Mellado-Gil J M, Aguilar-Diosdado M
Endocrinology Service and Research Unit, Puerta del Mar Hospital, Cadiz, Spain.
J Endocrinol. 2004 Oct;183(1):155-62. doi: 10.1677/joe.1.05542.
Pancreatic beta-cell apoptosis is known to participate in the beta-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 beta-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)-1beta, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma) 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-1beta 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.
已知胰腺β细胞凋亡参与糖尿病中发生的β细胞破坏过程。更好地了解其发生机制对于未来旨在预防β细胞丢失和糖尿病的治疗策略的发展至关重要。在本研究中，我们确定高糖浓度作为细胞因子和链脲佐菌素（STZ）介导的大鼠胰岛细胞体外凋亡增强剂可能发挥的作用，及其与促凋亡和抗凋亡蛋白表达潜在变化的关系。与在相同葡萄糖浓度（13.07±1.78%对6.09±0.78%；P<0.01）下未处理的胰岛相比，或与在5.5 mM葡萄糖浓度和细胞因子共同作用下的胰岛（13.07±1.78%对8.04±1.56%；P<0.05）相比，用细胞因子组合（白细胞介素（IL）-1β、肿瘤坏死因子（TNF）-α和干扰素（IFN）-γ）处理的大鼠胰岛在24.4 mM葡萄糖中孵育时，胰岛细胞凋亡显著增加。单独的IL-1β在正常或高糖浓度培养的胰岛细胞中未诱导凋亡率显著增加。与在相同葡萄糖浓度下未处理的胰岛相比，当胰岛在24.4 mM葡萄糖浓度下培养时，STZ显著增加胰岛细胞凋亡（6.02±0.62%对4.44±0.63%；P<0.05）。高糖诱导胰岛细胞中Fas表达增加，并且这种增加在细胞因子或STZ处理后得以维持。然而，抗凋亡介质如bcl-2和bcl-xL的表达未显示任何显著变化。这些结果表明，细胞因子和STZ介导的对胰岛细胞的凋亡作用可能由葡萄糖诱导的功能亢进状态介导，并与Fas（Apo-1，CD-95）表达增加以及抗凋亡蛋白bcl-xL和bcl-2表达无变化有关。
