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Gene therapy of diabetes using a novel GLP-1/IgG1-Fc fusion construct normalizes glucose levels in db/db mice

Gene Therapy volume 14, pages 162–172 (2007)Cite this article

Abstract

Glucagon-like peptide (GLP-1), a major physiological incretin, plays numerous important roles in modulating blood glucose homeostasis and has been proposed for the treatment of type 2 diabetes. The major obstacles for using native GLP-1 as a therapeutic agent are that it must be delivered by a parenteral route and has a short half-life. In an attempt to develop a strategy to prolong the physiological t1/2 and enhance the potency of GLP-1, a fusion protein consisting of active human GLP-1 and mouse IgG1 heavy chain constant regions (GLP-1/Fc) was generated. A plasmid encoding an IgK leader peptide-driven secretable fusion protein of the active GLP-1 and IgG1-Fc was constructed for mammalian expression. This plasmid allows for expression of bivalent GLP-1 peptide ligands as a result of IgG-Fc homodimerization. In vitro studies employing purified GLP-1/Fc indicate that the fusion protein is functional and elevates cAMP levels in insulin-secreting INS-1 cells. In addition, it stimulates insulin secretion in a glucose concentration-dependent manner. Intramuscular gene transfer of the plasmid in db/db mice demonstrated that expression of the GLP-1/Fc peptide normalizes glucose tolerance by enhancing insulin secretion and suppressing glucagon release. This strategy of using a bivalent GLP-1/Fc fusion protein as a therapeutic agent is a novel approach for the treatment of diabetes.

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Acknowledgements

This work was supported by grants from the Canadian Institute for Health Research (CIHR, to Q Wang) and the Juvenile Diabetes Research Foundation (JDRF, PI: Q Wang; Co-PI: G Prud’homme). Q Wang is a recipient of a Canadian Diabetes Association Scholarship. M Kumar is a recipient of the Canadian Diabetes Association Fellowship. The authors are grateful to Dr P Doherty (St Michael's Hospital, Toronto, Canada) for critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Medicine, University of Toronto, Ontario, Canada

    M Kumar, Y Hunag & Q Wang

  2. Department of Physiology, University of Toronto, Ontario, Canada

    M Kumar, Y Hunag & Q Wang

  3. Division of Endocrinology and Metabolism, St Michael's Hospital, Toronto, Canada

    M Kumar, Y Hunag & Q Wang

  4. Department of Laboratory Medicine, St Michael's Hospital, Toronto, Canada

    Y Glinka & G J Prud'Homme

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Correspondence to Q Wang.

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Kumar, M., Hunag, Y., Glinka, Y. et al. Gene therapy of diabetes using a novel GLP-1/IgG1-Fc fusion construct normalizes glucose levels in db/db mice. Gene Ther 14, 162–172 (2007). https://doi.org/10.1038/sj.gt.3302836

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