title: Induction of apoptosis of Beta cells of the pancreas by advanced glycation end-products, important mediators of chronic complications of diabetes mellitus.
abstract: We herein report cytotoxicity of advanced glycation end-products (AGEs) on pancreatic beta cells. AGEs stimulated reactive oxygen species (ROS) generation but did not arrest proliferation of the INS-1 cell line. Pancreatic beta cell lines or primary cultured islets possess a receptor for AGE (RAGE), and its expression increased after AGE treatment. TUNEL staining and FACS analysis using annexin V/PI antibodies showed that apoptosis increased in INS-1 cells or primary cultured islets when incubated with BSA conjugated with glyceraldehyde (AGE2) or glucoaldehyde (AGE3), compared with those conjugated with glucose (AGE1). Reaction of INS-1 cells to Ki67, which is a cellular marker for proliferation, was also increased after AGE treatment. The ability of primary cultured islets to secrete insulin was retained even after AGE treatment under either low or high glucose conditions. The antiserum against RAGE partially prevented AGE-induced cellular events. Treatment of beta cells with the antioxidant metallothionein results in a significant reduction in pathologic changes. AGEs might be able to induce apoptosis as well as proliferation of pancreatic beta cell lines or primary cultured islets. Moreover, antibody array showed that RAD51 and RAD52 were significantly decreased in AGE2-treated INS-1 cells. AGEs might inhibit homologous DNA recombination for repairing DNA of INS-1 cells damaged by ROS generation. It might be suggested that treatment of AGEs resulted in ROS production and apoptosis through their receptor on pancreatic beta cells. AGEs might deteriorate function of pancreatic beta cells in patients with long-term hyperglycemia.
authors.affiliation: Department of Internal Medicine and Bioengineering, Hanyang University College of Medicine and Engineering, Seoul, Korea.
authors.forename: Minsu
authors.initials: M
authors.lastname: Lim
authors.forename: Leejin
authors.initials: L
authors.lastname: Park
authors.forename: Geewook
authors.initials: G
authors.lastname: Shin
authors.forename: Hekyung
authors.initials: H
authors.lastname: Hong
authors.forename: Incheol
authors.initials: I
authors.lastname: Kang
authors.forename: Yongsoo
authors.initials: Y
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D002478:Cells, Cultured; D002908:Chronic Disease; D048909:Diabetes Complications / Q000209:etiology*; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D051135:Rad51 Recombinase / Q000378:metabolism; D051721:Rad52 DNA Repair and Recombination Protein / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: D017127:Glycation End Products, Advanced; D051721:Rad52 DNA Repair and Recombination Protein; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D051135:Rad51 Recombinase