Induction of Apoptosis of β 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.

Advanced Glycation End Product Receptor-1 Transgenic Mice Are Resistant to Inflammation, Oxidative Stress, and Post-Injury Intimal Hyperplasia

“…52 In both of these studies, high levels of AGEs were shown to result in hyperglycemia. Given that prooxidants such as AGEs are toxic to pancreatic islets [53][54][55] and that anti-AGE agents and diets protect against islet and ␤-cell injury and dysfunction, 30,53 it is possible that AGER1 overexpression could protect against ␤-cell injury as a matter of course. Further studies are required to elucidate the mechanisms involved in these effects.…”

Epigenetics: The missing link to understanding β-cell dysfunction in the pathogenesis of type 2 diabetes

“…102 Binding to the receptors for AGE (RAGE) on β-cells leads to increased ROS and induction of apoptosis. 103 Reactive oxygen species enhance AGE-induced signaling, which activates pathways associated with inflammation. 104,105 Thus, chronic exposure to elevated concentrations of nutrients, impairment in antioxidant status and activation of the inflammatory response are all inter-related and may contribute to cellular dysfunction and apoptosis (Fig.…”

Effect Of Chronic Administration Of Hexane Extract Of <i>Byrsonima Crassifolia</i> Seed On Β-Cell And Pancreatic Oxidative Parameters In Streptozotocin-Induced Diabetic Rat

“…In the present study, B. crassifolia lowered the level of blood glucose significantly as compared with that of the diabetic control group. Therefore, our data demonstrated that NS protected RIN-5F cells from AGEs-induced oxidative stress which is followed by decreasing insulin gene expression and secretion [Lim et al, 2008]. Although, the serum insulin level of the NS group tended to increase as compared with that of the diabetic control suggesting that NS might partially rescue exhausted pancreatic β-cells of rats from further AGEs-induced oxidative stress.…”