*3.1. Diabetes Mellitus*

#### 3.1.1. Type 1 Diabetes Mellitus (T1DM)

T1DM is characterized by progressively destroyed pancreatic β-cells and reducing or no insulin secretion [17], accounting for 5–10% diabetes mellitus [42]. Increasing studies have found the effects of tea against T1DM [43–45].

The main effective catechin of green tea is epigallocatechin gallate (EGCG) [46]. EGCG could protect the functions of pancreatic β-cells by inhibiting inflammatory factors and reducing reactive oxygen species (ROS) in vitro [47]. Further, EGCG could down-regulate the production of inducible nitric oxide synthase (iNOS) to protect pancreatic islet β-cells [48]. In addition, green tea was also found to reduce blood sugar level by promoting pancreatic β-cells to produce more insulin in diabetic mice [49]. Furthermore, dark tea containing gallic acid, a water-soluble ingredient, could promote skeletal muscle glucose transport in the absence of insulin by stimulating protein kinase B (Akt) phosphorylation [50].

#### 3.1.2. Type 2 Diabetes Mellitus (T2DM)

T2DM is defined as insulin resistance in the target tissue and a relative lack of insulin secreted by islet β-cells [51], accounting for 90–95% diabetes mellitus [42]. Increasing studies showed that tea was effective in preventing and managing T2DM [6]. Next, the molecular mechanisms of tea against T2DM are discussed according to the types of tea.

A type II arabinogalactan, 7WA, isolated from green tea, could increase glucose-stimulated insulin secretion through cyclic adenosine monophosphate-Akt (cAMP-Akt) pathway [44]. Additionally, green tea polyphenols, primarily EGCG, could activate the 5'-adenylic acid-activated protein kinase (AMPK) pathway to improve the closure of insulin stress signal pathway caused by phosphorylation of insulin receptor substrate-1 (IRS-1), finally ameliorating the insulin resistant status of human hepG2 hepatoma cells [52]. In addition, it was reported that supplement of green tea polyphenols could improve insulin sensitivity by upregulating the insulin signaling protein levels in insulin-resistant rats [53]. Moreover, green tea catechins, especially EGCG, could improve insulin resistance by scavenging ROS, which was able to block the transduction of insulin signal and prevent IRS-1 from binding to insulin receptor by decreasing tumor necrosis factor (TNF)-α-induced c-jun NH2-terminal kinase (JNK) phosphorylation [48,54]. Furthermore, EGCG played an insulin-like role in down-regulating the gene and protein expression of hepatocyte nuclear factor (HNF4), a key transcription factor controlling gluconeogenesis enzymes, such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase [55]. Moreover, green tea catechins could promote adipocyte differentiation and increase insulin sensitivity by directly activating peroxisome proliferator-activated receptor γ (PPARγ) [56]. EGCG-enriched green tea extract could also prevent T2DM by stimulating the production of soluble receptors for advanced glycation of end products (sRAGE) through a disintegrin and metallopoteases10 (ADAM10)-induced ectodomain shedding of extracellular RAGE [57].

Black tea regularly had antioxidant and anti-inflammatory effects [58] which could exert effects against T2DM. Black tea, abundant in theaflavins (accounting for 68.4% tea polyphenols), played a hypoglycemic role by inhibiting the action of ROS, such as singlet oxygen, superoxide, and hydroxyl radicals [20]. Further, black tea could reduce the risk of T2DM by inhibiting obesity through the phosphorylation of key metabolic regulator AMPK and promoting the browning of white adipose tissue [59].

Studies found that white tea had higher levels of tea polyphenols and better antioxidant activity than black tea [60]. White tea could exhibit antidiabetic activity by reducing insulin resistance, hyperlipidemia, and oxidative stress [61]. Additionally, white tea lowered blood sugar level by increasing insulin sensitivity and the synthesis of liver glycogen in T2DM rats [62]. Moreover, it was revealed that the combination of white tea and moringa oleifera had a good hypoglycemic effect [63].

It was found that the water extract of pu-erh tea contained less polyphenols but more caffeine, which could improve insulin sensitivity [5,64]. An in vitro study found that qingzhuan tea (a type of dark tea) had an inhibitory effect on α-glucosidase, which was attributed to EGCG and gallocatechin gallate (GCG) [65]. Pu-erh tea polysaccharides was also reported to regulate postprandial blood sugar by inhibiting α-glucosidase but have no effect on α-amylase activity, with older pu-erh tea exhibiting a higher inhibitory effect [66]. Moreover, it was found that ripened pu-erh tea had a better effect than raw pu-erh tea on the control of postprandial blood glucose in T2DM mice [67]. Additionally, pu-erh tea polysaccharides promoted adipocyte differentiation and glucose uptake by mimicking the properties of PPARγ and glucose transporter type 4 (GLUT4), ameliorating insulin resistance and lowering blood sugar [68]. Furthermore, Fu brick tea attenuated insulin resistance by down-regulating signal regulatory protein-α (SIRP-α) expression and activating insulin signaling in a Akt/GLUT4/FoxO1 and the target of rapamycin (mTOR)/S6K1 pathways in the skeletal muscle of male Sprague−Dawley rats [69].

Yellow tea could ameliorate glucose intolerance and insulin resistance without dose dependence [70]. Further, the roasted yellow tea could improve insulin sensitivity and reduce fasting blood sugar due to the strong affinity of GCG to target protein-glycosidase, and the strong inhibition effect of GCG on α-glucosidase activity [71].

In general, different types of tea exhibit antidiabetic effects in vitro and in vivo. Tea catechins, theaflavins, polysaccharides, and caffeine should be mainly responsible for the antidiabetic effects of tea. Notably, these bioactive compounds in tea can regulate signal pathways and key molecules involved in the regulation of insulin, blood sugar, and energy metabolism.
