**5. Tea and insulin resistance/diabetes**

Insulin resistance is a key feature of MetS and an important risk factor for CVD and T2D. Diabetes is a global health issue with high morbidity and mortality. The global prevalence of diabetes was 8.5% in 2014. In 2016, about 3.7 million deaths were caused by high blood glucose levels and diabetes. Almost half of the deaths caused by high blood glucose levels occur before the age of 70. T2D is linked to insulin resistance, altered lipid profile, hypertension, and endothelial dysfunction [49].

Recent evidence indicates that tea consumption improves insulin sensitivity and reduces the risk of T2D [9, 50]. Possibly, tea polyphenols act on gut microbiota, increase the probiotic species in the intestine, and attenuate the gene expression of enzymes involved in gluconeogenesis (phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase) and glucose production in the liver, mediated by AMPK activation [9].

In vitro, in vivo, and clinical studies have shown that green tea catechins, mainly EGCG, have various antidiabetic activities [50–53]. However, some studies have shown that there are no beneficial effects of tea on T2D [51, 52, 54, 55] (**Table 3**).

#### **5.1 Molecular mechanisms of tea regulating insulin resistance/T2D**

Green tea enhances glucose-stimulated insulin secretion through the cyclic adenosine monophosphate (cAMP)/Akt pathway. Moreover, EGCG could activate



*CRP, C-reactive protein; HbA1C, glycated hemoglobin A1C; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance index; GLP-1, glucagon-like peptide 1; LDL-C, low-density lipoprotein cholesterol; TNF, tumor necrosis factor; T2D, type 2 diabetes; ↓, Reduction; ↑, increase.*

#### **Table 3.**

*Studies that showed the effect of tea on insulin resistance and diabetes.*

AMPK to improve the shutdown of the insulin stress signal pathway caused by serine phosphorylation of insulin receptor substrate-1 (IRS-1), improving insulin resistance [50]. High plasma glucose level increases ROS production, while EGCG improved insulin resistance by scavenging ROS. ROS plays a key role in increasing JNK and IRS-1 serine phosphorylation and reducing the transduction of insulin signal [62]. Green tea catechin increases insulin sensitivity by directly activating peroxisome proliferator-activated receptor (PPAR) γ [50]. In addition to insulin sensitivity, EGCG can also inhibit glucose absorption by competitively binding with the sodium-glucose transporter-1 (SGLT-1) in intestinal epithelial cells and enhance glucose uptake in muscles and adipocytes via enhancement of the GLUT4 expression [44, 53].

Most studies showing the beneficial effects of EGCG on glucose homeostasis were performed in vitro. EGCG showed an insulin-like activity through the reduction of gluconeogenic enzymes (glucose-6-phosphatase and PEPCK) in hepatocytes by suppressing their gene expression [51, 52]. In myocytes, green tea or EGCG stimulates GLUT4 translocation and glucose uptake via the PI3-kinase/ Akt signaling pathway; alternatively, muscle glucose uptake occurs via AMPK [52]. In laboratory animals, EGCG improved insulin sensitivity in peripheral organs and inhibited gluconeogenesis [51]. In humans, EGCG can protect pancreatic β cell from cytokines, inhibiting the NF-kB activation [63]. Tea also reduces carbohydrate absorption by inhibiting α-amylase, β-glucosidase, and sodium-glucose transporters [51, 56].

Black tea rich in theaflavins decreases the risk of T2D by inhibiting obesity through AMPK phosphorylation and promoting the browning of white adipose tissue [50]. The pro-inflammatory cytokines TNF-α and interleukin (IL)-1 are involved in obesity-associated insulin resistance and T2D. Black tea consumption has a potential role in downregulating serum TNF-α and IL-1 levels and upregulating IL-10, an anti-inflammatory cytokine [63].
