The Effects And Mechanism Of Natural Compound TI90 Protecting Islet β Cells From The Toxicity Of High Glucose And Fatty Acid

Diabetes,characterized as hyperglycemia is a kind of metabolic disorders due to islet β cell dysfunction and relative or absolute reduction in amounts.Glucotoxicity and lipotoxicity are major causes accounting for β cell damage.In today’s society with vigorous growth,With the improvement of human living standards,unhealthy lifestyles and mental stress make trend of diabetes deteriorating in China.So,to find anti-diabetes therapeutic drugs with high effect,low cost and little side effects is still a tough task.In our previous study,we have constructed a screening model using PDX-1promoter to drive the expression of luciferase reporter vector and found that natural compound TI90,screened out from natural compound library in our laboratory can effectively activate PDX-1 promoter and promote the expression of PDX-1 in islet βcells.The purpose of this study is to further investigate the protective effect of TI90 on islet β cells from glucotoxicity and lipotoxicity and relative molecular mechanisms.To investigate whether TI90 can protect islet β cells from glucotoxicity and lipotoxicity.First of all,we established the glucotoxicity and lipotoxicity models in INS-1 cells induced by high glucose and high fat,palmitate.By using the established models,we detected effects of TI90 on the viability of INS-1 cells injured by high glucose and high fat through MTT.Subsequently,cell cycle was detected through flow cytometry and apoptosis was measured using DAPI staining,flow cytometry and western blot.Based on these data,a conclusion was drawn that TI90 can protect isletβ cells from glucotoxicity and lipotoxicity.Subsequently we investigated the underlying molecular mechanism by which TI90 protects islet β cells from damage of high glucose and high fat.Firstly,we found that expression of iNOS and NO production increased in INS-1 cells injured by high glucose and high fat,but TI90 treatment could abolish this elevation.Secondly,we found that high glucose and high fat restrained the activation of ERK and reduced the expression of PDX-1 in damaged INS-1 cells.Nevertheless,TI90 could restore the activation of ERK and PDX-1 expression.Meanwhile,ERK inhibitor U0126 blocked the effects of TI90 on expression of PDX-1 and apoptosis.These results suggest that TI90 may elicit protective effects on INS-1 cells through activation of ERK signaling pathway.Finally,we found that p38 signaling pathway was activated in high fattreated INS-1 cells and was responsible for islet β cell apoptosis since p38 inhibitor SB203580 suppressed the expression of apoptosis-related protein induced by high fat.What’s more,TI90 could block the activation of p38 induced by high fat,indicating that TI90 may inhibited the lipotoxicity-induced INS-1 cell apoptosis through repressing activation of p38/MAPK pathway.In summary,the natural compound TI90 can maintain the survival of islet β cells in glucotoxic and lipotoxic conditions.And TI90 might be a new promising anti-diabetes drug.