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Remission in models of type 1 diabetes by gene therapy using a single-chain insulin analogue

A Retraction to this article was published on 02 April 2009


A cure for diabetes has long been sought using several different approaches, including islet transplantation, regeneration of β cells and insulin gene therapy1. However, permanent remission of type 1 diabetes has not yet been satisfactorily achieved. The development of type 1 diabetes results from the almost total destruction of insulin-producing pancreatic β cells by autoimmune responses specific to β cells2,3,4,5,6. Standard insulin therapy may not maintain blood glucose concentrations within the relatively narrow range that occurs in the presence of normal pancreatic β cells7. We used a recombinant adeno-associated virus (rAAV) that expresses a single-chain insulin analogue (SIA), which possesses biologically active insulin activity without enzymatic conversion, under the control of hepatocyte-specific L-type pyruvate kinase (LPK) promoter, which regulates SIA expression in response to blood glucose levels. Here we show that SIA produced from the gene construct rAAV-LPK-SIA caused remission of diabetes in streptozotocin-induced diabetic rats and autoimmune diabetic mice for a prolonged time without any apparent side effects. This new SIA gene therapy may have potential therapeutic value for the cure of autoimmune diabetes in humans.

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Figure 1: Construction of pLPK-SIA, hypoglycaemic effect of pLPK-SIA and hepatocyte-specific expression of pLPK-SIA.
Figure 2: Hypoglycaemic effect of rAAV-LPK-SIA and integration of rAAV-LPK-SIA DNA into hepatocyte DNA.
Figure 3: Expression of SIA in hepatocytes and plasma of rAAV-LPK-SIA-treated rats.
Figure 4: Response of SIA to glucose in rAAV-LPK-SIA-treated STZ-induced diabetic rats.
Figure 5: Remission of autoimmune diabetes in NOD mice by administration of rAAV-LPK-SIA.


  1. Levine, F. & Leibowitz, G. Towards gene therapy of diabetes mellitus. Mol. Med. Today 5, 165–171 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Yoon, J. W. & Jun, H. S. in Encyclopedia of Immunology (eds Roitt, I. M. & Delves, P. J.) 2nd edn, 1390–1398 (Academic, London, 1998).

    Book  Google Scholar 

  3. Schranz, D. B. & Lernmark, A. Immunology in diabetes: an update. Diab. Metab. Rev. 14, 3–29 (1998).

    Article  CAS  Google Scholar 

  4. Tisch, R. & McDevitt, H. Insulin-dependent diabetes mellitus. Cell 85, 291–297 (1996).

    Article  CAS  Google Scholar 

  5. Bach, J. F. Insulin-dependent diabetes mellitus as a β cell targeted disease of immunoregulation. J. Autoimmun. 8, 439–463 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Rossini, A. A., Greiner, D. L., Friedman, H. P. & Mordes, J. P. Immunopathogenesis of diabetes mellitus. Diabetes Rev. 1, 43–75 (1993).

    Google Scholar 

  7. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New Engl. J. Med. 329, 977–986 (1993).

    Article  Google Scholar 

  8. Cuif, M. H., Doiron, B. & Kahn, A. Insulin and cyclic AMP act at different levels on transcription of the L-type pyruvate kinase gene. FEBS Lett. 417, 81–84 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Chen, R., Doiron, B. & Kahn, A. Glucose responsiveness of a reporter gene transduced into hepatocytic cells using a retroviral vector. FEBS Lett. 365, 223–226 (1995).

    Article  CAS  PubMed  Google Scholar 

  10. Decaux, J. F., Antoine, B. & Kahn, A. Regulation of the expression of the L-type pyruvate kinase gene in adult rat hepatocytes in primary culture. J. Biol. Chem. 264, 11584–11590 (1989).

    CAS  PubMed  Google Scholar 

  11. Cuif, M. H., Porteu, A., Kahn, A. & Vaulont, S. Exploration of a liver-specific, glucose/insulin-responsive promoter in transgenic mice. J. Biol. Chem. 268, 13769–13772 (1993).

    CAS  PubMed  Google Scholar 

  12. Bergot, M. O., Diaz-Guerra, M. J., Puzenat, N., Raymondjean, M. & Kahn, A. Cis-regulation of the L-type pyruvate kinase gene promoter by glucose, insulin and cyclic AMP. Nucleic Acids Res. 20, 1871–1877 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Muzyczka, N. Use of adeno-associated virus as a general transduction vector for mammalian cells. Curr. Top. Microbiol. Immunol. 158, 97–129 (1992).

    CAS  PubMed  Google Scholar 

  14. Clark, K. R., Liu, X., McGrath, J. P. & Johnson, P. R. Highly purified recombinant adeno-associated virus vectors are biologically active and free of detectable helper and wild-type viruses. Hum. Gene Ther. 10, 1031–1039 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Samulski, R. J. Adeno-associated virus: integration at a specific chromosomal locus. Curr. Opin. Genet. Dev. 3, 74–80 (1993).

    Article  CAS  PubMed  Google Scholar 

  16. Giraud, C., Winocour, E. & Berns, K. I. Site-specific integration by adeno-associated virus is directed by a cellular DNA sequence. Proc. Natl Acad. Sci. USA 91, 10039–10043 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  17. Kotin, R. M., Linden, R. M. & Berns, K. I. Characterization of a preferred site on human chromosome 19q for integration of adeno-associated virus DNA by non-homologous recombination. EMBO J. 11, 5071–5078 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cameron, N. E., Cotter, M. A. & Low, P. A. Nerve blood flow in early experimental diabetes in rats: relation to conduction deficits. Am. J. Physiol. 261, E1–E8 (1991).

    CAS  PubMed  Google Scholar 

  19. Studier, F. W., Rosenberg, A. H., Dunn, J. J. & Dubendorff, J. W. Use of T7 RNA polymerase to direct expression of cloned genes. Methods Enzymol. 185, 60–89 (1990).

    Article  CAS  PubMed  Google Scholar 

  20. Pollet, R. J., Standaert, M. L. & Haase, B. A. Insulin binding to the human lymphocyte receptor. Evaluation of the negative cooperativity model. J. Biol. Chem. 252, 5828–5834 (1977).

    CAS  PubMed  Google Scholar 

  21. Roth, J. Assay of peptide hormones using cell receptors: application to insulin and to human growth hormone. Methods Enzymol. 37, 66–82 (1975).

    Article  CAS  PubMed  Google Scholar 

  22. Frost, S. C. & Lane, M. D. Evidence for the involvement of vicinal sulfhydryl groups in insulin-activated hexose transport by 3T3-L1 adipocytes. J. Biol. Chem. 260, 2646–2652 (1985).

    CAS  PubMed  Google Scholar 

  23. Heath, W. F. et al. (A-C-B) human proinsulin, a novel insulin agonist and intermediate in the synthesis of biosynthetic human insulin. J. Biol. Chem. 267, 419–425 (1992).

    CAS  PubMed  Google Scholar 

  24. Yoon, J. W., Lesniak, M. A., Fussganger, R. & Notkins, A. L. Genetic differences in susceptibility of pancreatic β-cells to virus-induced diabetes mellitus. Nature 264, 178–180 (1976).

    Article  ADS  CAS  PubMed  Google Scholar 

  25. Ma, Z. et al. Effect of hemoglobin- and Perflubron-based oxygen carriers on common clinical laboratory tests. Clin. Chem. 43, 1732–1737 (1997).

    CAS  PubMed  Google Scholar 

  26. Yoon, J. W., Rodrigues, M. M., Currier, C. & Notkins, A. Long-term complications of virus-induced diabetes mellitus in mice. Nature 296, 566–569 (1982).

    Article  ADS  CAS  PubMed  Google Scholar 

  27. Yoon, J. W. et al. Control of autoimmune diabetes in NOD mice by GAD expression or suppression in cells. Science 284, 1183–1187 (1999).

    Article  ADS  CAS  PubMed  Google Scholar 

  28. Hirasawa, K. Possible role of macrophage-derived soluble mediators in the pathogenesis of EMC virus-induced diabetes in mice. J. Virol. 71, 4024–4031 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

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We thank R. J. Samulski for providing psub201 and pXX2, A. L. Kyle and K. Clarke for editorial assistance and B. Pinder for artwork. We also thank H. S. Jun for a critical review of the manuscript. J. W. Y. is a Heritage Medical Scientist awardee of the Alberta Heritage Foundation for Medical Research. This work was supported in part by Brain Korea 21 Project.

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Correspondence to Hyun Chul Lee.

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Lee, H., Kim, SJ., Kim, KS. et al. Remission in models of type 1 diabetes by gene therapy using a single-chain insulin analogue. Nature 408, 483–488 (2000).

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