beta-cell apoptosis and defense mechanisms - Lessons from type 1 diabetes

Increased evidence suggests that apoptosis is the main mode of beta -cell d eath in early type 1 diabetes. Cytokines mediate beta -cell apoptosis, and in this article, we discuss some of the cytokine-modified genes that may co ntribute to beta -cell survival or death. The gene encoding for the inducib le form of nitric oxide synthase is induced by interleukin (IL)-1 beta or I L-1 beta plus gamma -interferon in rodent and human islets, respectively. T his leads to nitric oxide (NO) formation, which contributes to a major exte nt to beta -cell necrosis and to a minor extent to the process of beta -cel l apoptosis. The main mode of cell death induced by cytokines in human beta -cells is apoptosis, whereas cytokines lead to both necrosis and apoptosis in rat and mouse beta -cells. It is suggested that the necrotic component in rodent islets is due to NO-induced mitochondrial impairment and conseque nt decreased ATP production. Human islets, possessing better antioxidant de fenses, are able to preserve glucose oxidation and ATP production, and can thus complete the apoptotic program after the de beta ath signal delivered by cytokines. We propose that this death signal results from cytokine-induc ed parallel and/or sequential changes in the expression of multiple proapop totic and prosurvival genes. The identity of these "gene modules" and of th e transcription factors regulating them remains to be established.