The Role And Mechanism Of AGEs Induced Apoptosis In Pancreatic β-cells

Diabetes mellitus is one of the most common metabolic diseases,typically characterized by absolute or relative insulin deficiency.It is well known that pancreatic beta cell failure is the pathogenesis basis of type 1 and type 2 diabetes.Chronic hyperglycemia in the diabetic setting initiates non-enzymatic reactions between reducing sugars and free amines of proteins,lipids,or nucleic acids and accelerates the formation and accumulation of endogenous advanced glycation end products(AGEs)in the circulation.AGEs contribute to the development of IR,inflammation,and all types of diabetes mellitus.It is well established that AGEs has been proved associated with pancreatic beta cell failure.However,the mechanism is less well-understood.The aim of this study was to explore the role and mechanism of AGEs induced pancreatic beta cell apoptosis in following two aspects,First,tumor suppressor p53 plays a critical role in mediating the cellular response to diverse stress signals,including oxidative stress and endoplasmic reticulum(ER)stress,in the majority of cells.The transactivation of p53 elicits pleiotropic biochemical and biological outcomes ranging from triggering the G1/S phase cell cycle checkpoint in response to milder damage to inducing replicative senescence and apoptosis.It has been reported that the activation of p53 mediated amylin-and lipotoxicity-induced apoptosis in pancreatic beta cells.However,the role of p53 in AGEs-mediated beta-cell apoptosis has not been defined.In this study,we reveal for the first time that the transcriptional activity of p53 can be provoked by glycation-serum(GS)and identified the contribution of p53 in GS-induced beta-cell apoptosis in INS-1 cells and isolated primary islets.We speculated that the nuclear translocation and activation of p53 may be caused by mitochondrial dysfunction.Second,insulin-like growth factor 1 receptor(IGF-1R),the receptor for IGFs(IGF1 and IGF2),is a tyrosine kinase receptor critical for cellular proliferation,survival,and transformation through the IGF1R/phosphatidylinositol 3-kinase(PI3K)/AKT pathway.In the present study,we found that GS induced beta-cell proliferation through IGF1R/AKT pathway.The activation of AKT caused the de-phosphorylation of FOXO1,leading to the decreased expression of IGFIR.The results of chromatin immunoprecipitation assays(ChIP)showed that FOXO1 could bind to the IGFIR gene promoter in vivo.Finally,the decrease of IGF1R blocked the AKT pathway and resulted in pancreatic beta cell apoptosis.In summary,in the present study we investigate the mechanisms of AGEs induced pancreatic beta cell apoptosis.We report for the first time that the transcriptional activity of p53 and IGFIR/AKT/FOXO1 pathway mediate GS-induced beta-cell apoptosis in INS-1 cells and isolated primary islets.Our findings contribute to the understanding of molecular mechanisms of AGEs-induced beta cell apoptosis and may provide a therapeutic target for the treatment and prevention of diabetes.