inflammation in mice fed a high-fat diet, animals were randomized into four groups: CW (chow diet and water); CG (chow diet and water + green tea extract); HW (high-fat diet and water); HG (high-fat diet and water + green tea extract).The mice were fed ad libitum with chow or a high-fat diet and concomitantly supplemented (oral gavage) with 400 mg/kg bodyweight/day of green tea extract (CG and HG, respectively). GTE promoted weight loss and reduction in adipose tissue pads, increased expression of lipases, decreased adipose mass, and reduced inflammatory molecules and cytokines.

In spontaneously hypertensive rats (SHR , model of metabolic syndrome with hypertension, insulin resistance, and overweight) treated with EGCG, after oral EGCG daily for 3 weeks, there was a modest reduction in body weight compared with a control group (45). EGCG might have direct or indirect pleiotropic effects to lower body weight that might be beneficial in the context of overweight.

A novel processed green tea, FGT (fermented green tea) extracts, exhibits anti-obesity effects (31). Moreover, FGT reduces body weight and fat mass in the absence of decreased food intake. Notably, FGT restores the changes in gut microbiota composition (e.g., the Firmicutes/Bacteroidetes and Bacteroides/Prevotella ratios), which are reported to be closely related to the development of obesity and insulin resistance induced by high-fat diets. In short, FGT reduced body weight and its associated symptoms and modulated composition of gut microbiota; thus, it could be used as a novel dietary component to control obesity and related symptoms.

As previously described, green tea catechins have been shown to suppress body weight in animals and humans. They activated adenosine monophosphate-activated protein kinase (AMPK) and thereby increased fatty acid oxidation in liver and skeletal muscles (32). This study also demonstrated that green tea catechins enhanced lipolysis in the presence of norepinephrine via a PKA-dependent pathway in 3T3-L1 adipocytes, providing a potential mechanism by which green tea catechins could reduce body fat.

Interestingly, post-fermented tea exhibited potential anti-obesity effects in mice fed a high-fat diet, and these effects may be mediated by first, inhibiting the absorption of lipids, second, by strengthening the feedback regulation of the expression of de novo lipogenic genes, and third, down-regulating carnitine palmitoyl transferase-1 (CPT1) expression in the liver (33). In addition, GT helps to control and prevent obesity by stimulating hepatic lipid metabolism. Lee et al (34) postulated a high-fat diet (HFD)-induced obesity pathway and validated it by investigating the key regulatory enzymes of mitochondrial β-oxidation: carnitine palmitoyltransferase-1 and -2, acyl-coenzyme A dehydrogenase, and acetyl-coenzyme A acyltransferase. The evidence showed that HFD-induced abnormal mitochondrial β-oxidation was moderated by the consumption of caffeine- and theanine-enriched GT. Results of metabolomic analysis of obese mice showed changes associated with abnormal lipid and energy metabolism, which were alleviated by GT intake, indicating the mechanism underlying the anti-obesity effects of GT.

Furthermore, obesity is currently regarded as an inflammatory condition partly because of the inflammatory cytokines and higher Th1 cell differentiation detected in obese animal models and human cohort studies. To explain therapeutic effects of EGCG in autoinflammatory diseases and obesity, the effects of EGCG on diet-induced obesity (DIO) mice and obese collagen-induced arthritis (CIA) mice were investigated. EGCG reduced the body weight and fat infiltration in liver tissue while improving serum lipid profiles in DIO mice. EGCG also induced a higher T-reg/Th17 cell ratio in CD4 (+) T-cell differentiation by decreasing the ratio of STAT3/STAT5 expression in DIO mice. EGCG was also effective in obese CIA mice (35).

A randomized clinical trial (36) investigated the possible effects of different daily doses of green tea (GT) intake on certain anthropometric, metabolic, and oxidative stress biomarkers of diabetic patients in 63 patients with type 2 diabetes (30 males and 33 females). After a 2-week period without green tea, they were randomly assigned into one of three groups, with a different daily intake of green tea: four cups of green tea per day (n = 24), two cups of green tea per day (n = 25), and the control group (n = 14) with no green tea intake for 2 months. Interestingly, consumption of four cups of GT per day caused a significant decrease in body weight (73.2 to 71.9Kg) (P < 0.001), body mass index (27.4 to 26.9) (P < 0.001), waist circumference (95.8 to 91.5Cm) (P < 0.001), and systolic blood pressure (126.2 to 118.6 mmHg) (P < 0.05).

Consumption of green tea has been linked to a reduction in body fat and body weight. This review assesses the studies of green tea and its epigallocatechin gallato (EGCG) content, evaluating their effect on body fat and body weight in humans. Research results have varied; however, daily consumption of green tea with doses of EGCG between 100 and 460 mg/day has shown greater effectiveness in reducing body fat and weight in intervention periods of 12 weeks or more (37). A Narrative Review focuses on the effect of epigallocatechin-gallate (EGCG) on oxidative stress and inflammation, linked to the metabolic dysfunction of skeletal muscle in obesity and underlying mechanisms. EGCG works by increasing the expression of antioxidant enzymes, reversing the increase of reactive oxygen species (ROS) production in skeletal muscle, and regulating mitochondria-involved autophagy. Moreover, EGCG increases muscle lipid oxidation and stimulates glucose uptake in insulin-resistant skeletal muscle (38). EGCG can decrease obesity only partially via activation of AMPK and epididymal white adipose tissue weight in mice (39). These results suggest the possible therapeutic potential of dietary epigallocatechin gallate-rich GTE supplementation for preventing the development and progression of hepatic steatosis and obesity (40). Human peroxisome proliferator-activated receptors (PPAR) gamma protein was selected as the potential target as it is a key transcription factor for differentiation of adipose cells. Docking analysis of PPAR gamma and epigallocatechin gallate demonstrated that epigallocatechin gallate binds with PPAR gamma at its active site and blocks its activity. This study helps in understanding the mode of action of epigallocatechin gallate that would help in anti-obesity drug development (41).

Collectively, these results indicated that EGCG upregulated autophagic lipolysis in adipocytes, supporting the therapeutic potential of EGCG as a caloric restriction mimetic to prevent obesity and obesity-related metabolic diseases (42). Conversely, another study showed that (43) green tea or GTE intake or its extracts exerted no statistically significant effect on the weight of overweight or obese adults. Although there was a small decrease in the percentage of fat mass, it was not clinically significant. Mechanisms need to be further studied. Moreover, green tea preparations appear to induce a small, statistically nonsignificant weight loss in overweight or obese adults. Because the amount of weight loss was small, it was not likely to be clinically important. Green tea had no significant effect on the maintenance of weight loss (44).

3.2. Hypertension

Hypertension is another condition linked to metabolic syndrome. Epidemiological and intervention studies provide evidence that consumption of tea and other polyphenol-containing foods lower blood pressure. EGCG, a green tea polyphenol, improves insulin sensitivity and endothelial function, reduces blood pressure, and protects against myocardial ischemia/reperfusion injury in spontaneously hypertensive rats (SHR). The acute actions of EGCG to stimulate production of nitric oxide from endothelium using phosphatidylinositol 3-kinase-dependent pathways may explain, in part, the beneficial effects of EGCG therapy in simultaneously improving metabolic and cardiovascular pathophysiology in SHR. These findings may be relevant to understanding potential benefits of green tea consumption in patients with the MetS (45).

Another study examined the effects of EGCG on blood pressure and other metabolic risk factors in overweight or obese men (46). Results showed that dietary supplementation with EGCG had no significant effect on insulin resistance or other associated metabolic risk factors in a sample of overweight and obese men but did reduce diastolic blood pressure. This antihypertensive effect may contribute to some of the cardiovascular benefits associated with habitual green tea consumption. More recently, Nantz et al (47) conducted a randomized, double-blind, placebo-controlled, parallel study in 111 healthy volunteers, comparing the effects of a standardized capsule containing 200 mg of decaffeinated catechin green tea extract with the effects of placebo. They observed a 5 mmHg decrease in systolic blood pressure that was significantly different from the effect of placebo. Furthermore, another study (48) revealed that mildly hypertensive type-2 diabetic individuals who drank three glasses of green or sour tea daily for 4 weeks showed significant decreased systolic and diastolic blood pressures.

During the past decade, the studies investigating the effects of green tea on blood pressure (BP) have generated inconsistent results. The overall outcome (49) suggested that green tea consumption significantly decreased systolic blood pressure (SBP) level by 21.98 mmHg (95% CI: 22.94, 21.01 mmHg; P < 0.001). Compared with the control group, green tea also showed a significant effect on lowering diastolic blood pressure (DBP) in the treatment group (21.92 mmHg; 95% CI: 23.17, 20.68 mmHg; P < 0.002). Interestingly, subgroup analysis further suggested that the positive effect of green tea polyphenols on BP was documented only in studies using a low-dose green tea polyphenol, with the long-term intervention duration or ruling out the confounding effects of caffeine. Furthermore, green tea or GTE supplementation was found to cause a small but significant reduction in BP among overweight and obese adults. Thus, more high-quality randomized controlled trials with large sample sizes are needed to further confirm the effect on BP in order to make recommendations for green tea or GTE supplementation among overweight and obese adults (50).

As previously described, the effect of tea intake on blood pressure is controversial; findings suggest that long-term (≥12 weeks) ingestion of tea could result in a significant reduction in systolic and diastolic BP (51). Furthermore, meta-analysis suggests that green tea and its catechins may improve blood pressure, and the effect may be greater in those with systolic blood pressure ≥130 mm Hg (52). Data from China (53) show that the consumption of green tea is inversely associated with 5-year blood pressure values, an effect abrogated by smoking. Also, many different dietary supplements are currently marketed for the management of hypertension, but the evidence for their effectiveness is mixed. Although green tea intake results in significant reductions in systolic blood pressure, total cholesterol, and LDL cholesterol, the effect on systolic blood pressure is small, whereas the effects on total and LDL cholesterol appear moderate. It is necessary to conduct longer term independent clinical trials to evaluate the effects of green tea on blood pressure (54).

Recently, it was reported that consumption of tea, especially green tea and British tea, was associated with lowering the risk of hypertension in Singaporean Chinese residents (55). On the other hand, resistance exercise (RE) may lead to a post-exercise hypotension (PEH) response. Other research results showed that three weeks of GTE ingestion did not influence systolic BP, diastolic BP, and heart rate but may have a favorable effect on mean arterial BP and rate pressure product in response to acute resistance exercise during a 1-h recovery period after the exercise (56)(Table 1).

Table 1. In vivo effects of green tea on metabolic syndrome and atherosclerosis
Compound(s)/Extract(s)Model SystemDosage GivenResultsReferences
GTEZebrafish5%Suppress body weight increasing20
EGCGmice0.32%,3.2 g/kg,20 mg/kg,50 mg/kg and 100 mg/kgDecrease lipid absorption, body weight and epididymis white adipose tissue weight21,22,35,39
GTPsrats0.5%Enhance antioxidant capacity and suppressing inflammation23
GTPrats0.5% wt./volRegulate obesity-related genes, anti-inflammation, anti-oxidant capacity24
GTPsmice0.25%Induce weight loss and anti-inflammatory and angiogenic effects25
GTrats400 or 800 mg kg⁻¹Reduce serum leptin levels and anti-inflammatory activity26
EGCGrats550 mg/500mLDecrease body weight28
GTPmice400 mg/kgIncrease the lipolytic pathway and reduce adipose tissue30
FGTmice500 mg/kgControl obesity and related symptoms31
GTCsmice0.2-0.5% (wt/wt)Reduce body fat32
JWFTmice0.5, 1.0 and 2.0 g/kgInhibit the increase in the body weight33
GTmice1% GTAnti-obesity34
GTEmice30 mg/kg ,60 mg/kg , and 120 mg/kgReduce body weight gain40
EGCGrats200 mg.kg(-1).day(-1)Lower systolic blood pressure45
EGCGmice150mg/kg/day;300mg/kg/day;Improve adipose insulin resistance59
GTEmice10 g GTE/kgPreventing both obesity and obesity-induced T2DM60
EGCGrats20.14+0.61 g per rat per day and 19.58+0.48 g per rat per dayAgainst hypercholesterolemia and hyperglycemia62
fGTmice400 mg/kg fGT extractsAnti-diabetic effects69
EGCGmice300mg/kg b.w., i.g.Therapeutic intervention in diabetes74
GTrabbits3 g/l,2.5%Reduce aortic lesion formation78,98,99
GTrats0.5 and 1.0% (wt/wt)Lower the lipid79
GTAErats1.1 and 2.0% GTAEPrevent on the accumulation of visceral fat80
GTmice4%Reduce the body fat content, hepatic triacylglycerol and cholesterol accumulation83
EGCGmice40 mg/kg/d, i.g,0.02%,10 mg/kgAnti-atherosclerotic effects86,90,96
Catechinsmice0.3%Inhibit the development of atherosclerosis87
GTPmice3.2 or 6.4 g/LInhibit atherogenesis88
EGCGrabbitEGCG was loaded in the nanoparticles 27 to yield EGCG-CS-PAA nanoparticlesAgainst rabbit atherosclerosis89
GTEmice50 mg/kg,100mg/kg,300mg/kgDecrease atherosclerosis91
EGCGrats100mg/kg BWDecrease the risk of cardiovascular disease92
GTrats150 mlPrevent atherosclerosis93
GTCmice0.2 or 4%,0.8 g/LInhibit atherosclerosis94,97

3.3. Insulin resistance and diabetes

Insulin resistance is an early marker of type 2 diabetes (T2D), and development of insulin resistance is associated with obesity (57). Insulin resistance results in the interruption of insulin signaling in responsive tissues, thus leading to hyperinsulinemia and ultimately T2D. Over a long period, the body is unable to produce enough insulin to overcome insulin resistance and the pancreas may reduce or stop insulin production (58). The increasing prevalence of type 2 diabetes mellitus (T2DM) is associated with the rapid spread of obesity. Obesity induces insulin resistance, results in pancreatic β-cell dysfunction, and thus T2DM. Epidemiologically, it has been suggested that green tea consumption prevented type 2 diabetes, but this effect is still in dispute. Green tea catechins (GTCs) significantly decreased glucose level and increased glucose tolerance in animals. GTCs reduced ROS content in both animal and adipocyte models (59). EGCG attenuated the generation of ROS promoted by dexamethasone and TNF-α and increased glucose uptake ability. EGCG also decreased JNK phosphorylation and promoted GLUT-4 translocation. EGCG and GTCs could improve adipocyte insulin resistance and exert this effect on their ROS scavenging functions.

To compare the effect of GTE with that of GTE coadministered with poly-γ-glutamic acid (γ-PGA), db/db mice and age-matched nondiabetic mice were provided with a normal diet containing GTE (1%) and γ-PGA (0.1%) or GTE+γ-PGA (1%:0.1%) for 4 weeks (60). Results suggested that GTE+γ-PGA treatment may be a more useful method for preventing both obesity and obesity-induced T2DM than GTE or γ-PGA alone. Kim (61) examined the effects and mechanisms of GTP on glycogen synthesis and lipogenesis in HepG2 cells. The findings showed that GTP was capable of enhancing insulin-mediated glucose and lipid metabolism by regulating enzymes involved in glycogen synthesis and lipogenesis.

Green tea has many biologically active ingredients such as flavanols and polyphenols. GTE has a role in mitigating metabolic syndrome, especially in hyperglycemia and hypercholesterolemia (62). Rats with hyperglycemia and hypercholesterolemia were given ethanol extracts of green tea for 8 weeks. The serum glucose level was reduced the most in hyperglycemic rats. Meanwhile, green tea did not adversely affect the red blood cell, white blood cell, and platelet quantities in the rats.

A study was conducted in elderly men and women living in Mediterranean islands during 2005-2007 (63). This was one of the few studies that evaluated this hypothesis in elderly individuals whose disease burden was high. The association between tea intake and blood glucose level was investigated and the study revealed that moderate (i.e., 1-2 cups per day) and long-term tea consumption were related to a significant reduction in fasting blood glucose level and consequently lower likelihood of diabetes mellitus, irrespective of various other clinical and lifestyle characteristics.

Studies (64) using stratified analysis revealed that tea consumption ≥ 4cups per day might play a role in the prevention of type 2 diabetes. However, no statistically significant association was observed for sex and the follow-up durations stratified between tea consumption and type 2 diabetes. The EPIC-Inter Act case-cohort study was conducted in eight European countries, and investigators observed a linear inverse association between tea consumption and incidence of type 2 diabetes (65). People who drank at least 4 cups of tea per day may have a 16% lower risk of developing type 2 diabetes than non-tea drinkers do. Furthermore, whether consumption of all types of tea was associated similarly with lower risk of type 2 diabetes and whether this association was causal should be further investigated. In another study, representative samples were selected by a multistage, stratified, cluster, random-sampling method from Fujian Province in China, and investigators found inverse associations in Chinese women and men between green tea consumption and IFG (Impaired Fasting Glucose) and also between rock tea consumption and IGT(Impaired Glucose Tolerance (66). These inverse associations were more pronounced in subjects who drank 16 to 30 cups of tea each week.

In one study, green tea consumption lowered fasting glucose and Hb A1c concentration significantly (67). Meanwhile, subgroup analysis with the data from high-quality trials showed that green tea consumption significantly reduced fasting insulin concentration. The results of a study investigating the phytophenolic profile of Mauritian green tea and its antioxidant propensity showed that the green tea regimen could be part of a healthy lifestyle that might ameliorate features of metabolic syndrome and subsequently lower risks for individuals with the propensity to develop type 2 diabetes (68).

To evaluate the anti-obesity effect of FGT(green tea fermented with Aquilariae Lignum), Kang (69) examined the anti-diabetic effect of FGT compared to unfermented green tea (GT) on mice with type 2 diabetes and found FGT had stronger anti-diabetic effects than GT did. These results suggested that fermentation with appropriate amount of Aquilariae Lignum (9:1) synergistically increased the anti-diabetic effects of GT in db/db mice. Thus, FGT could be as a new potent therapeutic agent for type 2 diabetes because it showed anti-obesity, anti-hypoglycemic, anti-hyperlipidemic, and antioxidant effects. GTE (green tea extract) significantly improved insulin resistance and increased glucagon-like peptide 1 only in within-group comparisons (70). Taking decaffeinated GTE daily with a dose of 856 mg EGCG for 16 weeks produced no severe adverse effects. In another study, tea consumption was linearly inversely associated with T2D risk (71). At the same time, a systematic review suggested that daily tea consumption (≥3 cups/day) was associated with a lower T2DM risk (72), which implies that the daily consumption level might be an important factor in determining the protective effect of tea against T2DM.

Furthermore, one trial (73) found green tea and sour tea could decrease oxidative stress and attenuate insulin resistance and might also decrease complications of diabetes mellitus (DM). In this study, 100 patients with type 2 diabetes were randomly assigned into a sour tea group (ST) and green tea group (GT). The patients were instructed to drink 150 ml sour tea or green tea infusion, respectively, three times a day for 4 weeks. Results revealed that green tea users had a significant decrease in fasting blood insulin. This study showed that daily use of 150 ml infusion of green tea or sour tea, three times a day for 4 weeks, had a positive effect on insulin resistance and certain lipoprotein metabolism in patients with type 2 DM. Thus, using these kinds of tea, particularly green tea, is recommended in patients with type 2 DM. EGCG improved glucose homeostasis and inhibited the process of gluconeogenesis (PEPCK and G-6-Pase) and lipogenesis (SREBP-1C, FAS, and ACC1) in the liver. Meanwhile, EGCG treatment activated PXR/CAR, accompanied by upregulated the expression of the PXR/CAR-mediated phase II drug metabolism enzyme in the small intestine and liver, involving SULT1A1, UGT1A1, and SULT2B1b. This study concluded that dietary polyphenol EGCG could serve as a promising PXR/CAR activator and therapeutic intervention in diabetes (74).

Conversely, GT did not lower plasma glucose, glycemic index, or insulin level in another study (75). This was a crossover design with 14 healthy volunteers, and the results suggested that green tea may increase satiety, but more clinical trials are needed to further evaluate the effects of green tea on satiety. Another study provided no evidence supporting that consumption of GT/GTE could reduce the levels of HbA1c, HOMA-IR, fasting insulin, or fasting glucose in people with pre-diabetes/T2DM (76).

3.4. Plasma cholesterol

Green tea and green tea polyphenols have been shown to modulate the levels of both HDL- and LDL-cholesterol in plasma and tissues. Improvement in serum lipid profiles is another possible mechanism that would account for the beneficial effect of tea on cardiovascular disease, and several observational studies suggest that tea might have such an effect. Earlier studies have shown no relationship between green or black tea consumption and total or LDL cholesterol levels (77). A recent study on cholesterol-fed New Zealand rabbits showed that green tea had potential anti-atherosclerotic effects (78). Previous studies (25) showed that a physiologically relevant dose of dietary EGCG reduced the development of obesity, hyperglycemia, insulin resistance, hypercholesterolemia, and hepatic steatosis in mice fed a high-fat diet. Histological analysis of liver samples showed decreased lipid accumulation in hepatocytes in mice treated with EGCG compared with mice on a high-fat diet without EGCG treatment. These effects may be related to decreased fat absorption and anti-inflammatory effects mediated by EGCG.

To understand whether GT inhibits the expression of genes regulating hepatic lipogenesis and intestinal lipid transport in fructose-fed ovariectomized (OX) rats, they fed OX rats with fructose to set up an animal model of diet-induced hypertriglyceridemia and found new evidence that GT significantly downregulated the expression of the sterol regulatory element-binding protein-1c (SREBP-1c) and its target genes such as fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1) in liver and the genes that regulate hepatic cholesterol synthesis (HMGR) and efflux (ABCA1). Thus, the TG-lowering effect of GT in plasma and liver may be mediated partly via the suppression of lipogenesis and inhibition of luminal hydrolysis and micellar transfer of lipids to the enterocyte (79). In addition, in one study 2.0% green tea aqueous extract significantly decreased body weight gain, prevented visceral fat accumulation, and decreased protein availability in rats fed a high-fat diet (80). Further evidence (81,82)showed that the consumption of green tea catechins was associated with a significant reduction in total and LDL cholesterol levels; however, there was no significant effect on HDL cholesterol or triglyceride levels. Meanwhile, subgroup and sensitivity analysis showed that these changes were not influenced by the type of intervention, treatment dose of green tea catechins, individual health status, study duration, or quality of the study. Conversely, in C57BL/6J mice fed a high-fat diet, GT strongly reduced the body fat content and hepatic triglycerol and cholesterol accumulation (83).

Considering that the liver is an important organ in glucose and lipid metabolism, the effects and mechanisms of GTP on glycogen synthesis and lipogenesis in HepG2 cells were examined (61). AMPK and ACC are key enzymes that regulate lipogenesis in the liver. GTP-EGCG treatment significantly increased phospho-AMPKα (Thr172) and phospho-ACC (Ser79) expression in HepG2 cells. The findings showed that the beneficial effects of GTP in metabolic syndrome and diabetes resulted from direct enhancement of glycogen synthesis in the liver and decreased hepatic lipogenesis.

To understand the influence of GTE on lipid digestion and absorption, 32 healthy volunteers aged 23 to 30 years with normal exocrine pancreatic function were studied (84). Breath tests of 13C-labelled mixed triglycerides were performed twice in all subjects with and without GTE ingestion. Interestingly, the findings showed a single dose of GTE decreased lipid digestion and absorption from a test meal in humans. Similarly, a pilot study showed that a long-term diet containing green tea decreased lipid assimilation without involvement of luminal effects (85) (Table 2).

Table 2. Clinical effects of green tea on metabolic syndrome and atherosclerosis
Compound(s) /Extract(s)Subjects UsedTreatment MethodDurationResultsReferences
GTE AR2570 patientsConsume capsules of green tea polyphenols12 weeksInhibit lipases and stimulate thermogenesis27
GTE28 healthy volunteers aged 19 to 28 yearsOral the test meal with GTE (GTE 4 g)1 weekDecrease starch digestion and absorption29
GT63 patients with type 2 diabetesConsumption of four cups of GT2 monthsReduce weight36
EGCG100 overweight or obese male subjects aged 40-65 years0.5% wt./vol8 weeksRegulate obesity-related genes, anti-inflammation, anti-oxidant capacity46
Camellia sinensis compoundsHealthy men (n=52) and women (n=72) 21 to 50 y of age100 mg of L-theanine3 monthsDecrease systolic blood pressure47
GT100 mildly hypertensive patients with diabetesDrink green tea infusion4 weeksDecrease systolic and diastolic blood pressures48
GT1109 Chinese menDrink green tea5 yearsGreen tea is inversely associated with 5-year BP change53
GTThe prevalence of hypertension (N=1184)Drink green tea12 monthsLower the risk of hypertension55
GTE300 men and womenGTE consumption4 weeksDid not influenced SBP and DBP56
GTaged 65 to 100 yearsDrink green tea2 yearsLower prevalence of diabetes63
GT9995 people were registeredDrink green tea<1, 1–15, 16–30, and >30 cups per weekProtect against the development of type 2 diabetes mellitus66
GTThree hundred prediabetic Mauritians age ranged from 35 to 65 yearsDrink green tea14 weeksAmeliorate features of metabolic syndrome68
GTE92 subjects with type 2 diabetes mellitus and lipid abnormalitiesTake green tea extract16 weeksDecrease triglyceride70
GT100 type 2 diabetes patientsTake green tea4 weeksPositive effect on insulin resistance and certain lipoproteins73
GT14 healthy volunteersTake green tea2 hoursDid not lower plasma glucose, glycemic index or insulin level75
GT207 of the men and 164 of the wivesDaily green tea intake (< 1 cup, 1-4 cups, and > 4 cups)3 daysDo not support the beneficial effects of green tea on serum lipid levels77
GTE32 healthy volunteers aged 23 to 30 yearsEGCG content-257.6 mg360 minutesDecrease lipid digestion and absorption84
GTEEight obese subjects aged 56-65 years188.3 mg and 242.1 mg EGCG3 monthsDecrease lipid assimilation85
GT512 patients aged 30 years or older0-1, 2–3, 4–6 cup/day1 yearInhibit coronary arteries100

3.5. Atherosclerosis and metabolic syndrome

Atherosclerosis is one of the metabolic syndrome-related diseases caused by obesity. The anti-obesity effects of green tea and its ingredients have been reported previously (18-44). To explore the effect and mechanism of EGCG on atherosclerosis, male mice 7 weeks old with apolipoprotein E-knockout (ApoE−/−) were fed with a high-fat diet (HFD) and meanwhile treated with normal saline or EGCG (40 mg/kg/d) for 18 weeks, and results showed EGCG significantly modulated the expression of high-fat-induced hepatic tetratricopeptide repeat domain protein 39B (TTC39B) in liver (86). Liu et al (87) investigated whether catechins and caffeine alone or in combination could prevent atherosclerosis, and the results indicated that the combination of catechin and caffeine had an inhibitory effect on the development of atherosclerosis in mice. In another study (88), green tea polyphenol supplements showed marked suppression effects on atherogenesis through improving lipid metabolism as well as through a direct impact on LDL and autophagy flux in the vessel wall. Moreover, the effectiveness of EGCG against atherosclerosis in rabbits was significantly improved by incorporating EGCG into the nanoformulation (89). EGCG inhibited porphyromonas gingivalis-induced atherosclerosis through anti-inflammatory and antioxidative (90).

Green tea not only reversed endothelial dysfunction but also reduced progression of atherosclerosis (91). It was also possible to decrease the risk of cardiovascular disease by reducing the inflammatory markers in rats with an atherogenic diet (92). Fermented tea has the effect of preventing hypercholesterolemia and atherosclerosis (93). Tea caused some improvement in a hamster model of atherosclerosis in plasma low-density lipoprotein (LDL), LDL/high density lipoprotein ratio, triglycerides, lipid peroxides, lower density lipoprotein lipid peroxides, and fibrinogen (94,95). In addition, EGCG differentially reduced evolving atherosclerotic lesions without influencing established atherosclerosis in apolipoprotein E-null mice (96), probably through the potent antioxidative activity of the tea (97). In female New Zealand white rabbits, green tea consumption reduced aortic lesion formation (78), as well as decreased the expression of vascular endothelial growth factor significantly in the atherosclerotic plaque of rabbit aorta (98). The relation between green tea consumption and coronary atherosclerosis was examined in Japan and the results showed green tea may be protective against coronary atherosclerosis in men (99).

4. Conclusions

In the last 30 years, research has identified tea as a potential promoter for human health. Given the high consumption, wide distribution, and the potential health effects of tea, further studies are reasonable and necessary. In this article, we have reviewed a representative part of the widely published literature about tea and its role in metabolic syndrome and atherosclerosis. In experimental models and human subjects, a few reasonable beneficial mechanisms have been identified, including anti-inflammatory, anti-platelet, and other favorable effects on the vascular endothelium. Future research needs to confirm the safety of tea consumption associated with its benefits and to clarify the potential mechanisms of action. Clinical intervention studies in the future could provide more convincing evidence of the effects of green tea.

5. Acknowledgments

The presented study was supported by Hangzhou science and Technology Bureau fund (20171334M01;20191203B96;20191203B105); Zhejiang Kang Enbei Hospital Management Soft Science Project (2017ZHA-KEB318); Hangzhou science and Technology Association ((2017)28); Excellent Youth Project of the Affiliated Hospital of Hangzhou Normal University (2019). The authors declare that they have no conflicts of interest.

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Juan Chen, Zhi Zhang, Ping Yu, Wen-Tao Gan, Kai-Han Ren, Fang Zhang, Feng Chen, Ming-Wei Wang, Jun-Zhe Bao, Tengfei Wang. Beneficial effects of green tea on age related diseases. Frontiers in Bioscience-Scholar. 2020. 12(1); 70-91.