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Endocrinology Service and Research Unit, Puerta del Mar Hospital, Cadiz, Spain
(Requests for offprints should be addressed to M Aguilar-Diosdado, Servicio de Endocrinologia, Hospital Puerta del Mar, Avda Ana de Viya 21, 11009 Cádiz, Spain; Email: manuel.aguilar.sspa{at}juntadeandalucia.es)
Pancreatic ß-cell apoptosis is known to participate in the ß-cell destruction process that occurs in diabetes. A better understanding of how it takes place is essential for future development of therapeutic strategies aimed at preventing ß-cell loss and diabetes. In this study we determine the possible role that high glucose concentration might play as an enhancer of cytokine- and streptozotocin (STZ)-mediated rat islet cell apoptosis in vitro and its relationship with potential changes in the expression of pro- and anti-apoptotic proteins. Rat islets treated with a cytokine combination (interleukin (IL)-1ß, tumor necrosis factor (TNF)-
and interferon (IFN)-
) displayed a significant increase in islet cell apoptosis when the islets were incubated in 24.4 mM glucose compared with untreated islets at the same glucose concentration (13.07 ± 1.78% vs 6.09 ± 0.78%; P < 0.01) or islets incubated in 5.5 mM glucose concentration and cytokines (13.07 ± 1.78% vs 8.04 ± 1.56%; P < 0.05). IL-1ß alone did not induce a significant increase in the apoptotic rates in islet cells cultured at normal or high glucose concentrations. STZ significantly increased islet cell apoptosis when islets were cultured in 24.4 mM glucose concentration compared with untreated islets at the same glucose concentration (6.02 ± 0.62% vs 4.44 ± 0.63%; P < 0.05). High glucose induced an increase in Fas expression in the islet cells, and this increase was maintained after cytokine or STZ treatment. However, the expression of anti-apoptotic mediators such as bcl-2 and bcl-xL did not show any significant change. These results suggest that cytokine- and STZ-mediated apoptotic effects on islet cells might be mediated by a glucose-induced hyperfunctional status and associated with an increase in Fas (Apo-1, CD-95) expression and no changes in the expression of the anti-apoptotic proteins bcl-xL and bcl-2.
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