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In vivo expression of GLP-1/IgG-Fc fusion protein enhances beta-cell mass and protects against streptozotocin-induced diabetes

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Abstract

Glucagon-like peptide 1 (GLP-1) and its analogue exendin-4 (Ex4) have displayed potent glucose homeostasis-modulating characteristics in type 2 diabetes (T2D). However, there are few reports of effectiveness in type 1 diabetes (T1D) therapy, where there is massive loss of β cells. We previously described a novel GLP-1 analogue consisting of the fusion of active GLP-1 and IgG heavy chain constant regions (GLP-1/IgG-Fc), and showed that in vivo expression of the protein, via electroporation-enhanced intramuscular plasmid-based gene transfer, normalized blood glucose levels in T2D-prone db/db mice. In the present study, GLP-1/IgG-Fc and Ex4/IgG-Fc were independently tested in multiple low-dose streptozotocin-induced T1D. Both GLP-1/IgG-Fc and Ex4/IgG-Fc effectively reduced fed blood glucose levels in treated mice and ameliorated diabetes symptoms, where as control IgG-Fc had no effect. Treatment with GLP-1/IgG-Fc or Ex4/IgG-Fc improved glucose tolerance and increased circulating insulin and GLP-1 levels. It also significantly enhanced islet beta-cell mass, which is likely a major factor in the amelioration of diabetes. This suggests that GLP-1/IgG-Fc gene therapy may be applicable to diseases where there is either acute or chronic beta-cell injury.

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Acknowledgements

This work was supported by grants from the Canadian Institute for Health Research (to Q Wang) and the Juvenile Diabetes Research Foundation (PI: Q Wang; Co-PI: G Prud'homme) and the Krembil Foundation (Toronto, Canada; Co-PI: G Prud'homme). Q Wang is a recipient of a Canadian Diabetes Association Scholarship. M Kumar was a recipient of the Canadian Diabetes Association Fellowship. N Soltani was partially supported by an Overseas Scholarship of Hormozgan Medical Science University from Iranian Health Ministry.

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Authors and Affiliations

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

    N Soltani, M Kumar & Q Wang

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

    N Soltani, M Kumar & Q Wang

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

    N Soltani, M Kumar & Q Wang

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

    Y Glinka & G J Prud'Homme

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  1. N Soltani
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  2. M Kumar
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  3. Y Glinka
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  5. Q Wang
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Correspondence to Q Wang.

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Soltani, N., Kumar, M., Glinka, Y. et al. In vivo expression of GLP-1/IgG-Fc fusion protein enhances beta-cell mass and protects against streptozotocin-induced diabetes. Gene Ther 14, 981–988 (2007). https://doi.org/10.1038/sj.gt.3302944

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