Geniposide inhibits glucolipotoxicity and cooperates with Txnip knockdown to potentiate cell adaption to endoplasmic reticulum stress in pancreatic beta cells.

Thioredoxin-interacting protein (Txnip), a negative regulator of thioredoxin, has become an attractive therapeutic target to alleviate metabolic diseases. Our previous data demonstrated that geniposide improved glucose-stimulated insulin secretion by accelerating Txnip degradation and prevented the early-stage apoptosis of pancreatic β cells induced by palmitate, but the underlying mechanisms are still unclear. The objective of this study is to identify the role of Txnip in geniposide preventing the apoptosis of pancreatic β cells induced by high glucose and palmitate (HG/PA). The results revealed that geniposide attenuated HG/PA-induced cell apoptosis and the expression of Bax and caspase-3, while increasing mitochondrial membrane potential and the anti-apoptotic protein levels of heme-oxygenase-1 (HO-1) and Bcl-2 in INS-1 rat pancreatic β cells. Knockdown of the Txnip gene raised the levels of anti-apoptotic proteins HO-1 and Bcl-2 and geniposide potentiated the effect of Txnip when the INS-1 cells were challenged by HG/PA. Furthermore, geniposide enhanced the adoptive unfolded protein response by increasing the phosphorylation of PERK/eIF2α and IRE1α in HG/PA-treated INS-1 cells. The results together suggest that geniposide might be useful to antagonize glucolipotoxicity and Txnip might be a pleiotropic cellular factor in pancreatic β cells.