Kojima Hideto, Fujimiya Mineko, Matsumura Kazuhiro, Younan Patrick, Imaeda Hirotsugu, Maeda Makiko, Chan Lawrence
Section of Diabetes, Endocrinology & Metabolism, Departments of Medicine and Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
Nat Med. 2003 May;9(5):596-603. doi: 10.1038/nm867. Epub 2003 Apr 21.
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; immuno-electron 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.
为了探索肝脏中诱导性胰岛新生作为治疗糖尿病的一种策略，我们使用了辅助依赖型腺病毒（HDAD）将胰腺十二指肠同源盒-1基因（Ipf1；也称为Pdx-1）导入经链脲佐菌素（STZ）处理的糖尿病小鼠体内。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处理的小鼠发生了暴发性肝炎。Ipf1下游的一个因子NeuroD（Neurod）经HDAD介导转移后，STZ小鼠的糖尿病得到部分逆转，而Neurod和β细胞ulin（Btc）联合使用则可使其完全逆转，且不会引发肝炎。在实验期间（>120天），经治疗的小鼠健康且血糖正常。我们在肝脏中检测到了胰岛素和其他胰岛特异性转录本，包括胰岛素加工酶、β细胞特异性葡萄糖激酶和磺脲类受体。免疫细胞化学检测到了组织成胰岛簇的胰岛素、胰高血糖素、胰多肽和生长抑素分泌细胞的存在；免疫电子显微镜显示出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景的诱导胰岛新生以治疗胰岛素依赖型糖尿病的方案。
