Abdel-Rahman M S, Elrakhawy F I, Iskander F A
Department of Pharmacology/Toxicology, New Jersey Medical School, Newark 07103-2714.
Toxicol Lett. 1992 Nov;63(2):155-64. doi: 10.1016/0378-4274(92)90007-7.
Alloxan induces diabetes in laboratory animals through the destruction of the endocrine pancreatic B cells. The mechanism of alloxan toxicity is still obscure. This study was conducted to investigate the effects of superoxide dismutase (SOD) or reduced nicotinamide adenine dinucleotide (NADPH) treatment on the B cells in isolated rat islets prior to alloxan treatment. Islets were treated with SOD (1000 U) or 0.1 mM NADPH for 10 min followed by alloxan treatment (0.18 mg) for 5 min. Insulin secretion was studied in samples incubated for 60 min in media supplemented with glucose (1.8 mg/ml). Morphological examinations were conducted on fixed samples after the alloxan treatment. SOD significantly protected the islets from the cytotoxic effect of alloxan. Although alloxan decreased insulin secretion to 35% of the control, SOD increased this level to 73% of the control values. NADPH did not provide any protection to the islets. Insulin secretion from islets treated with NADPH and alloxan was not different from that after alloxan treatment alone. Morphological changes were observed in the islets treated with alloxan alone or alloxan in the presence of NADPH. Islets exhibited multiple cellular necrosis, marked degranulation and extensive vesiculation of the endoplasmic reticulum and Golgi complex. Mitochondrial enlargement with disrupted cristae and mitochondrial ruptures were prominent. However, islets treated with SOD and alloxan were similar to the control except for the enlarged mitochondria. The increased insulin secretion from islets treated with SOD and alloxan reinforces the free radical hypothesis of alloxan toxicity. The markedly enlarged mitochondria was one of the targets through which alloxan destroyed the B cells.
四氧嘧啶通过破坏胰腺内分泌β细胞在实验动物中诱发糖尿病。四氧嘧啶毒性的机制仍不清楚。本研究旨在探讨超氧化物歧化酶（SOD）或还原型烟酰胺腺嘌呤二核苷酸（NADPH）处理对四氧嘧啶处理前分离的大鼠胰岛β细胞的影响。胰岛先用SOD（1000 U）或0.1 mM NADPH处理10分钟，然后用四氧嘧啶（0.18 mg）处理5分钟。在补充有葡萄糖（1.8 mg/ml）的培养基中孵育60分钟的样品中研究胰岛素分泌。在四氧嘧啶处理后对固定样品进行形态学检查。SOD显著保护胰岛免受四氧嘧啶的细胞毒性作用。尽管四氧嘧啶将胰岛素分泌降低至对照的35%，但SOD将该水平提高至对照值的73%。NADPH对胰岛没有提供任何保护作用。用NADPH和四氧嘧啶处理的胰岛的胰岛素分泌与单独用四氧嘧啶处理后没有差异。在用单独的四氧嘧啶或在NADPH存在下的四氧嘧啶处理的胰岛中观察到形态学变化。胰岛表现出多处细胞坏死、明显的脱颗粒以及内质网和高尔基体复合体的广泛空泡化。线粒体肿大，嵴断裂和线粒体破裂很明显。然而，用SOD和四氧嘧啶处理的胰岛除了线粒体肿大外与对照相似。用SOD和四氧嘧啶处理的胰岛中胰岛素分泌的增加强化了四氧嘧啶毒性的自由基假说。明显肿大的线粒体是四氧嘧啶破坏β细胞的靶标之一。
