Degradation Of Txnip Mediated By Geniposide Plays An Essential Role On Glucose-stimulated Insulin Secretion In Pancreatic Beta Cells

Type 2 diabetes mellitus(T2DM)is a growing public health issue,which was characterized by peripheral insulin resistance and progressive impairment of insulin secretion in pancreatic ? cells.A large number of evidence shows that elevated glucose levels have detrimental effect on the dysfunction and apoptosis of pancreatic ? cells.However,the exact molecular mechanisms by which glucotoxicity lead to the dysfunction and failure of ? cells are still not fully understood,and there are no efficient strategies to cope with it.It has been proposed that thioredoxin-interacting protein(Txnip),as a highly glucose-regulated proapoptotic factor,played a critical role on the dysfunction and apoptosis induced by high concentration of glucose in pancreatic ? cells.Our previous work showed that geniposide could affect glucose-stimulated insulin secretion(GSIS)in pancreatic beta cells.But the molecular mechanisms of geniposide-regulated GSIS and the effects of geniposide on the influence of Txnip protein level remain largely unknown.At present,we therefore aim to analyze the role of geniposide in the protein degradation of Txnip and determine the impact of Txnip on geniposide-regulated GSIS in pancreatic INS-1 cells.We show here glucose induces a rapid increase of Txnip protein,and geniposide accelerates the degradation of Txnip via proteasome pathway in the presence of high glucose(25 mM)in INS-1 pancreatic ? cells.MG132,an proteasomal inhibitor,potentiates glucose uptake,metabolism(ATP production)and glucose-stimulated insulin secretion(GSIS)in high glucose(25 mM)-treated INS-1 cells,but geniposide significantly prevents these effects.Furthermore,the combination of geniposide and Txnip knockdown shows substantial synergistic effects to reduce glucose uptake,metabolism and GSIS in high glucose(25 mM)-treated INS-1 cells.Together with the potential role of Txnip in redox-related cellular functions and pathophysiological processes,current data suggests geniposide might be a promising compound to halt pancreatic ? cell apoptosis induced by hyperglycemia and the development of type 2 diabetes mellitus and its complications.