Unexpected sensitivity of nonobese diabetic mice with a disrupted poly(ADP-ribose) polymerase-1 gene to streptozotocin-induced and spontaneous diabetes
Unexpected sensitivity of nonobese diabetic mice with a disrupted poly(ADP-ribose) polymerase-1 gene to streptozotocin-induced and spontaneous diabetes
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DOI：
10.2337/diabetes.51.5.1470
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发表时间：
2002-05-01
期刊：
影响因子：
7.7
通讯作者：
Lévi-Strauss, M
中科院分区：
文献类型：
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作者：
Gonzalez, C;de Murcia, JM;Lévi-Strauss, M
聚（ADP-核糖）聚合酶-1（PARP-1）是一种响应DNA链断裂而消耗NAD的核酶。它的过度激活似乎对胰腺β细胞特别有害，如PARP-1缺陷小鼠对链脲佐菌素诱导的毒性糖尿病的完全抗性所示。由于这种酶在1型糖尿病中的可能意义，许多使用烟酰胺（PARP-1的抑制剂）的人体试验已经在最近诊断的患者或高度易患这种疾病的受试者中进行。为了分析这种酶在小鼠1型糖尿病中的作用，我们将破坏的PARP-1等位基因渗入到自身免疫性糖尿病易感的非肥胖糖尿病（NOD）小鼠品系中。我们发现，这些小鼠既不受自发性糖尿病的保护，也不受环磷酰胺加速的糖尿病的保护。令人惊讶的是，它们对单次高剂量链脲佐菌素诱导的糖尿病也高度敏感，与携带相同失活PARP-1等位基因的C57 BL/6小鼠形成鲜明对比。我们的研究结果表明，NOD小鼠的特点不仅是他们的免疫功能障碍，但也由他们的胰岛的特殊性，导致PARP-1的链脲佐菌素诱导的β细胞死亡的独立机制。
Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that consumes NAD in response to DNA strand breaks. Its excessive activation seems particularly deleterious to pancreatic beta-cells, as exemplified by the complete resistance of PARP-1-deficient mice to the toxic diabetes induced by streptozotocin. Because of the possible implication of this enzyme in type 1 diabetes, many human trials using nicotinamide, an inhibitor of PARP-1, have been conducted either in patients recently diagnosed or in subjects highly predisposed to this disease. To analyze the role of this enzyme in murine type 1 diabetes, we introgressed a disrupted PARP-1 allele onto the autoimmune diabetes-prone nonobese diabetic (NOD) mouse strain. We showed that these mice were protected neither from spontaneous nor from cyclophosphamide-accelerated diabetes. Surprisingly they were also highly sensitive to the diabetes induced by a single high dose of streptozotocin, standing in sharp contrast with C57BL/6 mice that bear the same inactivated PARP-1 allele. Our results suggest that NOD mice are characterized not only by their immune dysfunction but also by a peculiarity of their islets leading to a PARP-1-independent mechanism of streptozotocin-induced beta-cell death.