The Mechanism Study On Advanced Glycation End Products(AGEs) Induced Pancreatic Beta Cell Impairment

Diabetes mellitus is one of the most common metabolic diseases in the world, typically characterized by absolute or relative insulin deficiency. The quantity and quality of the functional pancreatic beta cell plays a critical role in the development of diabetes mellitus. It is well established that glucotoxicity, lipotoxicity, and inflammation have been proven to be associated with pancreatic beta cell dysfunction and apoptosis, leading to the onset of diabetes mellitus. Chronic hyperglycemia in the diabetic setting initiates nonenzymatic reactions between reducing sugars and free amines of proteins and lipids, and accelerates the formation and accumulation of AGEs in the circulation. AGEs caused more severe damages to pancreatic beta cells than that of hyperglycemia, showing its pivotal disease character on sustained deterioration of diabetes. The burgeoning presence of toxic AGEs in modern foodstuffs has resulted from new technologies employed in the mass production of food in the past50years. A growing evidences revealed that AGEs could act as an independent factor to result in insulin resistence and other diseases in vivo, therefore, AGEs might be the initiator causing diabetes mellitus. However, the mechanism of AGEs induced daibetes mellitus and the complications is still unclear. It is also very urgent to rectify the harmful effects resulting from AGEs. Based on the critical role of: AGEs exhibited in the development of daibetes mellitus, the main aim of this study is to find out whether AGEs could impair pancreatic beta cells and to further explore the mechanism of AGEs toxicity. Glycation surum (GS) which includes various AGEs is used to mimic the in vivo diabetes settings. By utilizing GS, we investigated the potential mechanisms in insulin secreting (INS-1) cells from a pancreatic beta cell line, as well as primary rat islets. We found that GS inhibited insulin secretion and synthesis with short term treatment (with48h) because GS reduced Mafa and Pdxl protein levels by accelerating their protein degradation. Further more, GS greatly caused apoptosis in INS-1cell with extending treatment (after48h) because GS inhibited anti-apoptotic genes expression (Bc12, Bc1211), leading to mitochondial apoptosis pathway. More interestingly, all the toxic effects caused by GS was able to be restored by PPARy activation, like using PPARy agonist (Troglitazone, TRO). This study not only broadens our insight of AGEs mediating pancreatic beta cell failure, but also provides potential novel therapeutic targets against AGEs.