*3.3. Adjuvant Therapy*

Currently, acarbose, rosiglitazone, and metformin are the main antidiabetic drugs used in clinics [66,133]. Several studies reported that tea had synergistic e ffects with antidiabetic drugs on diabetes and its complications, making tea a promising adjuvant for diabetes treatment. It was shown that pu-erh tea could enhance the e ffect of rosiglitazone on antidiabetic nephropathy by preventing the diabetes-induced accumulation of AGEs and re-establishing a normal RAGE level in vivo [69]. Black tea and acarbose also showed a mixed-type e ffect on the modulation of postprandial hyperglycemia by inhibiting the α-glucosidase activity in the small intestine [134]. Low concentrations of green tea polyphenols or EGCG had a synergistic e ffect with acarbose on α-amylase and α-glucosidase in vitro [135].

To sum up, a grea<sup>t</sup> number of studies indicated that tea and its bioactive components could be used for the prevention and treatment of diabetes mellitus and its complications (Table 2). The main mechanisms of action included protecting pancreatic β-cells, ameliorating insulin resistance, anti-inflammatory, and antioxidant potentials (Figure 3). Furthermore, tea showed a synergistic e ffect with certain antidiabetic drugs on diabetes and its complications.

**Figure 2.** The molecular mechanisms of EGCG against diabetes mellitus and its complications. EGCG has shown effects against T2DM by improving IR, against diabetic cardiovascular disease by decreasing TG and [Ga<sup>2</sup>+], against diabetic nephropathy by decreasing ROS and against diabetic neuropathy by increasing Nrf2. The arrow means the direction of actions, and the black full lines indicate upregulation and red dotted lines refer to downregulation or inhibition. CRP, C-reactive protein; MAPK p38-NIK, NF-κB inducing kinase; LKB1, kelch-like ECH-associated protein-1; EEF2K, eukaryotic elongation factor-2 kinase; ARE, antioxidant-responsive element; GSK-3β, glycogen synthase kinase-3β; IR, insulin resistance; MnSOD, Mn superoxide dismutase; NA, noradrenalin; s6k1, ribosomal protein S6 kinase 1; AC, adenylate cyclase; HSL, hormone-sensitive lipase; TG, triglyceride; FA, fatty acid; GL, glycerinum; GSH, glutathione; GSSH, oxidized glutathione; mTOR, the target of rapamycin; EGCG, epigallocatechin gallate; IKK, IκB kinase; NF-κB, nuclear factor-κB; iNOS, inducible nitric oxide synthase; TNF-<sup>α</sup>, tumor necrosis factor-α; Nrf2, nuclear factor-erythrocyte-associated factor 2; PI3K, phosphatidylinositol 3-hydroxykinase; Akt, protein kinase B; AMPK, adenylic acid-activated protein kinase; T2DM, type 2 diabetes mellitus; GLUT, glucose transporter type; PKA, protein kinase A; ATP, adenosine triphosphate; cAMP, cyclic Adenosine monophosphate; COMT, catechol-O-methyltransferase, an enzyme responsible for the degradation of noradrenalin.






**Table 2.** *Cont.*



GFAP, glial fibriliary acidic protein; SRET, sterol regulatory element-binding transcription factor 1; SREP, synthase and sterol response element-binding protein; TIMP, tissue inhibitor of metalloproteinases; STZ, streptozotocin; SHR, spontaneous hypertension rat, ICR, Institute of Cancer Research; Akt, protein kinase B; eNOS, endothelial nitric oxide synthase; PPARγ, peroxisome proliferator-activated receptorγ; PI3K, phosphatidylinositol 3-hydroxykinase; GLUT, glucose transporter type; GSK-3β, glycogen synthase kinase-3β; TNF, tumor necrosis factor; AGEs, advanced glycation end products; SOD, superoxide dismutase; GSH-Px, glutathione peroxidase; SIRP, signal regulatory protein; Nrf2, nuclear factor-erythrocyte-associated factor 2; mTOR, the target of rapamycin; S6k1, ribosomal protein S6 kinase 1; JNK, jun NH2-terminal kinase; w/v, weight/volume; w/w, weight/weight.

**Figure 3.** The association between tea and diabetes and its complications. Tea has effects on type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) by protecting pancreatic β-cells and ameliorating insulin resistance. Besides, due to the anti-inflammatory and antioxidant properties of tea, diabetic complications, including diabetic cardiovascular complication, diabetic nephropathy, diabetic neuropathy, and diabetic hepatic tissue injury, could be prevented and treated by tea and its bioactive components.
