Skip to main content
SpringerLink
Log in

Development of β-cell Lines for Transplantation in Type 1 Diabetes Mellitus

  • Chapter
  • First Online:
Molecular Basis of Pancreas Development and Function

Part of the book series: Endocrine Updates ((ENDO,volume 11))

  • 170 Accesses

Abstract

For the better part of the 20th century, people with insulin-dependent (type 1) diabetes mellitus (IDDM) have relied on insulin administration as a life-saving treatment. However, periodical insulin injections are a crude substitute for the fine-tuned regulation of insulin release from the pancreatic islet β-cells, which is continuously and accurately adjusted to changing physiological conditions. As a result, most IDDM patients are exposed to episodes of hyperglycaemia and hypoglycaemia, leading to the development of severe complications. Modern diabetes research has two major goals: the first is to understand the aetiology of the disease sufficiently to be able to identify individuals at risk for developing IDDM and to intervene to prevent it. The second goal is to replace β-cell function in people who already have developed the disease with a safe, efficient, and convenient treatment that will prevent the complications of IDDM. This chapter summarizes the state of the art in the development of new approaches for β-cell replacement and evaluates the potential of cell therapy for treatment of IDDM.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Valera A, Fillat C, Costa C et al. Regulated expression of human insulin in the liver of transgenic mice corrects diabetic alterations. FASEB J 1994;8:440–447.

    PubMed  CAS  Google Scholar 

  2. Kolodka TM, Finegold M, Moss L, Woo SL. Gene therapy for diabetes mellitus in rats by hepatic expression of insulin. Proc Natl Acad Sci USA 1995;92:3293–3297.

    Article  PubMed  CAS  Google Scholar 

  3. Lipes MA, Cooper EM, Skelly R et al. Insulin-secreting non-islet cells are resistant to autoimmune destruction. Proc Natl Acad Sci USA 1996;93:8595–8600.

    Article  PubMed  CAS  Google Scholar 

  4. Goldfine ID, German MS, Tseng HC et al. The endocrine secretion of human insulin and growth hormone by exocrine glands of the gastrointestinal tract. Nat Biotechnol 1997;15:1378–1382.

    Article  PubMed  CAS  Google Scholar 

  5. Moore H-P, Walker MD, Lee F, Kelly RB. Expressing a human insulin cDNA in a mouse ACTH-secreting cell: intracellular storage, proteolytic processing, and secretionon stimulation. Cell 1983;35:531–538.

    Article  PubMed  CAS  Google Scholar 

  6. Vollenweider F, Irminger JC, Gross DJ, Villa-Komaroff L, Halban PA. Processing of proinsulin by transfected hepatoma (FAO) cells. J Biol Chem 1992;267:14629–14636.

    PubMed  CAS  Google Scholar 

  7. Simpson AM, Tuch BE, Swan MA, Tu J, Marshall GM. Functional expression of the human insulin gene in a human hepatoma cell line (HEP G2). Gene Therapy 1995;2:223–231.

    PubMed  CAS  Google Scholar 

  8. Serup P, Jensen J, Andersen FG et al. Induction of insulin and IAPP production in pancreatic islet glucagonoma cells by insulin promoter factor 1. Proc Natl Acad Sci USA 1996;93:9015–9020.

    Article  PubMed  CAS  Google Scholar 

  9. Groskreutz DJ, Sliwkowski MX, Gorman CM. Genetically engineered proinsulin constitutively processed and secreted as mature, active insulin. J Biol Chem 1994;269:6241–6245.

    PubMed  CAS  Google Scholar 

  10. Vollenweider F, Kaufmann J, Irminger J-C, Halban PA. Processing of proinsulin by furin, PC2, and PC3 in (co)transfected COS (monkey kidney) cells. Diabetes 1995;44:1075–1080.

    Article  PubMed  CAS  Google Scholar 

  11. Kaufmann JE, Irminger J-C, Mungall J, Halban PA. Proinsulin conversion in GH3 cells after coexpression of human proinsulin with the endoproteases PC2 and/or PC3. Diabetes 1997;46:978982.

    Google Scholar 

  12. Efrat S, Tal M, Lodish HF. The pancreatic 13-cell glucose sensor. Trends in Biochem Sci 1994;19:535–538.

    Article  CAS  Google Scholar 

  13. Vaulont S, Kahn A. Transcriptional control of metabolic regulation genes by carbohydrates. FASEB J 1994;8:28–35.

    PubMed  CAS  Google Scholar 

  14. Crystal RG. Transfer of genes to humans: Early lessons and obstacles to success. Science 1995;270:404–410.

    Article  PubMed  CAS  Google Scholar 

  15. Anderson WF. Human gene therapy. Nature 1998;392 (6679 suppl.):25–30.

    PubMed  CAS  Google Scholar 

  16. Lanza RP, Chick WL. Transplantation of pancreatic islets. Ann NY Acad Sci 1997;831:321–331.

    Google Scholar 

  17. Sullivan SJ, Maki T, Borland KM et al. Biohybrid artificial pancreas: long-term implantation studies in diabetic, pancreatectomized dogs. Science 1991;252:718–721.

    Article  PubMed  CAS  Google Scholar 

  18. Lacy PE, Hegre OD, Gerasimidi-Vazeou A, Gentile FT, Dionne KE. Maintenance of normoglycaemia in diabetic mice by subcutaneous xenografts of encapsulated islets. Science 1991;254:1782–1784.

    Article  PubMed  CAS  Google Scholar 

  19. Sun Y, Ma MX, Zhou D, Vacek I, Sun AM. Normalization of diabetes in spontaneously diabetic cynomolgus monkeys by xenografts of microencapsulated porcine islets without immunosuppression. J Clin Invest 1996;98:1417–1422.

    Article  PubMed  CAS  Google Scholar 

  20. Bach FH, Fishman JA, Daniels N et al. Uncertainty in xenotransplantation: individual benefit versus collective risk. Nature Med 1998;4:141–144.

    Article  PubMed  CAS  Google Scholar 

  21. Efrat S, Fusco-DeMane D, Lemberg H, Emran OA, Wang S. Conditional transformation of a pancreatic 13-cell line derived from transgenic mice expressing a tetracycline-regulated oncogene. Proc Natl Acad Sci USA 1995;92:3576–3580.

    Article  PubMed  CAS  Google Scholar 

  22. Hellerstrom C, Swenne I. Functional maturation and proliferation of foetal pancreatic 13-cells. Diabetes 1991;40 (Supp1.2):89–93.

    PubMed  Google Scholar 

  23. Bodnar AG, Ouellette M, Frolkis M et al. Extension of life-span by introduction of telomerase into normal human cells. Science 1998;279:349–352.

    Article  PubMed  CAS  Google Scholar 

  24. Kiyono T, Foster SA, Koop JI, McDougall JK, Galloway DA, Klingelhutz M. Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature 1998;396:84–88.

    Article  PubMed  CAS  Google Scholar 

  25. Thomson JA, Itskovitz-Eldor J, Shapiro SS et al. Embryonic stem cell lines derived from human blastocysts. Science 1998;282:1145–1147.

    Article  PubMed  CAS  Google Scholar 

  26. Edlund H. Transcribing pancreas. Diabetes 1998;47:1817–1823.

    Article  PubMed  CAS  Google Scholar 

  27. Kim SK, Melton DA. Pancreas development is promoted by cyclopamine, a Hedgehog signaling inhibitor. Proc Natl Acad Sci USA 1998;95:13036–13041.

    Article  PubMed  CAS  Google Scholar 

  28. Levine F, Wang S, Beattie G et al. Development of a cell line from the human foetal pancreas. Transplant Proc 1995;27:3410.

    PubMed  CAS  Google Scholar 

  29. Wang S, Beattie G, Mally M et al. Isolation and characterization of a cell line from the epithelial cells of the human foetal pancreas. Cell Transplant 1997;6:59–67.

    Article  PubMed  CAS  Google Scholar 

  30. Bonner-Weir S, Baxter LA, Schuppin GT, Smith FE. A second pathway for regeneration of adult exocrine and endocrine pancreas: a possible recapitulation of embryonic development. Diabetes 1993;42:1717–1720.

    Article  Google Scholar 

  31. Wang RN, Kloppel G, Bouwens L. Duct-to islet-cell differentiation and islet growth in the pancreas of duct-ligated adult rats. Diabetologia 1995;38:1405–1411.

    Article  PubMed  CAS  Google Scholar 

  32. Gu D, Sarvetnick N. Epithelial cell proliferation and islet neogenesis in IFN-a transgenic mice. Development 1993;118:33–46.

    PubMed  CAS  Google Scholar 

  33. Santerre RF, Cook RA, Crisel RMD et al. Insulin synthesis in a clonal cell line of simian virus 40-transformed hamster pancreatic beta cells. Proc Natl Acad Sci USA 1981;78:4339–4342.

    Article  PubMed  CAS  Google Scholar 

  34. Efrat S, Linde S, Kofod H et al. p-cell lines derived from transgenic mice expressing hybrid insulinoncogenes. Proc Natl Acad Sci USA 1988;85:9037–9041.

    Article  PubMed  CAS  Google Scholar 

  35. Miyazaki J-I, Araki K, Yamato E et al. Establishment of a pancreatic 0--cell line that retains glucose-inducible insulin secretion: special reference to expression of glucose transporter isoforms. Endocrinology 1990;127:126–132.

    Article  PubMed  CAS  Google Scholar 

  36. Hamaguchi K, Gaskins HR, Leiter EH. NIT-1, a pancreatic 0-cell line established from a transgenic NOD/Lt mouse. Diabetes 1991;40:842–849.

    Article  PubMed  CAS  Google Scholar 

  37. Radvanyi F, Christgau S, Baekkeskov S, Jolicoeur C, Hanahan D. Pancreatic 0-cells cultured from individual preneoplastic foci in a multistage tumorigenesis pathway: a potentially general technique for isolating physiologically representative cell lines. Mol Cell Biol 1993;13:4223–4232.

    PubMed  CAS  Google Scholar 

  38. Efrat S, Leiser M, Surana M et al. Murine insulinoma cell line with normal glucose-regulated insulin secretion. Diabetes 1993;42:901–907.

    Article  PubMed  CAS  Google Scholar 

  39. Knaack D, Fiore DM, Surana M et al. Clonal insulinoma cell line which stably maintains correct glucose responsiveness. Diabetes 1994;43:1413–1417.

    Article  PubMed  CAS  Google Scholar 

  40. Soldevila G, Buscema M, Marini V et al. Transfection with SV40 gene of human pancreatic endocrine cells. J Autoimmun 1991;4:381–396.

    Article  PubMed  CAS  Google Scholar 

  41. Gossen M, Bujard H. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci USA 1992;89:5547–5551.

    Article  PubMed  CAS  Google Scholar 

  42. Ewald D, Li M, Efrat S et al. Time-sensitive reversal of hyperplasia in transgenic mice expressing SV40 T antigen. Science 1996;273:1384–1386.

    Article  PubMed  CAS  Google Scholar 

  43. Fleischer N, Chen C, Surana M et al. Functional analysis of a conditionally-transformed pancreatic 13-cell line. Diabetes 1998;47:1419–1425.

    Article  PubMed  CAS  Google Scholar 

  44. Naldini L, Blomer U, Gage FH, Trono D, Verma IM. Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentivirus vector. Proc Natl Acad Sci USA 1996;93:11382–11388.

    Article  PubMed  CAS  Google Scholar 

  45. Gossen M, Freundlieb S, Bender G, Muller G, Hillen W, Bujard H. Transcriptional activation by tetracyclines in mammalian cells. Science 1995;268:1766–1769.

    Article  PubMed  CAS  Google Scholar 

  46. Sauer B, Henderson N. Cre-stimulated recombination at loxP-containing DNA sequences placed into the mammalian genome. Nuc Acids Res 1989;17:147–161.

    Article  CAS  Google Scholar 

  47. Welsh N, Eizirik DL, Bendtzen K, Sandler S. Interleukin-10-induced nitric oxide production in isolated rat pancreatic islets requires gene transcription and may lead to inhibition of the Krebs cycle enzyme aconitase. Endocrinology 1991;129:3167–3173.

    Article  PubMed  CAS  Google Scholar 

  48. Eizirik DL, Cagliero E, Bjorklund A, Welsh N. Interleukin-11 induces the expression of an isoform of nitric oxide synthase in insulin-producing cells, which is similar to that observed in activated macrophages. FEBS Lett 1992;308:249–252.

    Article  PubMed  CAS  Google Scholar 

  49. Mauricio D, Mandrup-Poulsen T. Apoptosis and the pathogenesis of IDDM. A question of life and death. Diabetes 1998;47:1537–1543.

    Article  PubMed  CAS  Google Scholar 

  50. Lenzen S, Drinkgern J, Tiedge M. Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues. Free Radical Biol Med 1995;20:463–466.

    Article  Google Scholar 

  51. Kubisch HM, Wang J, Luche R et al. Transgenic copper/zinc superoxide dismutase modulates susceptibility to type I diabetes. Proc Natl Acad Sci USA 1994;91:9956–9959.

    Article  PubMed  CAS  Google Scholar 

  52. Hohmeier HE, Thigpen A, Tran VV, Davis R, Newgard CB. Stable expression of manganese superoxide dismutase (MnSOD) in insulinoma cells prevents IL-1 beta-induced cytotoxicity and reduces nitric oxide production. J Clin Invest 1998;101:1811–1820.

    Article  PubMed  CAS  Google Scholar 

  53. Benhamou PY, Moriscot C, Richard MI et al. Adenovirus-mediated catalase gene transfer reduces oxidant stress in human, porcine, and rat pancreatic islets. Diabetologia 1998;41:1093–1100.

    Article  PubMed  CAS  Google Scholar 

  54. Hotta M, Tashiro F, Ikegami H et al. Pancreatic 0-cell-specific expression of thioredoxin, an antioxidative and antiapoptotic protein, prevents autoimmune and streptozotocin-induced diabetes. J Exp Med 1998;188:1445–1451.

    Article  PubMed  CAS  Google Scholar 

  55. Vaux DL, Strasser A. The molecular biology of apoptosis. Proc Natl Acad Sci USA 1996;93:2239–2244.

    Article  PubMed  CAS  Google Scholar 

  56. Raff M. Cell suicide for beginners. Nature 1998;396:119–122.

    Article  PubMed  CAS  Google Scholar 

  57. Adams JM, Cory S. The Bc1–2 protein family: arbiters of cell survival. Science 1998;281:1322–1326.

    Article  PubMed  CAS  Google Scholar 

  58. Iwahashi H, Hanafusa T, Eguchi Y et al. Cytokine-induced apoptotic cell death in a mouse pancreatic 0-cell line: inhibition by bd-2. Diabetologia 1996;39:530–536.

    Article  PubMed  CAS  Google Scholar 

  59. Liu Y, Rabinovitch A, Suarez-Pinzon W et al. Expression of the bc1–2 gene from a defective HSV-1 amplicon vector protects pancreatic 13-cells from apoptosis. Human Gene Therapy 1996;7:1719–1726.

    Article  PubMed  CAS  Google Scholar 

  60. Wold WSM, Gooding LR. Region E3 of adenovirus: a cassette of genes involved in host immunosurveillance and virus-cell interactions. Virology 1991;184:1–8.

    Article  PubMed  CAS  Google Scholar 

  61. Efrat S, Fejer G, Brownlee M, Horwitz MS. Prolonged survival of murine pancreatic islet allografts mediated by adenovirus early region 3 immunoregulatory transgenes. Proc Natl Acad Sci USA 1995;92:6947–6951.

    Article  PubMed  CAS  Google Scholar 

  62. von Herrath MG, Efrat S, Oldstone MBA, Horwitz MS. Expression of adenoviral E3 transgenes in 13-cells prevents autoimmune diabetes. Proc Natl Acad Sci USA 1997;94:9808–9813.

    Article  Google Scholar 

  63. Oldstone MBA, Nerenberg M, Southern P, Price J, Lewicki H. Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: Role of anti-self (virus) immune response. Cell 1991;65:319–331.

    CAS  Google Scholar 

  64. Lenschow DJ, Zeng Y, Thistlethwaite JR et al. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4Ig. Science 1992;257:789–792.

    Article  PubMed  CAS  Google Scholar 

  65. Weber CJ, Hagler MK, Chryssochoos JT et al. CTLA4-Ig prolongs survival of microencapsulated neonatal porcine islet xenografts in diabetic NOD mice. Cell Transplant 1997;6:505–508.

    Article  PubMed  CAS  Google Scholar 

  66. Mueller R, Krahl R, Sarvetnick N. Pancreatic expression of interleukin-4 abrogates insulitis and autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med 1996;184:1093–1099.

    Article  PubMed  CAS  Google Scholar 

  67. Gallichman WS, Kafri T, Krahl T, Verma IM, Sarvetnick N. Lentivirus-mediated transduction of islet grafts with interleukin 4 results in sustained gene expression and protection from insulitis. Hum Gene Ther 1998;9:2717–2726.

    Article  Google Scholar 

  68. Moritani M, Yoshimoto K, Wong SF et al. Abrogation of autoimmune diabetes in nonobese diabetic mice and protection against effector lymphocytes by transgenic TGF-ß. J Clin Invest 1998;102:499–506.

    Article  PubMed  CAS  Google Scholar 

  69. Lee M-S, Stephen S, Arnush M et al. Transforming growth factor-0 fails to inhibit allograft rejection or virus-induced autoimmune diabetes in transgenic mice. Transplantation 1996;61:1112–1113.

    Google Scholar 

  70. Balasa B, Sarvetnick N. The paradoxical effects of interleukin 10 in the immunoregulato of autoimmune diabetes. J Autoimmun 1996;9:283–286.

    Article  PubMed  CAS  Google Scholar 

  71. Moore KW, Vieira P, Fiorentino DF, Trounstine ML, Khan TQ, Mosmann TR. Homology of cytokine synthesis inhibitory factor (IL-10) tto the Epstein-Barr virus gen BCRFI. Science 1990;248:1230–1234.

    Article  PubMed  CAS  Google Scholar 

  72. Suzuki T, Tahara H, Narula S, Moore KW, Robbins PD, Lotze MT. Viral interleukin 10 (IL-10), the human herpes virus 4 cellular IL-10 homologue, induces local anergy to allogeneic and syngeneic tumors. J Exp Med 1995;182:477–486.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Human Genetics and Molecular Medicine Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, 69978, Israel

    Shimon Efrat Ph.D.

Authors
  1. Shimon Efrat Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Laboratory of Molecular Endocrinology, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA

    Joel F. Habener M.D.

  2. Department of Medicine, Clinical and Molecular Endocrinology, New York University Medical Center, New York, NY

    Mehboob A. Hussain M.D.

Rights and permissions

Reprints and permissions

Copyright information

© 2001 Springer Science+Business Media New York

About this chapter

Cite this chapter

Efrat, S. (2001). Development of β-cell Lines for Transplantation in Type 1 Diabetes Mellitus. In: Habener, J.F., Hussain, M.A. (eds) Molecular Basis of Pancreas Development and Function. Endocrine Updates, vol 11. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1669-9_22

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-1669-9_22

  • Published:

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-5669-1

  • Online ISBN: 978-1-4615-1669-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation