Abstract
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, β-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.
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Acknowledgements
We thank R. Kikkawa, A. Kashiwagi and Y. Shigeta for interest and support; K. Oka, E.A. Nour, B. Thompson and M. Nishimura for technical assistance; and the Central Research Laboratory of Shiga University of Medical Science for technical support in fluorescence and electron microscopy. This work was supported by the Rutherford Chair in Diabetes Research at St. Luke's Episcopal Hospital and Baylor College of Medicine (to L.C.) and grants (HL-51586, HL-16512 and HL-59314) from the National Institutes of Health and the Japan Foundation for Aging and Health.
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Kojima, H., Fujimiya, M., Matsumura, K. et al. NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Nat Med 9, 596–603 (2003). https://doi.org/10.1038/nm867
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DOI: https://doi.org/10.1038/nm867
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