Mechanisms Of EGCG Autoxidation Products Reducing Blood Glucose Levels By RAS Regulation In Db/db Mice

Type 2 diabetes(T2D)is a multifactorial disease,accompanied by typical metabolic syndromes such as hyperglycemia,polyuria,diabetes,and polyphagia.Among them,osmotic diuresis caused by hyperglycemia is considered to be the first clinical condition of diabetes.Due to polyuria and severe water loss,polydipsia and compensatory polydipsia are induced.Due to the serious loss of urinary glucose,it leads to increased hunger and compensatory polyphagia.The increase in food intake will further increase hyperglycemia.The risk of polyuria,urinary glucose,polydipsia and polyphagia is a vicious circle.Insulin resistance is the core cornerstone of type 2 diabetes and its metabolic syndrome.The study of new molecular targets closely related to insulin resistance has been a hot spot in the field of diabetes research in the past decade.This research mainly focuses on the following targets:1)Renin-angiotensin system(RAS),RAS is highly expressed in type 2 diabetes,and RAS has a dual regulatory effect on glucose metabolism.Inhibiting the harmful axis of glucose metabolism while activating the beneficial axis of glucose metabolism in RAS is a new strategy for the treatment of type 2 diabetes.2)Selenoprotein P(SELENOP)is mainly found in the liver and skeletal muscle.The overproduction of SELENOP is the main factor leading to insulin resistance and inducing hyperglycemia in type 2 diabetes.3)Thioredoxin interacting protein(TXNIP)plays an important role in the pathological process of diabetes.It is involved in changes in insulin sensitivity,glucose uptake,insulin secretion,islet cell apoptosis,original glycogen synthesis and regeneration process.4)Glutathion peroxidase(GPx),through the regulation of H₂O₂,thereby affecting the TNF?pathway related to insulin signal transduction,and indirectly regulating insulin sensitivity.In short,activating the beneficial RAS axis(ACE2/AT2R/Mas R)and/or inhibiting the harmful RAS axis(renin/ACE/Ang II/AT1R),inhibiting SELENOP,TXNIP,GPx,etc.can increase insulin sensitivity.Epigallocatechin-3-gallate(EGCG)is the main tea polyphenol with the highest content and the strongest biological activity in green tea.It can improve metabolic syndrome,cardiovascular disease,neurodegenerative disease and prevent tumor and other functions.EGCG is unstable and easily autoxidizes to form macromolecular oxidation products.Catechins in black tea,which are mainly oxidized catechins,mostly exist in the form of theaflavins,thearubigins and theabrownins.Oxidized catechins or polyphenols have also been confirmed to have a variety of physiological activities.This study investigated the effects and mechanisms of green tea and black tea in the treatment of type 2 diabetes.Studies have shown that tea soup intervention with green tea and black tea can effectively alleviate polyuria/glycemia in type 2 diabetic mice(db/db mice),thereby inhibiting compensatory polydipsia/polyphagia and lowering blood sugar.Its mechanism of action involves up-regulating renal water reabsorption-related proteins in diabetic mice,including protein kinase C-?,aquaporin 2 and urea transporter A1.Although tea drinking has a unique pharmacological mechanism in the treatment of type 2 diabetes,the difference between catechins and oxidized catechins is not reflected.In order to exclude other interfering factors,EGCG and its autoxidation products were prepared in this study.Investigate its therapeutic effect and mechanism on type 2 diabetic mice(db/db mice).Studies have shown that the oxidation time and molecular weight of EGCG autoxidation products can reduce blood glucose and increase insulin sensitivity in db/db mice.by activating the beneficial axis and/or suppressing the deleterious axis of RAS in multiple tissues including the liver,kidney,pancreatic islet,muscle and abdominal adipose,and by suppressing renal PEPCK/G6Pase-?and pancreatic SELENOP and TXNIP.With the prolonged oxidation time at the same dose,the safety of EGCG autoxidation products increases in healthy Kunming mice.Based on the study of Hep G2 cells,it is found that EGCG autoxidation products can regulate the harmful axis of RAS,and the relationship between oxidation time and molecular weight is dependent.Based on the study of Hep G2 cells,it is found that the regulation of EAOPs on the harmful axis of RAS presents a relationship between oxidation time dependence and molecular weight dependence.In conclusion,based on the above studies,we have demonstrated for the first time that EGCG autoxidation products can simultaneously regulate RAS,SELENOP and TXNIP to increase insulin sensitivity,thus proposing a potential drug for the treatment of type 2diabetes.