Masutani M, Suzuki H, Kamada N, Watanabe M, Ueda O, Nozaki T, Jishage K, Watanabe T, Sugimoto T, Nakagama H, Ochiya T, Sugimura T
Biochemistry Division, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo, 104-0045 Japan.
Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2301-4. doi: 10.1073/pnas.96.5.2301.
Streptozotocin (STZ), a glucose analogue known to induce diabetes in experimental animals, causes DNA strand breaks and subsequent activation of poly(ADPribose) polymerase (Parp). Because Parp uses NAD as a substrate, extensive DNA damage will result in reduction of cellular NAD level. In fact, STZ induces NAD depletion and cell death in isolated pancreatic islets in vitro. Activation of Parp therefore is thought to play an important role in STZ-induced diabetes. In the present study, we established Parp-deficient (Parp-/-) mice by disrupting Parp exon 1 by using the homologous recombination technique. These mice were used to examine the possible involvement of Parp in STZ-induced beta-cell damage in vivo. The wild-type (Parp+/+) mice showed significant increases in blood glucose concentration from 129 mg/dl to 218, 370, 477, and 452 mg/dl on experimental days 1, 7, 21, and 60, respectively, after a single injection of 180 mg STZ/kg body weight. In contrast, the concentration of blood glucose in Parp-/- mice remained normal up to day 7, slightly increased on day 21, but returned to normal levels on day 60. STZ injection caused extensive necrosis in the islets of Parp+/+ mice on day 1, with subsequent progressive islet atrophy and loss of functional beta cells from day 7. In contrast, the extent of islet beta-cell death and dysfunction was markedly less in Parp-/- mice. Our findings clearly implicate Parp activation in islet beta-cell damage and glucose intolerance induced by STZ in vivo.
链脲佐菌素（STZ）是一种已知可在实验动物中诱发糖尿病的葡萄糖类似物，它会导致DNA链断裂并随后激活聚（ADP - 核糖）聚合酶（Parp）。由于Parp以NAD作为底物，广泛的DNA损伤会导致细胞内NAD水平降低。事实上，STZ在体外可诱导分离的胰岛中NAD耗竭和细胞死亡。因此，Parp的激活被认为在STZ诱导的糖尿病中起重要作用。在本研究中，我们通过同源重组技术破坏Parp外显子1，建立了Parp缺陷（Parp - / - ）小鼠。这些小鼠被用于研究Parp在体内STZ诱导的β细胞损伤中可能的作用。野生型（Parp + / + ）小鼠在单次注射180 mg STZ / kg体重后，在实验第1、7、21和60天，血糖浓度分别从129 mg / dl显著增加到218、370、477和452 mg / dl。相比之下，Parp - / - 小鼠的血糖浓度在第7天之前保持正常，在第21天略有升高，但在第60天恢复到正常水平。STZ注射在第1天导致Parp + / + 小鼠的胰岛广泛坏死，随后从第7天开始胰岛逐渐萎缩，功能性β细胞丧失。相比之下，Parp - / - 小鼠的胰岛β细胞死亡和功能障碍程度明显较轻。我们的研究结果清楚地表明，Parp激活在体内STZ诱导的胰岛β细胞损伤和葡萄糖不耐受中起作用。
