beta-cell apoptosis and defense mechanisms: lessons from type 1 diabetes.

Abstract

Increased evidence suggests that apoptosis is the main mode of ␤-cell death in early type 1 diabetes. Cytokines mediate ␤-cell apoptosis, and in this article, we discuss some of the cytokine-modified genes that may contribute to ␤-cell survival or death. The gene encoding for the inducible form of nitric oxide synthase is induced by interleukin (IL)-1␤ or IL-1␤ plus ␥-interferon in rodent and human islets, respectively. This leads to nitric oxide (NO) formation, which contributes to a major extent to ␤-cell necrosis and to a minor extent to the process of ␤-cell apoptosis. The main mode of cell death induced by cytokines in human ␤-cells is apoptosis, whereas cytokines lead to both necrosis and apoptosis in rat and mouse ␤-cells. It is suggested that the necrotic component in rodent islets is due to NO-induced mitochondrial impairment and consequent decreased ATP production. Human islets, possessing better antioxidant defenses, are able to preserve glucose oxidation and ATP production, and can thus complete the apoptotic program after the death signal delivered by cytokines. We propose that this death signal results from cytokine-induced parallel and/or sequential changes in the expression of multiple proapoptotic and prosurvival genes. The identity of these "gene modules" and of the transcription factors regulating them remains to be established. Diabetes 50 (Suppl. 1):S64-S69, 2001 H yperglycemia in type 1 diabetes probably results from a long-term negative balance between immune-mediated ␤-cell damage (1) and ␤-cell repair/regeneration (2). Once macrophages and T-cells have been attracted to the islets and activated, they secrete soluble mediators such as cytokines, oxygen free radicals, and nitric oxide (NO), which probably contribute to ␤-cell dysfunction and death (3-5). Under in vitro conditions, interleukin (IL)-1␤, in combination with interferon (IFN)-␥ and/or tumor necrosis factor (TNF)-␣, induces severe functional suppression and death by apoptosis in rodent pancreatic islet cells (3,6,7). Human islets are less sensitive to the deleterious effects of cytokines, but their exposure for several days to IL-1␤ plus TNF-␣ plus IFN-␥ induces ␤-cell functional impairment and death by apoptosis (4,8). Interestingly, neither IL-1␤ nor IFN-␥ alone induces apoptosis in human ␤-cells, whereas the combination of these cytokines directly induces ␤-cell death (8,9). A potential indirect effect of cytokines is upregulation of the ␤-cell Fas receptor, increasing the susceptibility of these cells to apoptosis mediated by Fas ligand (FasL), expressed on the surface of invading T-cells and macrophages (10)(11)(12). Recent data indicate that Fas expression and apoptosis are also present in human ␤-cells in the early stages of type 1 diabetes (11,13).Apoptosis is apparently the main mode of ␤-cell death in NOD mice (14). In this species, ␤-cell apoptosis precedes massive T-cell infiltration (15), reinforcing a putative role for inflammatory mediators produced by early infiltrating cells such as macrophages and dendritic cel...

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