Role of pancreatic beta-cells in the process of beta-cell death

Studies on the pathogenesis of type 1 diabetes have mainly focused on the role of the immune system in the destruction of pancreatic beta-cells. Lack of data on the cellular and molecular events at the beta-cell level is caused by the inaccessibility of these cells during development of the disease. Indirect information has been collected from isolated rodent and human islet cell preparations that were exposed to cytotoxic conditions. This article reviews in vitro experiments that investigated the role of beta-cells in the process of beta-cell death. beta-Cells rapidly die in necrosis because of toxic levels of oxidizing radicals or of nitric oxide; they progressively become apoptotic after prolonged culture at low glucose or with proinflammatory cytokines. Their susceptibility to necrosis or apoptosis varies with their functional state and thus with the environmental conditions. A change in cellular phenotype can alter its recognition of potentially cytotoxic agents and its defense mechanisms against cell death. These observations support the view that beta-cells are not necessarily passive victims of a cytotoxic process but can actively participate in a process of beta-cell death. Their role will be influenced by neighboring non-beta-cells, which can make the islet internal milieu more protective or toxic for the beta-cells. We consider duct cells as potentially important contributors to this local process.