NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice

被引:334
作者
Kojima, H
Fujimiya, M
Matsumura, K
Younan, P
Imaeda, H
Maeda, M
Chan, L [1 ]
机构
[1] Baylor Coll Med, Dept Med, Sect Diabet Endocrinol & Metab, Houston, TX 77030 USA
[2] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
[3] Shiga Univ Med Sci, Dept Anat, Otsu, Shiga 52021, Japan
关键词
D O I
10.1038/nm867
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:596 / 603
页数:8
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