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

Nature Medicine volume 9, pages 596–603 (2003)Cite this article

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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Figure 1: Effect of HDAD-Ipf1 on STZ mice.
Figure 2: Effect of various HDAD treatments on liver histology and function.
Figure 3: HDAD gene therapy of STZ diabetic mice.
Figure 4: Fluorescence immunocytochemistry of insulin-producing cells in the liver from STZ mice 4 months after the treatment with Neurod only (3 × 1011 particles; a–h) or Neurod (3 × 1011 particles) plus Btc (1 × 1011 particles; i–p).
Figure 5: Electron microscopy and immuno-electron microscopy of insulin-producing cells in the liver of mice treated with HDAD-Neurod (3 × 1011 particles) plus HDAD-Btc (1 × 1011 particles).

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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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Authors and Affiliations

  1. Departments of Medicine and Molecular & Cellular Biology, Section of Diabetes, Endocrinology & Metabolism, Baylor College of Medicine, Houston, Texas, USA

    Hideto Kojima, Kazuhiro Matsumura, Patrick Younan, Makiko Maeda & Lawrence Chan

  2. Department of Anatomy, Shiga University of Medical Science, Otsu, Japan

    Mineko Fujimiya, Hirotsugu Imaeda & Makiko Maeda

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  1. Hideto Kojima
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Correspondence to Lawrence Chan.

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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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