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首页> 外文期刊>Molecular and Cellular Biology >Increased Susceptibility to Streptozotocin-Induced β-Cell Apoptosis and Delayed Autoimmune Diabetes in Alkylpurine- DNA-N-Glycosylase-Deficient Mice
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Increased Susceptibility to Streptozotocin-Induced β-Cell Apoptosis and Delayed Autoimmune Diabetes in Alkylpurine- DNA-N-Glycosylase-Deficient Mice

机译：烷基嘌呤-DNA-N-糖基化酶缺乏症小鼠对链脲佐菌素诱导的β细胞凋亡和迟发性自身免疫性糖尿病的敏感性增加。

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Type 1 diabetes is thought to occur as a result of the loss of insulin-producing pancreatic β cells by an environmentally triggered autoimmune reaction. In rodent models of diabetes, streptozotocin (STZ), a genotoxic methylating agent that is targeted to the β cells, is used to trigger the initial cell death. High single doses of STZ cause extensive β-cell necrosis, while multiple low doses induce limited apoptosis, which elicits an autoimmune reaction that eliminates the remaining cells. We now show that in mice lacking the DNA repair enzyme alkylpurine-DNA-N-glycosylase (APNG), β-cell necrosis was markedly attenuated after a single dose of STZ. This is most probably due to the reduction in the frequency of base excision repair-induced strand breaks and the consequent activation of poly(ADP-ribose) polymerase (PARP), which results in catastrophic ATP depletion and cell necrosis. Indeed, PARP activity was not induced in APNG?/? islet cells following treatment with STZ in vitro. However, 48 h after STZ treatment, there was a peak of apoptosis in the β cells of APNG?/? mice. Apoptosis was not observed in PARP-inhibited APNG+/+ mice, suggesting that apoptotic pathways are activated in the absence of significant numbers of DNA strand breaks. Interestingly, STZ-treated APNG?/? mice succumbed to diabetes 8 months after treatment, in contrast to previous work with PARP inhibitors, where a high incidence of β-cell tumors was observed. In the multiple-low-dose model, STZ induced diabetes in both APNG?/? and APNG+/+ mice; however, the initial peak of apoptosis was 2.5-fold greater in the APNG?/? mice. We conclude that APNG substrates are diabetogenic but by different mechanisms according to the status of APNG activity.
机译：据认为1型糖尿病是由于环境触发的自身免疫反应导致胰岛素生产性胰腺β细胞损失的结果而发生的。在糖尿病的啮齿动物模型中，链脲佐菌素（STZ）是一种针对β细胞的遗传毒性甲基化剂，可用于触发初始细胞死亡。高剂量的STZ会引起广泛的β细胞坏死，而低剂量的多个会诱导有限的细胞凋亡，从而引发自身免疫反应，从而消除剩余的细胞。我们现在显示，在缺乏DNA修复酶烷基嘌呤-DNA- N -糖基化酶（APNG）的小鼠中，单剂STZ后，β细胞坏死明显减弱。这很可能是由于碱基切除修复诱导的链断裂频率降低以及随后的聚（ADP-核糖）聚合酶（PARP）激活所致，这导致灾难性的ATP耗竭和细胞坏死。实际上，在体外用STZ处理后，APNG ？/？胰岛细胞中并未诱导PARP活性。然而，在STZ处理后48小时，APNG α/β小鼠的β细胞凋亡达到峰值。在PARP抑制的APNG + / + 小鼠中未观察到细胞凋亡，这表明在没有大量DNA链断裂的情况下细胞凋亡途径被激活。有趣的是，与以前使用PARP抑制剂的研究相反，经STZ处理的APNG α/β小鼠在治疗后8个月就死于糖尿病，而后者的β细胞肿瘤发生率很高。在多剂量低剂量模型中，STZ在APNG ？/？和APNG + / + 小鼠中均诱发糖尿病;然而，APNG α/β小鼠的细胞凋亡的初始峰值是后者的2.5倍。我们得出的结论是，APNG底物是致糖尿病的，但根据APNG活性的状态，其机制不同。

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