(Journal Article): Apoptosis in Autoimmune Diabetes: The Fate of β-Cells in the Cleft between Life and Death
 
Sia C, Hanninen A (United Biomedical Inc., 25 Davids Drive, Hauppauge, New York 11788, USA, csia@unitedbiomedical.com )
 
IN: Rev Diabetic Stud 2006; 3(1):39-46
Impact Factor(s) of Rev Diabetic Stud: 0.125 (2006)

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ABSTRACT: Cytokine-induced β-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 β-cells. Evidence for this mechanism arose from the finding that β-cells in NOD mice could be protected from apoptosis by blocking the Fas-FasL pathway. Glucose is a regulator of Fas expression on human β-cells and elevated glucose levels may contribute to accelerated β-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 β-cell destruction. Much experimental work has been carried out to manipulate β-cells in transgenic mice expressing apoptosis modulators in islets. For example, the transcription factor, nuclear factor-κB (NF-κB), promotes the expression of several β-cell genes, including pro- and anti-apoptotic genes. The prevention of cytokine-induced gene expression of several NF-κB targets, such as inducible nitric oxide synthase, Fas, and manganese superoxide dismutase can prevent β-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.

TYPE OF PUBLICATION: Review

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