Alleviating Effects And Mechanisms Of Large-leaf Yellow Tea On Type 2 Diabete And Diabetic Nephropathy

Objective:To investigate the ameliorating effects and mechanisms of action of large-leaf yellow tea（LYT）administration on typical symptoms of type 2 diabetes,glucose and lipid metabolism,intestinal flora and its metabolites SCFAs,and diabetic nephropathy.Methods:Diabetic model was established through HFD plus a single intraperitoneal injection of STZ after overnight fasting at week 6 post HFD consumption.One week after the STZ injection,mice with FBG at the range of 11.1-25.0 mmol/L were divided into four groups with even FBG levels:diabetic control group（Model）,diabetic with low dose LYT group（1/100,w/v）,diabetic with high dose LYT group（1/50,w/v）,and positive control group（Dapagliflozin,8μg/m L）.Age-matched wild type C57BL/6J mice were used as normal control group（control）.Mice were allowed free access to water（Control and Model）,LYT infusion（1/100 or 1/50,w/v）or dapagliflozin aqueous solution,and normal chow diet（Control）or HFD（diabetic mice）for 4 consecutive weeks.Drinking fluids were refreshed daily.Urine output and fluid and food intakes were recorded twice a week.FBG was measured weekly.At the end of the experiment,all mice were fasted for 12 h,peripheral blood was collected from the ophthalmic vein after anesthetized and then the mice were sacrificed by cervical dislocation.Serum was obtained by centrifugation at 3000 round/min for 15 min at 4℃and stored at-80℃.Livers and kidneys were collected and stored at-80℃.Fresh fecal samples of each mouse were collected respectively and divided into two portions and stored at-80℃during the final 3 days of the animal experiment.Results:1.LYT（1/100 and 1/50,w/v）improved diabetic polydipsia and polyuria,increased glucose tolerance and insulin sensitivity.Improved diffuse fat infiltration,reduced glycogen accumulation and lipid accumulation,and decreased fasting blood glucose（FBG）in diabetic mice.LYT treatment can rectify diabetic glucose and lipid dysmetabolism,and the potential mechanisms involve downregulating lipogenesis-related SREBP-1 protein and upregulating fatty acid oxidation metabolism-associated CPT-1 proteins,downregulating gluconeogenesis-related TXNIP and FBP proteins and FBP enzyme activity and modifying gut microbiota.2.LYT（1/50,w/v）regulated the structure and abundance of intestinal microbiome in type 2 diabetic mice.LYT increased the relative abundance of Lactobacillus,Alloprevotella,Alistipes,Parabacteroides,Akkermansia,and Mucispirillum,which are beneficial for alleviating the metabolic syndrome,and decreased the relative abundance of Coriobacteriaceae＿UCG-002,Allobaculum and Faecalibaculum which are not beneficial to metabolic syndrome.In addition,LYT decreased the levels of fecal caproic acid and serum propionic acid in type 2 diabetic mice.Correlation analysis showed that reduced fecal caproic acid and serum propionic acid levels were highly positively correlated with fasting blood glucose（FBG）,insulin resistance index（HOMA-IR）,or glucose intolerance(AUC_GTT).Furthermore,The decrease in fecal caproic acid levels was associated with a decrease in the abundance of Faecalibaculum and Coriobacteriaceae＿UCG-002 and an increase in the abundance of Parabacteroides.3.The consumption of LYT（1/50,w/v）significantly reduced the serum Cr and BUN levels in type 2 diabetic mice.It alleviated renal mesangial dilatation and tubule endothelial cell edema,improved hyperglycemic osmotic diuresis,and down-regulated renal NLRP3 proteins as well as renal membrane PKC-α,AQP2 and glycosylated AQP2 proteins in diabetic mice.Conclusions:LYT administration can alleviate diabetic symptoms,including hyperglycemia,polydipsia and polyuria,mitigate glucose and lipid dysmetabolism,regulate the structure and abundance of intestinal flora,and prevente diabetic nephropathy in high-fat diet combining streptozotocin-induced type 2 diabetic mice.