NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice
NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice
复制标题
DOI：
10.1038/nm867
复制
发表时间：
2003-05-01
期刊：
影响因子：
82.9
通讯作者：
Chan, L
中科院分区：
文献类型：
--
作者：
Kojima, H;Fujimiya, M;Chan, L
为了探索肝脏中诱导胰岛新生作为治疗糖尿病的策略，我们使用辅助依赖性腺病毒 (HDAD) 将胰腺十二指肠同源盒-1 基因 (Ipf1；也称为 Pdx-1) 传递给链脲佐菌素 (STZ) 治疗的糖尿病小鼠。 HDAD 相对无毒，因为它不含编码病毒蛋白的基因。然而，由于 Ipf1 的外分泌分化活性，用 HDAD-Ipf1 治疗的小鼠出现了暴发性肝炎。 STZ 小鼠的糖尿病可通过 HDAD 介导的 NeuroD (Neurod)（Ipf1 下游因子）的转移部分逆转，并通过 Neurod 和 betacellulin (Btc) 的组合完全逆转，且不会产生肝炎。在实验期间（>120天），接受治疗的小鼠健康且血糖正常。我们在肝脏中检测到胰岛素和其他胰岛特异性转录物，包括胰岛素原加工酶、β细胞特异性葡萄糖激酶和磺酰脲受体。免疫细胞化学检测到存在组织成胰岛簇的胰岛素、胰高血糖素、胰多肽和生长抑素产生细胞；免疫电镜显示典型的含胰岛素颗粒。我们的数据表明 Neurod-Btc 基因疗法是一种有前途的诱导胰岛新生治疗胰岛素依赖性糖尿病的方案。
To explore induced islet neogenesis in the liver as a strategy for the treatment of diabetes, we used helper-dependent adenovirus (HDAD) to deliver the pancreatic duodenal homeobox-1 gene (Ipf1; also known as Pdx-1) to streptozotocin (STZ)-treated diabetic mice. HDAD is relatively nontoxic as it is devoid of genes encoding viral protein. Mice treated with HDAD-Ipf1 developed fulminant hepatitis, however, because of the exocrine-differentiating activity of Ipf1. The diabetes of STZ mice was partially reversed by HDAD-mediated transfer of NeuroD (Neurod), a factor downstream of Ipf1, and completely reversed by a combination of Neurod and betacellulin (Btc), without producing hepatitis. Treated mice were healthy and normoglycemic for the duration of the experiment (>120 d). We detected in the liver insulin and other islet-specific transcripts, including proinsulin-processing enzymes, beta-cell-specific glucokinase and sulfonylurea receptor. Immunocytochemistry detected the presence of insulin, glucagon, pancreatic polypeptide and somatostatin-producing cells organized into islet clusters; immunoelectron microscopy showed typical insulin-containing granules. Our data suggest that Neurod-Btc gene therapy is a promising regimen to induce islet neogenesis for the treatment of insulin-dependent diabetes.