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Reversal of streptozotocin-induced diabetes in rats by gene therapy with betacellulin and pancreatic duodenal homeobox-1

Gene Therapy volume 14, pages 1102–1110 (2007)Cite this article

Abstract

Ultrasound-targeted microbubble destruction (UTMD) was used to direct betacellulin (BTC) and pancreatic duodenal homeobox-1 (PDX1) to rat pancreas 48 h after islet destruction by streptozotocin (STZ). Sprague–Dawley rats were rendered diabetic by STZ injection. Controls included normal rats, STZ only without UTMD, and UTMD with DsRed reporter gene. Blood glucose increased dramatically in all rats 48 h after STZ, and continued to rise after UTMD with BTC alone. Blood glucose declined from day 3 to day 10 after UTMD with PDX1, but remained elevated (261±8 mg/dl). However, in rats treated with both BTC and PDX1, blood glucose remained below 200 mg/dl throughout day 10. This was accompanied by normalization of blood insulin and C-peptide. Histology demonstrated islet-like clusters of glucagon-staining cells in the rats treated with BTC and PDX1, but these clusters disappeared by 30 days after UTMD treatment. Although regeneration of insulin-producing islets was not seen, diabetes was reversed for up to 15 days after a single UTMD treatment by ectopic insulin production by pancreatic acinar cells. These cells co-expressed amylase and insulin and demonstrated several β-cell markers by reverse transcription-PCR. Gene therapy by UTMD can reverse diabetes in vivo in adult rats by restoring pancreatic insulin production.

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Acknowledgements

This work was supported by NIH grant P01 DK58398, and the Mark Shepherd Research Fund of the Baylor Foundation.

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Authors and Affiliations

  1. Division of Cardiology, Department of Internal Medicine, Baylor University Medical Center, Baylor Heart and Vascular Institute, Dallas, TX, USA

    S Chen & P A Grayburn

  2. Institute of Metabolic Disease, Baylor University Medical Center, Dallas, TX, USA

    J Ding, B Yang & D R Wood

  3. Division of Vascular Surgery, Department of Surgery, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA

    C Yu

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  1. S Chen
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  2. J Ding
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  3. C Yu
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Correspondence to P A Grayburn.

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Chen, S., Ding, J., Yu, C. et al. Reversal of streptozotocin-induced diabetes in rats by gene therapy with betacellulin and pancreatic duodenal homeobox-1. Gene Ther 14, 1102–1110 (2007). https://doi.org/10.1038/sj.gt.3302963

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