Theaflavins Improve Insulin Resistance In HepG2 Cells And Type 2 Diabetes Mice And The Related Molecular Mechanisms

Black tea is widely consumed all over the world.Theaflavins(TFs),which have benzhdroxyphenol structure formed by the oxidative polymerization of polyphenols in black tea,possess various bioactivities in vitro and in vivo.In this research,we investigated the improvement effects of TFs on insulin resistance in HepG2 cells induced by palmitic acidand the type 2 diabetic C57 BL / 6 mice induced by high-fat diet combined with STZ.Hepatic transcriptome analysis were performed to evaluate the effect of TFs on type 2 diabetic mice in gene expression level.The main results are as follows:1.TFs could protect HepG2 cells against PA-induced insulin resistance by increasing glucose uptake and modulating the IRS-1/Akt/GLUT4 pathway.In addition,TFs were found to increase mitochondrial DNA copy number,decrease PGC-1βmRNA levels,and increase PRC mRNA levels by real-time PCR.Mdivi-1,a selective mitochondrial division inhibitor that attenuates glucose uptake induced by TFs.These findings extend the understanding of the physiological function of theaflavins in obesity,insulin resistance and diabetes.2.In high-fat and streptozotocin-induced type 2 diabetic mice,TFs can effectively reduce blood glucose,improve glucose tolerance and insulin resistance,increase plasma insulin levels,and reduce insulin resistance index.These avtivities are comparable to that of the positive control metformin.In addition,theaflavins could significantly increase liver and muscle mitochondrial content in liver and muscle.This effect was more obvious in the liver,which might be through regulating PGC-1β expression.3.Transcriptome sequencing analysis was performed to explorethe effects of theaflavins on type 2 diabetic mice.Among the 20554 genes,131 genes were significantly upregulated,and113 genes were significantlydownregulated.GO enrichment analysis results showed that a number of differently-expressed genes invoved in biological processes,molecular functions and cellular components.Muscle contraction and regulation,phosphocreatine metabolic process,proteolysis,digestion,pancreatic juice secretion,inflammation,etc.are major biological processes enriched with differentially expressed genes.KEGG signal pathway analysis showed that 76 significantdifferentially expressed genes enriched to 9 signalling pathways.TFs up-regulates signal pathways such as pancreatic secretion,protein digestion and absorption,tight junction,fat digestion and absorption,and glycerolipid metabolism.In conclusion,this study proved TFs could improve hepatocellular insulin resistance induced by PA,at least partly through promoting mitochondrial biogenesis.TFs can significantly reduce fasting blood glucose and improve insulin sensitivity in type 2 diabetic mice induced by high fat combined with STZ.TFs are promising functional food ingredients or medicines for improving insulin resistance-related metabolic disorders.