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The primary objective in managing DM is to attain optimal glycemic control and to stave off or slow down the emergence and advancement of DM complications[10]. A fundamental component of contemporary DM management encompasses the utilization of clinical medications aimed at regulating blood glucose levels. These medications, owing to the multifaceted nature of DM's pathophysiology, operate via a variety of mechanisms to modulate glucose levels[4,11−13], which can be divided into five main categories (as shown in Table 1): (1) In an oral or injection form, insulin can be administered to hormone-deficient T1DM patients and T2DM patients with poor glycemic management. (2) Another approach to manage DM involves the usage of insulin sensitizers, exemplified by thiazolidinediones and biguanides. Thiazolidinediones, like pioglitazone and rosiglitazone, alongside biguanides such as metformin and buformin, generally enhance insulin receptor sensitivity in peripheral tissues like muscle, adipose tissue, and liver, thereby ameliorating insulin resistance. (3) Insulin secretion enhancers such as sulfonylureas are another treatment option. Oral sulfonylureas (e.g., glimepiride, gliquidone, gliclazide, and glipizide) stimulate insulin secretion from pancreatic β-cells. Nevertheless, it's worth noting that sulfonylureas can provoke insulin secretion independently of glucose levels, potentially leading to episodes of hypoglycemia. (4) Therapeutic medications based on incretin hormones, such as dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists, offer additional treatment options. (5) Other drugs, including α-glucosidase inhibitors and sodium-glucose cotransporter-2 (SGLT2) inhibitors, are other treatment options. Notably, commonly used α-glucosidase inhibitors like miglitol, voglibose, and acarbose may induce side effects like gastric flatulence and diarrhea with long-term use[14]. SGLT2 inhibitors increase renal glucose excretion by decreasing renal tubular reabsorption of glucose[14]. Antidiabetic medications may be administered as single agents or combined in dual or triple therapy regimens to effectively manage hyperglycemia. However, despite their efficacy in treating DM, these hypoglycemic medications are highly susceptible to a variety of adverse effects with long-term use, including weight gain, hypoglycemia, nephron- and hepatotoxicity, allergies, and abdominal discomfort (diarrhea, vomiting, and nausea)[4,11−13]. Moreover, they are also expensive. Therefore, there is a high demand for alternative natural hypoglycemic drugs for the management of DM.
Table 1. Summary of the categories of hypoglycemic medicines, common clinical drugs, hypoglycemic mechanisms, and adverse effects.
Categories of hypoglycemic medicines Common clinical drugs Hypoglycemic mechanisms Adverse effects Insulin Insulin Enhance glucose uptake and utilization by systemic tissues and cells while inhibiting glycogenolysis and glycogen isogenesis. Hypersensitivity, lipodystrophy, and lipohypertrophy Thiazolidinediones Rosiglitazone; Pioglitazone Increase insulin sensitivity in liver, muscle, and adipose tissue. Abnormal liver function and weight gain Biguanides Pioglitazone; Buformin; Metformin Inhibit hepatic glucose output, improve the insulin sensitivity of peripheral tissues, and increase glucose uptake and utilization. Loss of appetite, nausea, abdominal discomfort, and diarrhea Sulfonylureas Glimepiride; Gliquidone; Gliclazide; Glipizide Reduce blood glucose levels by stimulating β-cells insulin secretion. Hypoglycemic reaction, loss of appetite, nausea and vomiting, diarrhea, and increased risk of cardiovascular disease Dipeptidyl peptidase-4
(DPP-4) inhibitorsLinagliptin; Saxagliptin; Vigliptin Reduce glucagon and hypoglycemia. Nasopharyngitis, headache, and upper respiratory tract infection Glucagon-like peptide 1
(GLP-1) receptor agonistLixisenatide; Albiglutide; Dulaglutide; Semaglutide Reduce blood glucose levels by increasing insulin secretion and inhibiting postprandial glucagon secretion. Nausea, vomiting, diarrhea, injection-site inflammation, and pancreatitis α-Glucosidase inhibitors Acrobose; Miglitol; Voglibose Hinder the decomposition and absorption
of dietary carbohydrates by inhibiting pancreatic α-amylase and intestinal α-glucosidase.Gastric flatulence and diarrhea Sodium-glucose-cotransporter type-2 (SGLT-2) inhibitors Canagliflozin; Ertugliflozin; Dapagliflozin; Empagliflozin Inhibit glucose reabsorption in the kidney and eliminate glucose from the urine. Urinary tract infection -
The mechanisms by which the bioactive components of tea (tea polyphenols, tea polysaccharides, and alkaloids) help prevent and treat DM and its complications mainly include improving insulin resistance, inhibiting carbohydrate digestion and absorption (inhibiting α-amylase and α-glucosidase activity), regulating gut microbiota, inflammatory cytokines, and gene and protein expressions in the insulin signaling pathway, as well as ameliorating DM complications (as shown in Fig. 2 & Table 2).
Figure 2.
The mechanisms of tea bioactive components (tea polyphenols, polysaccharides, and alkaloids) help prevent and treat DM and its complications (image source from Freepik.com).
Table 2. The effects and mechanisms of tea and its bioactive components on DM based on in vitro and in vivo studies
Tea/bioactive components Animal models Doses (day) Duration (weeks) Effects and mechanisms Ref. Yellow tea extract C57BL/6J mice 60 or 120 mg/kg 10 Improves impaired glucose tolerance, pyruvate tolerance, and insulin resistance. [45] Black tea extract Wistar rats 25, 50, or 100 mg/kg 30 d Decreases the level of glucose, glycated hemoglobin and increases the levels of insulin. [47] White tea extract Wistar rats / 8 Improves glucose tolerance and insulin sensitivity. [48] Pu-erh tea extract Wistar rats 120, 160, 600, or
800 mg/kg6 Increases the abundance of the beneficial bacteria. [49] Fu brick tea extract C57BL/6J mice 100, 200, or
400 mg/kg8 Ameliorates the T2DM-induced gut dysbiosis by decreasing the Firmicutes/Bacteroidota ratio at the phylum level. [50] Liubao tea extract C57BL/6J mice 834 or 1,667 mg/kg 10 Increases the diversity of intestinal flora. [51] Tea polyphenols Wistar rats 200 mg/kg 6 Improves insulin sensitivity and decreases the inflammatory factors. [55] Kaempferol Sprague–Dawley rats 50 or 150 mg/kg 10 Enhances insulin sensitivity. [56] Theaflavins Spontaneously diabetic torii rats 25 mg/kg 20 Improves impaired glucose tolerance. [57] Tea polysaccharides ICR mice 150, 200, or 300 mg/kg 4 Improves insulin resistance. [60] EGCG; Epiafzelechin-3-gallate; ECG / / / Exhibits inhibitory effects against α-glucosidase. [64] Oolong tea polyphenols; EGCG; EGCG3″Me / / / Exhibits inhibitory effects against α-amylase. [67] Quercetin-3-O-(6″-O-galloyl)-β-galactopyranoside; Quercetin-3-O-(3″-O-galloyl)-β-glucopyranoside / / / Exhibits inhibitory effects against α-glucosidase. [68] Tea polysaccharides ICR mice 1 or 5 mg/kg / Exhibits inhibitory effects against α-glucosidase. [69] Tea polysaccharides ICR mice 50 mg/kg / Exhibits inhibitory effects against α-glucosidase. [70] Tea polysaccharides / / / Exhibits inhibitory effects against α-amylase and α-glucosidase. [71] Tea polysaccharides / / / Exhibits inhibitory effects against α-glucosidase. [72] Tea polysaccharides C57BL/6 mice 200, 400, or
800 mg/kg8 Increases the phylogenetic diversity of HFD-induced microbiota. [76] EGCG Db/db mice 10, 50, or 100 mg/kg 8 Increases the abundance of beneficial bacteria. [78] Tea polysaccharides Wistar rats 100, 200, or
400 mg/kg/ Modulates gut microbiota diversity and increases the abundance of beneficial genera. [79] Quercetin Wistar rats 50 mg/kg 3 Exhibits anti-inflammatory activity. [82] Caffeine KK-Ay mice 250 mg/L 5 Reduces inflammatory cytokine expression (TNFα, IL-6, and MCP-1). [83] EGCG Db/db mice 2.5, 5.0, or 10.0 g/kg 7 Decreases the PEPCK mRNA expression in the adipose and liver tissues. [87] Tea polyphenols Wistar rats 200 mg/kg 6 Upregulates the insulin signaling protein levels. [55] Tea polysaccharides Kunming mice 200, 400, or
800 mg/kg4 Upregulates the expressions of the critical proteins in the PI3K/Akt signal pathway including GLUT4, p-Akt, and PI3K. [90] Tea polyphenols; Tea polysaccharides; Caffeine Sprague–Dawley rats 400 or 800 mg/kg 6 Reduces rat serum leptin levels, inhibits the absorption of fatty acids, and reduces the expression levels of the IL-6 and
TNF-α genes.[91] EC Sprague–Dawley rats 50 or 100 mg/kg 2 Improves advanced glycation end products-induced retinal vascular injury. [94] Improvement of insulin resistance
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Insulin resistance, a fundamental characteristic of T2DM, arises when liver, adipose, and muscle cells improperly utilize the insulin produced by islet β-cells[13]. Impaired glucose homeostasis and insulin resistance lead to the development of cellular hyperglycemia and hyperinsulinemia[52].
Experimental evidence has indicated that green tea extract possesses the potential to ameliorate insulin resistance and enhance glycemic control[53]. For example, it improved insulin resistance in human HepG2 liver cancer cells by activating the 5'-adenosine monophosphate-activated protein kinase pathway[54]. And this activation mitigated the obstruction of insulin stress signaling pathways caused by the phosphorylation of insulin receptor substrate-1[54]. Furthermore, green tea polyphenols exhibited the capacity to enhance insulin sensitivity in insulin-resistant rats via upregulating insulin signaling protein levels[55]. A previous study showed that kaempferol ameliorates insulin resistance in T2DM rats by modulating hepatic IKK/NF-κB signaling[56]. Spontaneously diabetic Torii rats elevated fasting glucose levels to 139 ± 23 mg/dL at 28 weeks of intervention, and the ingestion of TF significantly reduced the fasting glucose level to 74 ± 11 mg/dL, which may be due to the induction of the increase in incretin secretion by TF[57]. Moreover, it has been demonstrated that TF-DG could effectively improve glucose uptake in insulin-resistant HepG2 cells and regulate glucose levels in diabetic zebrafish[58]. Additionally, it has been speculated that the richness of tea polysaccharides and polyphenols in yellow tea may contribute to the improvement of insulin resistance and the imbalance of glucolipid metabolism[59]. Among the polysaccharides from black (fully fermented), green (unfermented), oolong (semi-fermented), and dark (post-fermented) teas, black tea polysaccharides exhibited superior efficacy in controlling blood glucose levels and improving insulin resistance, indicating that the fermentation degree significantly increases the hypoglycemic effect of tea polysaccharides[60]. An in vitro experiment reported that pu-erh tea polysaccharides exhibit similar properties to glucose transporter type 4 and peroxisome proliferator-activated receptor γ by improving insulin resistance and reducing blood glucose levels, which could enhance adipocyte differentiation and glucose uptake[61].
Inhibition of digestion and absorption of carbohydrates (inhibit of α-amylase and α-glucosidase activity)
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Carbohydrates constitute the primary exogenous sugars for the body, and starchy foods contribute significantly to overall energy intake. Upon ingestion, starch undergoes initial hydrolysis by salivary and α-amylase, resulting in the production of reducing sugars like maltose and maltotriose. Subsequently, α-glucosidase further hydrolyzes these intermediates to yield glucose[62]. Thus, the two enzymes mentioned above both play crucial roles in regulating starch digestion, and inhibiting their activity has been proposed as a strategy to impede starch digestion and attenuate the rapid increase in postprandial blood glucose levels[63].
Notably, the inhibitory impact on α-glucosidase was significantly augmented through the galloylation of polyphenols[64]. Nongalloylated polyphenols, such as EGC, epiafzelechin, and EC, showed a weaker inhibitory activity than their corresponding galloylated polyphenols EGCG, epiafzelechin-3-gallate, and ECG, respectively[64]. In addition, in the cases of tea polyphenols, typically comprising catechins and TFs, it has been reported that the presence of 3- and 3'-galloyl moiety on the C ring enhances the affinity of catechins and TFs for α-amylase, thereby heightening the inhibitory activities of both polyphenols against the enzyme[65]. Among four different tea extracts (black tea, green tea, oolong tea, and dark tea extracts), black tea extract exhibited the most pronounced hypoglycemic activity, presumably due to the rich content of TFs in black tea, which inhibited sucrase-isomaltase activity and thus delayed the hydrolysis of isomaltose, maltose, and sucrose, leading to lower postprandial blood glucose[66]. Another investigation revealed that oolong tea polyphenols, 3′′-methyl-epigallocatechin gallate (EGCG3″Me) and EGCG, exhibited inhibitory effects against α-amylase with IC50 values of 0.375, 0.572, and 0.350 mg/mL, respectively[67]. In the realm of quercetin glycosides, quercetin-3-O-(6"-O-galloyl)-β-galactoside (IC50 value: 1.35 ± 0.06 μM) and quercetin-3-O-(3"-O-galloyl)-β-galactoside (IC50 value: 0.97 ± 0.02 μM) emerged as the most potent α-glucosidase inhibitors among the tested compounds. Their inhibitory potency surpassed that of the positive control acarbose (IC50 value: 50.58 ± 0.25 μM) by approximately 37 and 52 times, respectively[68]. Pu-erh dark tea polysaccharide has been reported to lower blood glucose levels in starch-fed mice by inhibiting α-glucosidase activity[69]. A study by Xu et al.[70] showcased that polysaccharides isolated from pu-erh tea possess anti-α-glucosidase activities comparable to or even superior to the clinically used antidiabetic drug acarbose. Interestingly, the anti-α-glucosidase activities demonstrated an increase with the fermentation time of pu-erh tea, suggesting that longer fermentation may lead to the polymerization of proteins and polysaccharides, thereby altering their configuration and conformation and enhancing biological activity. Furthermore, it was reported that tea polysaccharides with smaller molecular weights exhibit better biological activities, such as lowering blood glucose and antioxidant activity, andα-amylase inhibition was significantly and positively correlated with arabinose or galactose content[71]. Moreover, a recent study highlighted the pu-erh tea polysaccharides, which was characterized by the highest total protein and phenolic contents, and displayed the strongest α-glucosidase inhibitory and antidiabetic activities compared to polysaccharides from the other five tea categories
Regulation of gut microbiota
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Numerous studies have shown that excessive consumption of foods rich in sugar and fat may disturb the natural balance of gut flora and contribute to the onset of DM[24]. Bioactive compounds in tea could increase probiotic levels by modulating the gut flora, thereby improving gut health to alleviate DM.
Nie et al. observed a decreased ratio of the major phyla Firmicutes/Bacteroidetes and a significant reduction of Bifidobacteria in patients with DM[73]. Another study also confirmed the former finding that the genera Fusobacterium, Blautia, and Ruminococcus were positively associated with DM, while the genera Bifidobacterium, Akkermansia, Roseburia, Faecalibacterium, and Bacteroides were negatively associated with DM[74]. Flavonoids modulate the intestinal flora, increase the diversity and abundance of beneficial bacterial species, and improve intestinal barrier function, thereby reducing insulin resistance[75]. Black tea contains high levels of water-soluble dietary fiber, such as the oxidative polymerization products of tea polysaccharides and polyphenols (e.g., catechins and TFs). These components have the potential to improve lipid and glucose metabolism by regulating the intestinal flora[76]. Huang et al. found that bound polyphenols could modulate diabetic rats' imbalanced microbial community by significantly decreasing harmful bacteria, such as Proteobacteria[77]. A previous animal study demonstrated that the oral administration of EGCG at a dose of 100 mg/kg daily for eight weeks improved glucose homeostasis by increasing glucose tolerance in diabetic mice[78]. Additionally, this diet intervention led to an elevation in the population of bacteria from the Christensencelaceae family while concurrently decreasing the prevalence of Enterobacteriaceae in the intestine of diabetic mice[78]. In addition, polyphenols, such as EGCG, EGC, GC, and other catechins, demonstrated the capacity to hinder the proliferation of numerous pathogens, such as Staphylococcus, Salmonella, Clostridium perfringens, Escherichia coli, and certain gram-negative mimics of the genus Bacillus[73]. These actions have the potential to contribute to the enhancement of intestinal microecology, which may be beneficial for managing DM[73]. It has been shown that tea polysaccharides might exhibit hypoglycemic effects through the regulation of gut microbiota diversity and the augmentation of the relative prevalence of beneficial genera[79]. The antidiabetic effects of Liupao dark tea may be attributed to the increased amount of beneficial bacteria, such as Bacteroides, S24-7, Lactobacillus, Clostridiales, Prevotella, and Ruminococcaceae, in the gut microbiota, which might be modulated by the high contents of polyphenols[80]. These results suggest that the intake of bioactive components from teas may lead to a more balanced environment to promote gut microbiota diversity and maintain a healthy state.
Regulation of inflammatory cytokines
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Inflammatory cytokines are linked to the development of DM, and inflammatory responses may lead to insulin resistance, which in turn contributes to the development of DM[81]. Medicine targeting inflammatory cytokines is considered as one of the strategies for preventing and managing DM.
Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine generated by adipose cells. It can cause an increase in the release of fatty acids by adipocytes and resulted in increased levels of free fatty acids which deteriorate insulin signaling and decrease insulin secretion[81]. In contrast, IL-10 is an anti-inflammatory cytokine produced by type 2 macrophages and lymphocytes, which play key roles in suppressing pro-inflammatory cytokines production like TNF-α and IL-6[81]. Various studies have demonstrated that bioactive components in teas exert hypoglycemic effects by lowering the concentrations of pro-inflammatory cytokines and elevating the levels of anti-inflammatory cytokines. For example, the anti-inflammatory effect was observed in quercetin by increasing plasma adiponectin and reducing TNF-α levels in diabetic rats[82]. Moreover, tea polysaccharides may increase immunoreactivity by boosting immune cell activity via enhancing the levels of anti-inflammatory cytokines (e.g., IL-10, IgM, IgG, IL-4, IL-2, and IgA ), and decreasing the levels of pro-inflammatory cytokines like TNF-α and IL-6[22]. Additionally, the beneficial impact of caffeine in KK-Ay mice primarily resulted from its ability to diminish the expression of inflammatory cytokine expression (TNF-α, IL-6, and MCP-1) and ameliorate fatty liver conditions[83]. In addition, the anti-inflammatory effect of TFs should also be considered as they are the major phenolic compounds of black tea and have been reported to inhibit nitric oxide synthase by downregulating the activation of NF-κB in macrophages[84].
Regulation of gene and protein expressions of the insulin signaling pathway
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The bioactive compounds present in tea contribute to the regulation of blood glucose levels by promoting/inhibiting the expressions of genes and proteins involved in glycometabolism and the insulin signaling pathway[85].
It has been reported that EGCG promoted the tyrosine phosphorylation expressions of the insulin receptor and insulin receptor substrate-1, and inhibited the expression of phosphoenolpyruvate carboxykinase gene for the treatment of DM[86]. In addition, it also lowered the mRNA expression of the phosphoenolpyruvate carboxykinase in H4IIE cells, as well as in the liver tissue and adipose of db/db mice[87]. In addition, it was reported that a supplement of tea polyphenols could improve insulin sensitivity by upregulating the insulin signaling protein levels in insulin-resistant rats[55]. Another study showed that the hypoglycemic mechanism of theasinensin A and B involved the facilitation of glucose transporter 4 translocation to the plasma membrane, thus enhancing glucose intake in rat skeletal muscle cells, which was mediated by the CaMKK/AMPK signaling pathway[88]. Following treatment with tea polysaccharides, there was a notable augmentation in insulin secretion under high glucose conditions (25 mM). In addition, this treatment resulted in the upregulation of gene transcriptions for GLUT2, PKA, INS-2, INS-1, GLP-1R, GCK, and PDX-1 at the mRNA level, alongside increased expression of PDX-1 at the protein level[89]. Furthermore, the antidiabetic effects of tea polysaccharides were counteracted by PKA and AC inhibitors but not by PLC inhibitors, suggesting that tea polysaccharides enhanced antidiabetic activity through the cAMP-PKA signaling pathway[89]. Li et al. evaluated the hypoglycemic effect and possible mechanism of tea polysaccharides in T2DM mice model[90]. It was found that tea polysaccharides enhanced the expression of pivotal proteins within the PI3K/Akt signaling pathway, encompassing GLUT4, p-Akt, and PI3K, which indicated the participation of the PI3K/Akt signal pathway in the hypoglycemic mechanism of tea polysaccharides[90]. Moreover, polyphenols, polysaccharides, and caffeine exhibited the capacity to enhance blood lipid and antioxidant levels, effectively reducing rat serum leptin levels and the expression levels of the IL-6 and TNF-α genes[91].
Amelioration of DM complications
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DM is often associated with many complications, including diabetic cardiovascular dyslipidemia, diabetic retinopathy, diabetic foot infections, diabetic nephropathy, diabetic neuropathy, and diabetic hepatopathy. Some reports suggesting that these complications can be improved by the bioactive compounds in tea.
TFs and catechins effectively mitigated the disruption of insulin signaling caused by high glucose levels[92]. In addition, they also curbed lipid accumulation, suppressed fatty acid synthesis, and promoted fatty acid oxidation through the activation of the LKB1-AMPK pathway[92]. The lack of insulin deficiency and insulin resistance can trigger exaggerated vascular constriction, leading to an increased risk of diabetic cardiovascular dyslipidemia[93]. Another study also confirmed the above finding that black tea polyphenols enhance vasoconstriction by modulating the PI3K-Akt pathway and endothelial nitric oxide synthase phosphorylation[93]. EC destroyed glycated human serum albumin in a dose-dependent manner and decreased the accumulation of advanced glycosylation end products in the retina, thereby having beneficial effects on diabetic retinopathy[94]. It has been shown that patients with diabetes treated with EGCG or green tea polyphenols can sustain normal levels of apoptosis in podocytes, but the proportion of apoptotic podocytes were significantly increased in untreated diabetes patients[95]. Additionally, the potential effect of old tree white tea on diabetic nephropathy is attributed to its high contents of polyphenols (particularly EGCG) and polysaccharides[96].
This agrees with the findings presented by Xu et al.[97] and Yi et al.[98], which indicated that the hypoglycemic and antioxidant properties of tea polysaccharides and tea polyphenols have the potential to significantly ameliorate and prevent diabetic kidney injury. An in vivo investigation revealed that tea polyphenols could potentially inhibit autonomic dysfunction by preventing alterations in arterial pressure variability[99]. Additionally, another study proposed that tea polyphenols could exert significant effects on diabetic liver injury through their antioxidant activity[100].
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Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
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About this article
Cite this article
Gao J, Chen D, Lin Z, Peng J, Yu S, et al. 2023. Research progress on the antidiabetic activities of tea and its bioactive components. Beverage Plant Research 3:32 doi: 10.48130/BPR-2023-0032
Research progress on the antidiabetic activities of tea and its bioactive components
- Received: 19 July 2023
- Revised: 28 September 2023
- Accepted: 13 October 2023
- Published online: 04 December 2023
Abstract: Diabetes mellitus (DM) is a pressing global public health issue with a high incidence of morbidity and mortality due to its complications. Although there are many medicines available for the treatment of DM, long-term use causes various adverse effects, such as diarrhea, vomiting, and nausea. Tea, owing to its richness of diverse bioactive components including tea polyphenols, tea polysaccharides, and alkaloids, has displayed promising antidiabetic properties. Screening antidiabetic bioactive compounds derived from teas is receiving increasing attention. Epidemiological and clinical investigations have demonstrated an inverse relationship between tea consumption and the incidence of DM. Both in vitro and in vivo experiments have substantiated the hypoglycemic effects of tea and its bioactive components through several possible mechanisms, including improvement of insulin resistance, inhibition of carbohydrates digestion and absorption (inhibit α-amylase and α-glucosidase activity), regulations of gut microbiota, inflammatory cytokines, and gene and protein expressions in the insulin signaling pathway, as well as amelioration of DM complications. This comprehensive review provides an up-to-date overview of the hypoglycemic properties associated with tea and its bioactive components. It also delves into their potential mechanisms, offering a theoretical foundation for further research into tea's antidiabetic properties and for the development of innovative antidiabetic functional products.
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Key words:
- Tea /
- Bioactive components /
- Diabetes mellitus /
- Mechanisms