Streptozotocin is responsible for the induction and progression of renal tumorigenesis in diabetic wistar-furth rats treated with insulin or transplanted with agarose encapsulated porcine islets
Streptozotocin is responsible for the induction and progression of renal tumorigenesis in diabetic wistar-furth rats treated with insulin or transplanted with agarose encapsulated porcine islets
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DOI：
10.4161/isl.3.4.16129
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发表时间：
2011-07-01
期刊：
影响因子：
2.2
通讯作者：
Smith, Barry H.
中科院分区：
文献类型：
--
作者：
Vinerean, Horatiu V.;Gazda, Lawrence S.;Smith, Barry H.
链脲佐菌素 (STZ) 是一种具有 DNA 烷基化特性的亚硝基脲，在 I 型糖尿病实验模型中被广泛用于通过特异性破坏胰岛中产生胰岛素的 β 细胞来诱导高血糖。然而，STZ 已知的致癌特性引起了人们对其是否适合长期研究的担忧。我们对长期存活的糖尿病 Wistar-Furth 大鼠中 STZ 的致癌作用进行了正式研究。为了确定胰岛素治疗或胰岛移植是否会加剧肿瘤发生，将大鼠随机分配到四个实验组之一：未接受治疗的正常动物（第 1 组，n = 12）；将猪胰岛腹膜植入双层琼脂糖中形成胰岛大珠的正常动物（正常 + 胰岛；第 2 组，n = 12）； STZ 治疗后每日外源性胰岛素（STZ + 胰岛素；第 3 组，n = 18），STZ 治疗后腹膜内植入猪胰岛大珠（STZ + 胰岛；第 4 组，n = 14）。在 STZ 诱导后 215 天，未接受 STZ 的动物（第 1 组和第 2 组）中没有观察到肾脏增殖性病变，而第 3 组和第 4 组的腺瘤发生率为 57% 和 34%。通过第 351 天的终末尸检，在第 3 组的 67% 和第 4 组的 60% 动物中观察到肾增殖性病变的发生率和严重程度随着管状癌的增加而增加。我们得出的结论是，由于进行性肾肿瘤发生，STZ诱导的糖尿病大鼠模型不适合长期研究。我们的实验还证明了猪胰岛大珠治疗糖尿病的安全性和有效性。
Streptozotocin (STZ), a nitrosourea with DNA alkylating properties, has been widely used to induce hyperglycemia by specifically destroying the insulin-producing beta-cells of the islets of Langerhans in experimental models of Type I diabetes. STZ's known carcinogenic properties, however, raise concerns about its suitability for long-term studies. We conducted a formal study of STZ's carcinogenic effects in long-term surviving diabetic Wistar-Furth rats. To determine if insulin therapy or islet transplantation exacerbated tumorigenesis, rats were randomly assigned to one of four experimental groups: normal animals with no treatment (Group 1, n = 12); normal animals that underwent peritoneal implantation of porcine islets encapsulated in a double layer of agarose to form islet macrobeads (Normal + Islets; Group 2, n = 12); STZ treatment followed by daily exogenous insulin (STZ + insulin; Group 3, n = 18) and STZ treatment followed by the intraperitoneal implantation of porcine islet macrobeads (STZ + Islets; Group 4, n = 14). At 215 days post-STZ induction, no renal proliferative lesions were observed in animals that did not receive STZ (Groups 1 and 2) whereas adenoma incidences of 57% for Group 3 and 34% for Group 4 were observed. By terminal necropsy at day 351, the incidence and severity of renal proliferative lesions increased with tubular carcinoma observed in 67% of Group 3 and 60% of Group 4 animals. We conclude that the STZ-induced diabetic rat model is not suitable for long-term studies because of progressive renal tumorigenesis. Our experiments also demonstrate the safety and effectiveness of porcine islet macrobeads for the treatment of diabetes.