Celastrol inhibits TXNIP expression to protect pancreatic β cells in diabetic mice

Celastrol (CEL) has a great potential in the treatment of a wide variety of metabolic diseases. However, whether CEL protects pancreatic β cells and its underlying mechanism are not yet clear. This study investigates to determine the effects of CEL on the pathogenesis of pancreatic β cells damage. C57BLKS/Leprdb (db/db) mice and rat insulinoma INS-1 cell line or mouse J774A.1 cell line were used as in vivo and in vitro models for investigating the protective effect of CEL on pancreatic β cells under high glucose environment and the related mechanism. The phenotypic changes were evaluated by immunofluorescence, immunohistochemical staining, flow cytometry and the measurement of biochemical indexes. The molecular mechanism was explored by biological techniques such as western blotting, qPCR, ChIP-qPCR, co-immunoprecipitation and lentivirus infection. Our results showed that CEL at the high dose (CEL-H, 0.2 mg/kg) protects db/db mice against increased body weight and blood glucose. CEL-H inhibits pancreatic β cell apoptosis in db/db mice and high glucose-induced INS-1 cells. CEL-H also reduced IL-1β production in islet macrophages. The further study found that CEL suppressed TXNIP expression and NLRP3 inflammasome activation in pancreatic β cells and islet macrophages. Importantly, the inhibitory effect of CEL on pancreatic β cell apoptosis and IL-1β production was also dependent on TXNIP. Mechanically, CEL inhibits Txnip transcription by promoting the degradation of ChREBP. Celastrol inhibits TXNIP expression to protect pancreatic β cells in vivo and in vitro. Our research pointed out another mechanism by which celastrol functions under the condition leptin signaling is ineffective.