Insulin resistance is identified as an impaired biological response to insulin stimulation of the target tissues, prominently in the muscles, liver, and adipose tissue ^[1][51]. It impairs sensitivity to insulin-mediated glucose disposal, resulting in a compensatory increase in pancreatic β-cell insulin production to maintain normal blood glucose levels. Consequently, it results in a cluster of abnormalities including hyperinsulinemia, hyperglycemia, dyslipidemia, visceral adiposity, obesity, hyperuricemia, hypertension, endothelial dysfunction, and elevated inflammatory markers ^[2][52].

Insulin increases glucose uptake in the muscles and liver and inhibits hepatic gluconeogenesis and lipolysis. However, insulin resistance impairs insulin-mediated inhibition of lipolysis in adipose tissues leading to increased circulating lipids, which further inhibit the antilipolytic effect of insulin ^[1][51]. Non-esterified fatty acids or free fatty acids (FFAs) inhibit protein kinase activation in the muscles leading to reduced glucose uptake. Conversely, FFAs increase the activation of protein kinases in the liver, promoting hepatic gluconeogenesis and stimulating adipose lipogenesis as well as lipolysis ^[3][4][5][53,54,55]. Thus, higher levels of circulating FFAs directly affect the liver and muscle metabolism, and further aggravate insulin resistance ^[6][56]. Overall, the progression of insulin resistance may lead to metabolic syndrome, polycystic ovary syndrome, non-alcoholic fatty liver disease (NAFLD), type 2 diabetes, sleep apnea, and certain forms of cancer.

The anti-insulin resistance and glucose homeostasis effects of EGCG have been consistently described. Yan et al. ^[7][57] revealed that green tea catechins significantly decreased glucose levels and improved glucose tolerance in the animal experiment. Green tea EGCG reduced ROS in adipocytes, attenuated dexamethasone, and TNF-α as a result of ROS, and increased glucose uptake ability hence alleviating adipose insulin resistance ^[7][57]. Fasting serum glucose, insulin levels, and insulin resistance were reduced significantly in obese hypertensive patients following the uptake of green tea extract in the randomized double-blind, placebo control clinical trial study ^[8][58]. Similarly, Liu et al. ^[9][44] conducted a randomized double-blind, placebo control clinical trial experiment involving 92 subjects with type 2 diabetes and lipid abnormalities; found that green tea extract (GTE) significantly alleviated insulin resistance, increased glucagon-like peptide-1 and high-density lipoprotein (HDL) levels, and decreased triglycerides levels. At the same time, EGCG ameliorated insulin resistance by upregulating and increasing phosphorylation of the insulin receptor substrate-1 (IRS-1), which is essential for the stimulation of glucose uptake in response to insulin ^[10][59]. For instance, EGCG reversed high glucose- and glucosamine-induced insulin resistance in SH-SY5Y neuronal cells by improving the oxidized cellular status and mitochondrial function ^[10][59]. Similarly, a study that employed a GTE in mice, showed that EGCG attenuated insulin resistance induced by a high-fat diet ^[11][47]. Additionally, EGCG was shown to improve glucose tolerance in mice ^[12][60]. According to Lee et al. ^[13][61] green tea-derived products such as extracts and water-soluble polysaccharides exhibit hypoglycemic effects as they caused delayed intestinal absorption of glucose. The hypoglycemic mechanism of EGCG has been contributed by its inhibitory effect on α-glucosidase activity, enhancement of glucose uptake, and promotion of glucose transporter-4 (GLUT4) translocation to the plasma membrane through a phosphatidylinositide-3-kinase/activated protein kinase B (PI3K/AKT) signaling pathway in skeletal muscle cells ^[14][15][62,63]. When EGCG uptake was combined with regular exercise in overweight or obese postmenopausal women, it resulted in reduced plasma glucose concentration in subjects with impaired glucose tolerance ^[16][64]. Collectively, green tea EGCG alleviates insulin resistance, increases glucose uptake, and lowers blood glucose, which are important for glucose homeostasis.

Several studies suggest that EGCG can decrease energy and food intake, lipogenesis as well as preadipocyte differentiation and proliferation, while increasing lipolysis, and fat oxidation. Green tea EGCG was revealed to reduce tissue and blood lipid accumulation in the FFAs-induced human liver hepatocellular carcinoma cell line (HepG2) via activation of the AMPK pathway ^[17][43]. Consequently, AMPK activation shifts some FFAs toward oxidation, away from lipid and triglycerides storage, and suppresses hepatic gluconeogenesis, which is implicated in the reduction of adipose mass and body weight.

Findings from a systematic review by Asbaghi et al. ^[18][65] revealed that, supplementing >800 mg GTE/day for eight or more weeks significantly improved lipid profile by reducing serum triglycerides and total cholesterol concentrations in patients with type 2 diabetes. Similarly, the consumption of green tea EGCG significantly lowered low-density lipoprotein (LDL) as well as total cholesterol levels in normal weight and obese individuals ^[19][66]. Moreover, supplementing EGCG for four to eight weeks to patients with obesity reduced plasma triglycerides and serum kisspeptin levels ^[20][67].

A study involving healthy Japanese women revealed that elevated plasma and urinary concentration of green tea catechins was associated with improved plasma lipid profile ^[21][68]. Randomized double-blind placebo-controlled clinical trials involving obese women in Taiwan, reported a significant decrease in total cholesterol, LDL, and triglyceride, and increased levels of HDL as well as plasma adiponectin in groups administered with GTE for 12 weeks ^[22][23][69,70]. Furthermore, a combination of EGCG and caffeine produced a synergistic effect on gut microbiota: increasing Bifidobacterium count and fecal short-chain fatty acid (SCFAs) levels and enhanced fecal bile acids excretion in experimental rats ^[24][71]. At the same time, the combination effect increased the expression of hepatic G-coupled protein receptor 1 and activation of intestinal farnesoid X receptor (FXR). The activation of intestinal and hepatic FXR induces endocrine hormone fibroblast growth factor 15 (FGF15) and small intestine heterodimer partner production, which collectively inhibits hepatic bile acid biosynthesis via signaling cascades ^[24][71]. A randomized double-blind parallel placebo-controlled clinical trial showed that administering 400, 600, or 800 g EGCG (depending on body weight) for 12 months in men with Down syndrome resulted in weight loss, reduced body fat, and improved lipid profile ^[25][72]. In addition, Choi. et al. ^[12][60] revealed that EGCG regulates lipid catabolism through AMPK-mediated mechanisms increasing lipolysis and suppressing lipogenesis in the adipocytes. Therefore, EGCG reduces visceral adiposity by activating autophagy and lipolysis in white adipose tissue through an AMPK-mediated mechanism.

Uric acid is the final catabolic product of the enzymatic degradation of purines as well as other dietary components and can scavenge ROS, thus protecting the erythrocytes membrane from oxidation in humans ^[26][73]. Hyperuricemia is considered a metabolic disease, while elevated serum uric acid is the metabolic disease biomarker ^[27][20]. Hyperuricemia induces oxidative stress and endothelial dysfunction, resulting in the development of a series of diseases including insulin resistance, type 2 diabetes, coronary artery diseases, chronic kidney diseases, kidney stone, and gout, thus becoming a metabolic disease that threatens human health ^[28][29][13,74]. Moreover, hyperuricemia has been reported to involve in the manifestation of NAFLD. Maintaining serum urate levels below 7 and 6 mg/dL in men and women, respectively, is clinically important for the prevention of hyperuricemia, type 2 diabetes, cerebrovascular, cardiovascular diseases, and gout ^[30][75].

At present drugs such as allopurinol, oxypurinol, febuxostat, and topiroxostat, which are xanthine oxidase inhibitors, and the recombinant uricase (rasburicase), uricosuric agent (probenecid) are currently used to treat hyperuricemia ^[31][32][76,77]. However, these drugs have side effects such as causing uric acid stones, liver and kidney stones, liver damage, and/or may lead to hypersensitivity reactions, which may not be tolerated by the patient ^[32][33][77,78]. Of interest, EGCG has been studied to have a uric acid-lowering effect. Thus, can be used to manage or develop nutraceutical drugs for hyperuricemia and alleviate metabolic diseases.

In animal studies using mice, tea ranging from green, yellow, black, or dark tea extract significantly increased uric acid excretion by upregulating the expression of uric acid secretion transporters ABCG2, organic anion transporter 1 (OTA1), organic anion transporter 3 (OTA3) and organic cation transporter 1 (OCT1), and by downregulating the expression of uric acid reabsorption transporter; urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in the kidney ^[34][35][79,80]. Likewise, Li et al. ^[36][14] reported that EGCG significantly promoted the expression of OAT1 and downregulated the expression of GLUT9 in renal tissues of hyperuricemia rats. At the same time, tea extract significantly lowers serum urate levels through the inhibition of XOD and ADA to produce uric acid ^[37][38]. Moreover, interventions using tea extract revealed that tea components upregulate the expression of the intestinal ABCG2 protein and alleviated hyperuricemia by modulating the gut microbiota. The study of Sang et al. ^[35][80] reports yellow tea to be the best in alleviating hyperuricemia in mice and indicated 50% EGCG oral bioavailability.

Using human normal liver cell line HL-7702 (L-02), Wu et al. ^[38][81] revealed that tea extract limit uric acid production via inhibition of XOD activity, with green tea showing the strongest inhibitory activity followed by yellow, oolong, white, black, and dark tea. Zhang et al. ^[39][37], using spectroscopic and computer simulation methods, found that EGCG at a concentration of 0.13 mmol/L inhibited 80% XOD activity by binding to the vicinity of flavine adenine dinucleotide (FAD) in XOD, hindering the entry of the substrate. In xanthine-stimulated BRL 3A rat liver cells, EGCG significantly reduced uric acid levels in vitro. Additionally, it was revealed that EGCG significantly reduced serum uric acid and inhibited XOD activity in rats treated with potassium oxonate ^[36][14].

A randomized cross-over study in Japan revealed a significant increase in the excretion of uric acid and uric acid precursor (xanthine and hypoxanthine) in the group of healthy men receiving distilled spirit (Shōchū) with catechin-enriched green tea ^[40][82]. Similarly, Jatuworapruk et al. ^[41][83] reported the hypouricemic effect of green tea in healthy individuals, that serum uric acid decreased with decreased uric acid clearance after two weeks of the randomized study. The studies on healthy individuals reflected the idea of green tea extract components particularly EGCG to inhibit XOD activity and thus reduce the production of uric acid and increase the excretion of uric acid precursor (xanthine and hypoxanthine) with urine.