title: Apoptosis in autoimmune diabetes: the fate of beta-cells in the cleft between life and death.
abstract: Cytokine-induced beta-cell death is the end-stage event in the pathogenesis of autoimmune diabetes. Beside cytokines, several pro-apoptotic pathways mediated through nitric oxide, reactive oxygen species, glucose and Fas ligation can be involved, suggesting that programmed cell death (PCD) is a critical aspect in this process. The apoptotic program is activated by the utilization of the Fas/Fas-ligand (FasL) axis in the interrelation of T and beta-cells. Evidence for this mechanism arose from the finding that beta-cells in NOD mice could be protected from apoptosis by blocking the Fas-FasL pathway. Glucose is a regulator of Fas expression on human beta-cells and elevated glucose levels may contribute to accelerated beta-cell destruction by constitutively expressed FasL independently of the autoimmune reaction. It can thus be concluded that immunological, as well as metabolic, pathways may act in concert to cause beta-cell destruction. Much experimental work has been carried out to manipulate beta-cells in transgenic mice expressing apoptosis modulators in islets. For example, the transcription factor, nuclear factor-kappaB (NF-kappaB), promotes the expression of several beta-cell genes, including pro- and anti-apoptotic genes. The prevention of cytokine-induced gene expression of several NF-kappaB targets, such as inducible nitric oxide synthase, Fas, and manganese superoxide dismutase can prevent beta-cell death. Thus, modulating the expression of apoptotic mediators may significantly affect the end-stage outcome of autoimmune diabetes and could thus be a potential avenue for clinical therapy, even though currently existing findings remain exploratory due to the restrictions of transgenic mouse models.
authors.affiliation: United Biomedical Inc., 25 Davids Drive, Hauppauge, New York 11788, USA. csia@unitedbiomedical.com
authors.forename: Charles
authors.initials: C
authors.lastname: Sia
authors.forename: Arno
authors.initials: A
authors.lastname: Hänninen