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The endocrine secretion of human insulin and growth hormone by exocrine glands of the gastrointestinal tract

Nature Biotechnology volume 15, pages 1378–1382 (1997)Cite this article

Abstract

The exocrine pancreas, liver, and submandibular glands of the rat were used to express and secrete two exogenous, human protein hormones (growth hormone and insulin) into blood at physiological concentrations. Transfection, expression, and secretion were achieved by the in vivo retrograde injection of plasmid DNA into the secretory ducts of these glands. Pancreatic acinar cells secreted physiological concentrations of growth hormone into the circulation, and its secretion was enhanced by cholinergic stimulation. A human insulin gene was engineered to allow normal processing of insulin in non-β cells. With this gene, the secretion of human insulin by the exocrine pancreas normalized elevated blood glucose levels in diabetic rats. These in vivo observations demonstrate the utility of retrograde ductal administration of naked DNA into exocrine organs as a novel method for the regulated systemic delivery of protein-based Pharmaceuticals.

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References

  1. Crystal, R.G. 1995. Transfer of genes to humans: early lessons and obstacles to success. Science 270: 404.

    Article  CAS  Google Scholar 

  2. Lever, A.M. and Goodfellow, P. 1995. pp. 1–91 in Gene therapy. Churchill Livingstone, New York.

    Google Scholar 

  3. Friedmann, T. 1996. Human gene therapy—an immature genie, but certainly out of the bottle. Nature Med. 2: 144.

    Article  CAS  Google Scholar 

  4. Buckel, P. 1996. Recombinant proteins for therapy. Trends Pharma. Sci. 17: 450.

    Article  CAS  Google Scholar 

  5. Liebow, C. 1988. Nonparallel pancreatic secretion: its meaning and implications. Pancreas 3: 343–351.

    Article  CAS  Google Scholar 

  6. Saito, A. and Kanno, T. 1973. Concentration of pancreozymin as a determinant of the exocrine-endocrine partitioning of pancreatic enzymes. Jpn. J. Physiol. 23: 477–95.

    Article  CAS  Google Scholar 

  7. Isenman, L.D. and Rothman, S.S. 1977. Transport of α-amylase across the basolateral membrane of the pancreatic acinar cell. Proc. Natl. Acad. Sci. USA 74: 4068–4072.

    Article  CAS  Google Scholar 

  8. Papp, M., Feher, S., Nemeth, E.P., Somogyi, V. and Folly, G. 1980. Exit routes for secretory proteins from the dog pancreas. Acta Physiol. Acad. Sci. 56: 401–410.

    CAS  Google Scholar 

  9. Geokas, M.C., Largman, C., Brodrick, J.W. and Fassett, M. 1980. Molecular forms of immunoreactive pancreatic elastase in canine pancreatic and peripheral blood. Am. J. Physiol. 238: 238–246.

    Google Scholar 

  10. Miyasaka, K. and Rothman, S.S. 1981. The endocrine secretion of α-amylase by the pancreas Am. J. Physiol. 241: 170–175.

    Google Scholar 

  11. Grendell, J.H. and Rothman, S.S. 1982. The effect of changes in circulating amylase levels on amylase output in bile Am. J. Physiol. 243: 54–59.

    Google Scholar 

  12. Niederau, C., Grendell, J.H. and Rothman, S.S. 1985. The effects of proglumide on ductal and basolateral secretion of pancreatic digestive enzymes. Am. J. Physiol. 249: 100–107.

    Google Scholar 

  13. O'Connell, B.C., Xu, T., Walsh, T.J., Sein, T., Mastrangeli, A., Crystal, R.G. et al. 1996. Transfer of a gene encoding the anticandidal protein histatin 3 to salivary glands. Hum. Gene Ther. 7: 2255–2261.

    Article  CAS  Google Scholar 

  14. Adesanya, M.R., Redman, R.S., Baum, B.J. and O'Connell, B.C. 1996. Immediate inflammatory responses to adenovirus-mediated gene transfer in rat salivary glands. Hum. Gene Ther. 7: 1085–1093.

    Article  CAS  Google Scholar 

  15. Raper, S.E. and DeMatteo, R.P. 1996. Adenovirus-mediated in vivo gene transfer and expression in normal rat pancreas. Pancreas 12: 401–410.

    Article  CAS  Google Scholar 

  16. Barka, T. and Van der Noen, H.M. 1996. Retrovirus-mediated gene transfer into salivary glands in vivo. Hum. Gene Ther. 7: 613–618.

    Article  CAS  Google Scholar 

  17. O'Connell, B.C., Ten Hagen, K.G., Lazowski, K.W., Tabak, L.A. and Baum, B.J. 1995. Facilitated DNA transfer to rat submandibular gland in vivo and GRP-Ca gene regulation. Am. J. Physiol. 268: 1074–1078.

    Google Scholar 

  18. Mastrangeli, A., O'Connell, B., Aladib, W., Fox, P.C., Baum, B.J. and Crystal, R.G. 1996. Direct in vivo adenovirus-mediated gene transfer to salivary glands. Am. J. Physiol. 266: 1146–1155.

    Google Scholar 

  19. Kagami, H., O'Connell, B.C. and Baum, B.J. 1996. Evidence for the systemic delivery of a transgenic product from salivary glands. Hum. Gene Ther. 7: 2177–2184.

    Article  CAS  Google Scholar 

  20. Hahn, T.M., Copeland, K.C. and Woo, S.L.C. 1996. Phenotypic correction of dwarfism by constitutive expression of growth hormone. Endocrinol. 137: 4988.

    Article  CAS  Google Scholar 

  21. Kolodka, T.M., Finegold, M., Moss, L. and Woo, S.L.C. 1995. Gene therapy for diabetes mellitus in rats by hepatic expression of insulin. Proc. Natl. Acad. Sci. USA 92: 3293–3297.

    Article  CAS  Google Scholar 

  22. Schneider, S.W., Sritharan, K.C., Geibel, J.P., Oberleithner, H. and Jena, B.P. 1997. Surface dynamics in living acinar cells imaged by atomic force microscopy: Identification of plasma membrane structures involved in exocytosis. Proc. Nat. Acad. Sci. USA 94: 316–321.

    Article  CAS  Google Scholar 

  23. Melese, T. and Rothman, S.S. 1983. Distribution of three hexose derivatives across the pancreatic epithelium: paracellular shunts or cellular passage? Biochem. Biophys. Acta 763: 212–219.

    Article  CAS  Google Scholar 

  24. Melese, T. and Rothman, S.S. 1983. The pancreatic epithelium is permeable to sucrose and inulin across secretory cells. Proc. Nat. Acad. Sci. USA 80: 4870–4874.

    Article  CAS  Google Scholar 

  25. Rothman, S.S. 1989. The regulation of digestive reactions by the pancreas, pp. 465–476 in Handbook of physiology: the gastrointestinal system III. Forte, J.G. (ed.). Oxford University Press, New York.

    Google Scholar 

  26. German, M.S. and Wang, J. 1994. The insulin gene contains multiple transcriptional elements that respond to glucose. Mol. Cell Biol. 14: 4067–4075.

    Article  CAS  Google Scholar 

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Author notes

  1. Ira D. Goldfine: (e-mail: idg@itsa.ucsf.edu).

Authors and Affiliations

  1. Schools of Medicine and Dentistry, University of California at San Francisco, San Francisco, CA

    Michael S. German, Hsien-Chen Tseng, Juemin Wang, Janice L. Bolaffi, Je-Wei Chen, David C. Olson & Stephen S. Rothman

  2. the Genteric Corporation, Berkeley, CA

    Michael S. German, Hsien-Chen Tseng, Juemin Wang, Janice L. Bolaffi, Je-Wei Chen, David C. Olson & Stephen S. Rothman

Authors
  1. Ira D. Goldfine
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  2. Michael S. German
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  3. Hsien-Chen Tseng
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  4. Juemin Wang
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  5. Janice L. Bolaffi
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  6. Je-Wei Chen
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  7. David C. Olson
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  8. Stephen S. Rothman
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Goldfine, I., German, M., Tseng, HC. et al. The endocrine secretion of human insulin and growth hormone by exocrine glands of the gastrointestinal tract. Nat Biotechnol 15, 1378–1382 (1997). https://doi.org/10.1038/nbt1297-1378

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