Langenbeck's Archives of Surgery

, Volume 392, Issue 3, pp 239–253

Islet cell transplantation today

  • Reinhard G. Bretzel
  • Henning Jahr
  • Michael Eckhard
  • Isabel Martin
  • Daniel Winter
  • Mathias D. Brendel
Current Concepts in Clinical Surgery



Long-term studies strongly suggest that tight control of blood glucose can prevent the development and retard the progression of chronic complications of type 1 diabetes mellitus. In contrast to conventional insulin treatment, replacement of a patient’s islets of Langerhans either by pancreas organ transplantation or by isolated islet transplantation is the only treatment to achieve a constant normoglycemic state and avoiding hypoglycemic episodes, a typical adverse event of multiple daily insulin injections. However, the cost of this benefit is still the need for immunosuppressive treatment of the recipient with all its potential risks.

Materials and methods

Islet cell transplantation offers the advantage of being performed as a minimally invasive procedure in which islets can be perfused percutaneously into the liver via the portal vein. Between January 1990 and December 2004, 458 pancreatic islet transplants worldwide have been reported to the International Islet Transplant Registry (ITR) at our Third Medical Department, University of Giessen/Germany.


Data analysis of islet cell transplants performed in the last 5 years (1999–2004) shows at 1 year after adult islet transplantation a patient survival rate of 97%, a functioning islet graft in 82% of the cases, whereas insulin independence was meanwhile achieved in 43% of the cases. However, using a novel protocol established by the Edmonton Center/Canada, the insulin independence rates have improved significantly reaching meanwhile a 50–80% level.


Finally, the concept of islet cell or stem cell transplantation is most attractive, as it offers many perspectives: islet cell availability could become unlimited and islet or stem cells my be transplanted without life-long immunosuppressive treatment of the recipient, just to mention two of them.


Diabetes mellitus Islet cell transplantation Tolerance induction Xenotransplants Stem cell therapy 


  1. 1.
    Onkamo P, Vaananen S, Karvonen M, Tuomilehto J (1999) Worldwide increase in incidence of Type I diabetes—the analysis of the data on published incidence trends. Diabetologia 42:1395–1403PubMedGoogle Scholar
  2. 2.
    Wild S, Roglic G, Green A, Sicree R, King H (2004) Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27:1047–1053PubMedGoogle Scholar
  3. 3.
    The Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986Google Scholar
  4. 4.
    Wang PH, Lau J, Chalmers TC (1993) Meta-analysis of effects of intensive blood-glucose control on late complications of type-1 diabetes. Lancet 341:1306–1309PubMedGoogle Scholar
  5. 5.
    Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group (2003) Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA 290:2159–2167Google Scholar
  6. 6.
    The Diabetes Control and Complications Trial Research Group (1997) Hypoglycemia in the Diabetes Control and Complications Trial. Diabetes 46:271–286Google Scholar
  7. 7.
    Sutherland DE, Gores PF, Farney AC, Wahoff DC, Matas AJ, Dunn DL, Gruessner RW, Najarian JS (1993) Evolution of kidney, pancreas, and islet transplantation for patients with diabetes at the University of Minnesota. Am J Surg 166:456–491PubMedGoogle Scholar
  8. 8.
    Bretzel RG, Browatzki CC, Schultz A, Brandhorst H, Klitscher D, Bollen CC, Raptis G, Friemann S, Ernst W, Rau WS, Hering BJ (1993) Clinical islet transplantation in diabetes mellitus—report of the Islet Transplant Registry and the Giessen Center experience. Diab Stoffw 2:378–390Google Scholar
  9. 9.
    International Pancreas Transplant Registry (IPTR) Updated September 2006 (
  10. 10.
    Gross CR, Limwattananon C, Matthees BJ (1998) Quality of life after pancreas transplantation: a review. Clin Transplant 12:351–361PubMedGoogle Scholar
  11. 11.
    Ryan EA (1998) Pancreas transplants: for whom? Lancet 351:1072–1073PubMedGoogle Scholar
  12. 12.
    Gruessner RWG, Sutherland DER, Troppmann C, Benedetti E, Hakim N, Dunn DL, Gruessner AC (1997) The surgical risk of pancreas transplantation in the cyclosporine era: an overview. J Am Coll Surg 185:128–144PubMedGoogle Scholar
  13. 13.
    Manske CL (1999) Risks and benefits of kidney and pancreas transplantation for diabetic patients. Diabetes Care 22:B114–B120PubMedGoogle Scholar
  14. 14.
    Venstrom JM, McBride MA, Rother KI, Hirshberg B, Orchard TJ, Harlan DM (2003) Survival after pancreas transplantation in patients with diabetes and preserved kidney function. JAMA 290:2817–2823PubMedGoogle Scholar
  15. 15.
    Weimar B, Rauber K, Brendel MD, Bretzel RG, Rau WS (1999) Percutaneous transhepatic catheterization of the portal vein: a combined CT- and fluoroscopy-guided technique. Cardiovasc Interv Radiol 22:342–344Google Scholar
  16. 16.
    Scharp DW, Lacy PE, Santiago JV, McCullough CS, Weide LG, Falqui L, Marchetti P, Gingerich RL, Jaffe AS, Cryer PE, Anderson CB, Flye MW (1990) Insulin independence after islet transplantation into type I diabetic patient. Diabetes 39:515–518PubMedGoogle Scholar
  17. 17.
    Socci C, Falqui L, Davalli AM, Ricordi C, Braghi S, Bertuzzi F, Maffi P, Secchi A, Gavazzi F, Freschi M, Magistretti P, Socci S, Vignali A, Carlo V, Pozza G (1991) Fresh human islet transplantation to replace pancreatic endocrine function in type 1 diabetic patients. Report of six cases. Acta Diabetol 28:151–157PubMedGoogle Scholar
  18. 18.
    Warnock GL, Kneteman NM, Ryan EA, Rabinovitch A, Rajotte RV (1992) Long-term follow-up after transplantation of insulin-producing pancreatic islets into patients with Type 1 (insulin-dependent) diabetes mellitus. Diabetologia 35:89–95PubMedGoogle Scholar
  19. 19.
    Gores PF, Najarian JS, Stephanian E, Lloveras JJ, Kelley SL, Sutherland DE (1993) Insulin independence in type I diabetes after transplantation of unpurified islets from single donor with 15-deoxyspergualin. Lancet 341:19–21PubMedGoogle Scholar
  20. 20.
    Alejandro R, Lehmann R, Ricordi C, Kenyon NS, Angelico MC, Burke G, Esquenazi V, Nery J, Betancourt AE, Kong SS, Miller J, Mintz DH (1997) Long-term function (6 years) of islet allografts in type 1 diabetes. Diabetes 46:1983–1989PubMedGoogle Scholar
  21. 21.
    Ricordi C, Lacy PE, Finke EH, Olack BJ, Scharp DW (1988) Automated method for isolation of human pancreatic islets. Diabetes 37:413–420PubMedGoogle Scholar
  22. 22.
    Hering BJ, Bretzel RG, Hopt UT, Brandhorst H, Brandhorst D, Bollen CC, Raptis G, Helf F, Grossmann R, Mellert J, Ernst W, Scheuermann E-H, Schoeppe W, Rau W, Federlin K (1994) New protocol toward prevention of early human islet allograft failure. Transplant Proc 26:570–571PubMedGoogle Scholar
  23. 23.
    Bretzel RG, Brandhorst D, Brandhorst H, Eckhard M, Ernst W, Friemann S, Rau W, Weimar B, Rauber K, Hering BJ, Brendel MD (1999) Improved survival of intraportal pancreatic islet cell allografts in patients with type 1 diabetes mellitus by refined peritransplant management. J Mol Med 77:140–143PubMedGoogle Scholar
  24. 24.
    Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 343:230–238PubMedGoogle Scholar
  25. 25.
    Bretzel RG (1999) Biological alternatives to insulin therapy. Exp Clin Endocrinol Diabetes 107:S39–S43CrossRefGoogle Scholar
  26. 26.
    von Mering J, Minkowski O (1890) Diabetes mellitus nach Pankreas exstirpation. Arch Exp Pathol Pharmakol 26:37Google Scholar
  27. 27.
    Minkowski O (1892) Weitere Mittheilungen über den Diabetes mellitus nach Exstirpation des Pankreas. Berlin Klin Wochenschr 29:90–94Google Scholar
  28. 28.
    Banting FG, Best CH (1922) The internal secretion of the pancreas. J Lab Clin Med 7:251–266Google Scholar
  29. 29.
    Williams PW (1894) Notes on diabetes treated with extract and by grafts of sheep’s pancreas. Br Med J 2:1303Google Scholar
  30. 30.
    Hering B, Ricordi C (1999) Islet transplantation for patients with Type 1 diabetes: results, research priorities, and reasons for optimism. Graft 2:12–17Google Scholar
  31. 31.
    Brendel M, Hering B, Schulz A, Bretzel R (1999) Newsletter No. 8 of the International Islet Transplant Registry Report. University of Giessen, GermanyGoogle Scholar
  32. 32.
    Ryan EA, Lakey JRT, Rajotte RV, Korbutt GS, Kin T, Imes S, Rabinovitch A, Elliott JF, Bigam D, Kneteman NM, Warnock GL, Larsen I, Shapiro AM (2001) Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes 50:710–719PubMedGoogle Scholar
  33. 33.
    Ryan EA, Lakey JRT, Paty BW, Imes G, Korbutt GS, Kneteman NM, Bigam D, Rajotte RV, Shapiro AM (2002) Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes 51:2148–2157PubMedGoogle Scholar
  34. 34.
    Dobroschke J, Schwemmle K, Langhoff G, Laube H, Bretzel RG, Federlin K (1978) Autotransplantation von Langerhansschen Inseln nach totaler Duodenopankreatektomie bei einem Patienten mit chronischer Pankreatitis. Dtsch Med Wochenschr 103:1905–1910PubMedCrossRefGoogle Scholar
  35. 35.
    Pyzdrowski KL, Kendall DM, Halter JB, Nakleh RE, Sutherland DE, Robertson RP (1992) Preserved insulin secretion and insulin independence in recipients of islet autografts. N Engl J Med 327:220–226PubMedCrossRefGoogle Scholar
  36. 36.
    Sutherland DE, Gruessner RW, Gores PF, Brayman K, Wahoff D, Gruessner A (1995) Pancreas transplantation: an update. Diab Metab Rev 11:337–363CrossRefGoogle Scholar
  37. 37.
    Farney AC, Hering BJ, Nelson L, Tanioka Y, Gilmore T, Leone J, Wahoff D, Najarian J, Kendall D, Sutherland DE (1998) No late failures of intraportal human islet autografts beyond 2 years. Transplant Proc 30:420PubMedGoogle Scholar
  38. 38.
    Brendel MD, Eckhard M, Brandhorst D, Brandhorst H, Winter D, Jaeger C, Jahr H, Ziegler A, Iken M, Shen H, Weimer R, Rau W, Padberg W, Bretzel RG (2003) Inselzelltransplantation—aktueller Stand und Perspektiven. Diab Stoffw 12:239–252Google Scholar
  39. 39.
    Shapiro AM, Ricordi C, Hering B (2003) Edmonton’s islet success has indeed been replicated elsewhere. Lancet 362:1242PubMedGoogle Scholar
  40. 40.
    Ault A (2003) Edmonton’s islet success tough to duplicate elsewhere. Lancet 361:2054PubMedGoogle Scholar
  41. 41.
    Shapiro AMJ, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Robertson RP, Secchi A, Brendel MD, Berney T, Brennan DC, Cagliero E, Alejandro R, Ryan EA, DiMercurio B, Morel P, Polonsky KS, Reems JA, Bretzel RG, Bertuzzi F, Froud T, Kandaswamy R, Sutherland DE, Eisenbarth G, Segal M, Preiksaitis J, Korbutt GS, Barton FB, Viviano L, Seyfert-Margolis V, Bluestone J, Lakey JR (2006) International trial of the Edmonton protocol for islet transplantation. N Engl J Med 355:1318–1330PubMedGoogle Scholar
  42. 42.
    Morris PJ, Monaco AP (2005) Pancreatic islet transplantation: is the glass half-empty or half-full? Transplantation 79:1287–1288PubMedGoogle Scholar
  43. 43.
    Meyer C, Hering BJ, Grossmann R, Brandhorst H, Brandhorst D, Gerich J, Federlin K, Bretzel RG (1998) Improved glucose counterregulation and autonomic symptoms after intraportal islet transplants alone in patients with type I diabetes mellitus. Transplantation 66:233–240PubMedGoogle Scholar
  44. 44.
    Ryan EA, Paty BW, Senior PA, Bigam D, Alfadhi E, Kneteman NM, Lakey JR, Shapiro AM (2005) Five-year follow-up after clinical islet transplantation. Diabetes 54:2060–2069PubMedGoogle Scholar
  45. 45.
    Rickels MR, Schutta MH, Mueller R, Markmann JF, Barker CF, Naji A, Teff KL (2005) Islet cell hormonal responses to hypoglycemia after human islet cell transplantation for type 1 diabetes. Diabetes 54:3205–3211PubMedGoogle Scholar
  46. 46.
    Ryan EA, Shapiro AMJ (2006) A patient with severe, recurrent hypoglycemia and glycemic lability who underwent islet transplantation. Nat Clin Pract Endocrinol Metab 2:349–353PubMedGoogle Scholar
  47. 47.
    Fiorina P, Folli F, Zerbini G, Maffi P, Gremizzi C, Di Carlo V, Socci C, Bertuzzi F, Kashgarian M, Secchi A (2003) Islet transplantation is associated with improvement of renal function among uremic patients with type 1 diabetes mellitus and kidney transplants. J Am Soc Nephrol 14:2150–2158PubMedGoogle Scholar
  48. 48.
    Fiorina P, Venturini M, Folli F, Losio C, Maffi P, Placidi C, La Rosa S, Orsenigo E, Socci C, Capella C, Del Maschio A, Secchi A (2005) Natural history of kidney graft survival, hypertrophy, and vascular function in end-stage renal disease type 1 diabetic kidney-transplanted patients: beneficial impact of pancreas and successful islet cotransplantation. Diabetes Care 28:1303–1310PubMedGoogle Scholar
  49. 49.
    Senior PA, Zeman M, Paty BW, Ryan EA, Shapiro AMJ (2007) Changes in renal function after clinical islet transplantation: four-year observational study. Am J Transplant 7:91–98PubMedGoogle Scholar
  50. 50.
    Andres A, Toso C, Morel P, Demuylder-Mischler S, Bosco D, Baertschinger R, Pernin R, Bucher P, Majno PE, Buhler LH, Berney T (2005) Impairment of renal function after islet transplant alone or islet-after-kidney transplantation using a sirolimus/tacrolimus-based immunosuppressive regimen. Transplant Int 18:1226–1230Google Scholar
  51. 51.
    Fung MA, Warnock GL, Ao Z et al (2007) The effect of medical therapy and islet cell transplantation on diabetic nephropathy: an interim report. Transplantation (in press)Google Scholar
  52. 52.
    Maffi P, Bertuzzi F, De Taddeo F, Magistretti P, Nano R, Fiorina P, Caumo A, Pozzi P, Socci C, Venturini M, Del Maschio A, Secchi A (2007) Kidney function after islet transplant alone in type 1 diabetes: impact of immunosuppressive therapy on progression of diabetic nephropathy. Diabetes Care (Epub ahead of print)Google Scholar
  53. 53.
    Vargas F, Vives-Pi M, Somoza N, Armengol P, Alcalde L, Marti M, Costa M, Serradell L, Dominguez O, Fernandez-Llamazares J, Julian JF, Sanmarti A, Pujol-Borrell R (1998) Endotoxin contamination may be responsible for the unexplained failure of human pancreatic islet transplantation. Transplantation 65:722–727PubMedGoogle Scholar
  54. 54.
    Kaufman DB, Platt JL, Rabe FL, Dunn DL, Bach FH, Sutherland DE (1990) Differential roles of Mac-1+ cells and CD4+ and CD8+ T lymphocytes in primary nonfunction and classical rejection of islet allografts. J Exp Med 172:291–302PubMedGoogle Scholar
  55. 55.
    Bottino R, Fernandez LA, Ricordi C, Lehmann R, Tsan MF, Oliver R, Inverardi L (1998) Transplantation of allogeneic islets of Langerhans in the rat liver. Effects of macrophage depletion on graft survival and microenvironment activation. Diabetes 47:316–323PubMedGoogle Scholar
  56. 56.
    Menger MD, Vajkoczy P, Leiderer R, Jager S, Messmer K (1992) Influence of experimental hyperglycemia on microvascular blood perfusion of pancreatic islet isografts. J Clin Invest 90:1361–1369PubMedGoogle Scholar
  57. 57.
    Berney T, Molano RD, Cattan P, Pileggi A, Vizzardelli C, Oliver R, RIcordi C, Inverardi L (2001) Endotoxin-mediated delayed islet graft function is associated with increased intra-islet cytokine production and islet cell apoptosis. Transplantation 71:125–132PubMedGoogle Scholar
  58. 58.
    Bennet W, Sundberg B, Groth CG, Brendel MD, Brandhorst D, Brandhorst H, Bretzel RG, Elgue G, Larsson R, Nilsson B, Korsgren O (1999) Incompatibility between human blood and isolated islets of Langerhans: a finding with implications for clinical intraportal islet transplantation? Diabetes 48:1907–1914PubMedGoogle Scholar
  59. 59.
    El-Ouaghlidi A, Jahr H, Pfeiffer G, Hering BJ, Brandhorst D, Brandhorst H, Federlin K, Bretzel RG (1999) Cytokine mRNA expression in peripheral blood cells of immunosuppressed human islet transplant recipients. J Mol Med 77:115–117PubMedGoogle Scholar
  60. 60.
    Shapiro AM, Gallant H, Hao E, Wong J, Rajotte R, Yatscoff R, Kneteman N (1997) Portal vein immunosuppressant levels and islet graft toxicity. Transplant Proc 30:641Google Scholar
  61. 61.
    Drachenberg CB, Klassen DK, Weir MR, Wiland A, Fink JC, Bartlett ST, Cangro CB, Blahut S, Papadimitriou JC (1999) Islet cell damage associated with tacrolimus and cyclosporine: morphological features in pancreas allograft biopsies and clinical correlation. Transplantation 68:396–402PubMedGoogle Scholar
  62. 62.
    Jaeger C, Hering BJ, Dyrberg T, Federlin K, Bretzel RG (1996) Islet cell antibodies and GAD65 antibodies in IDDM patients undergoing kidney and islet after kidney transplantation. Transplantation 62:424–426PubMedGoogle Scholar
  63. 63.
    Jaeger C, Brendel MD, Hering BJ, Eckhard M, Bretzel RG (1997) Progressive islet graft failure occurs significantly earlier in autoantibody positive than in autoantibody negative IDDM recipients of intrahepatic islet allografts. Diabetes 46:1907–1910PubMedGoogle Scholar
  64. 64.
    Jaeger C, Brendel MD, Eckhard M, Bretzel RG (2000) Islet autoantibodies as potential markers for disease recurrence in clinical islet transplantation. Exp Clin Endocrinol Diabetes 108:328–333PubMedGoogle Scholar
  65. 65.
    Braghi S, Bonifacio E, Secchi A, di Carlo V, Pozza G, Bosi E (2000) Modulation of humoral islet autoimmunity by pancreas allotransplantation influences allograft outcome in patients with type 1 diabetes. Diabetes 49:218–224PubMedGoogle Scholar
  66. 66.
    Tyden G, Reinholt FP, Sundkvist G, Bolinder J (1996) Recurrence of autoimmune diabetes in recipients of cadaveric pancreatic grafts. N Engl J Med 335:860–863PubMedGoogle Scholar
  67. 67.
    Halloran PF, Homik J, Goes N, Lui SL, Urmson J, Ramassar V, Cockfield SM (1997) The "injury response": a concept linking nonspecific injury, acute rejection, and long-term transplant outcomes. Transplant Proc 29:79–81PubMedGoogle Scholar
  68. 68.
    Roep BO, Stobbe I, Duinkerken G, van Rood JJ, Lernmark A, Keymeulen B, Pipeleers D, Claas FH, de Vries RR (1999) Auto- and alloimmune reactivity to human islet allografts transplanted into type-1 diabetic patients. Diabetes 48:484–490PubMedGoogle Scholar
  69. 69.
    Bretzel RG, Eckhard M, Brendel MD (2004) Pancreatic islet and stem cell transplantation: new strategies in cell therapy of diabetes mellitus. Panmin Med 46:25–42Google Scholar
  70. 70.
    Bretzel RG, Eckhard M, Jahr H, Brendel MD (2006) Islet transplantation, stem cell transfer and regenerative therapy in diabetes mellitus. Dtsch Med Wochenschr 131:903–936PubMedGoogle Scholar
  71. 71.
    Ryan EA, Lakey JR, Paty BW, Imes S, Korbutt GS, Kneteman NM, Bigam D, Rajotte RV, Shapiro AM (2002) Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes 51:2148–2157PubMedGoogle Scholar
  72. 72.
    Waldmann H (1999) Transplantation tolerance: where do we stand? Nat Med 11:1245–1248Google Scholar
  73. 73.
    Acholonu IN, Ildsta ST (1999) The role of bone marrow transplantation in tolerance: organ-specific and cellular grafts. Curr Opin Organ Transpl 4:189–196Google Scholar
  74. 74.
    Kenyon NS, Chatzipetron M, Masetti M, Ranuncoli A, Oliveira M, Wagner JL, Kirk AD, Harlan DM, Burkly LC, Ricordi C (1999) Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD 154. Proc Natl Acad Sci USA 96:8132–8137PubMedGoogle Scholar
  75. 75.
    Kenyon NS, Fernandez LA, Lehmann R, Masetti M, Ranuncoli A, Chatzipetrou M, Iaria G, Han D, Wagner JL, Ruiz P, Berho M, Inverardi L, Alejandro R, Mintz DH, Kirk AD, Harlan DM (1999) Long-term survival and function of intrahepatic islet allografts in baboons treated with humanized anti-CD 154. Diabetes 48:1473–1481PubMedGoogle Scholar
  76. 76.
    Faendrich F, Lin X, Chai GX, Schulze M, Ganten D, Bader M, Holle J, Huang DS, Parwaresch R, Zavazava N, Binas B (2002) Preimplantation-stage stem cells induce long-term allogenic graft acceptance without supplementary host conditioning. Nat Med 8:171–178Google Scholar
  77. 77.
    Chong AS, Yin D, Boussy IA (2002) Transplantation tolerance: of mice and men. Graft 5:27–33Google Scholar
  78. 78.
    Kawai T, Andrews D, Colvin RB, Sachs DH, Cosimi AB (2000) Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand. Nat Med 6:114Google Scholar
  79. 79.
    Kirk AD, Harlan DM (2000) Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand (reply). Nat Med 6:114Google Scholar
  80. 80.
    Markmann JF, Deng S, Desai NM, Huang X, Velidedeoglu E, Frank A, Liu C, Brayman KL, Lian MM, Wolf B, Bell E, Vitamaniuk M, Doliba N, Matschinsky F, Markmann E, Barker CF, Naji A (2003) The use of non-heart-beating donors for isolated pancreatic islet transplantation. Transplantation 75:1423–1429PubMedGoogle Scholar
  81. 81.
    Matsumoto S, Okitsu T, Iwanaga Y, Noguchi H, Nagata H, Yonekawa Y, Yamada Y, Fukuda K, Tsukiyama K, Suzuki H, Kawasaki Y, Shimodaira M, Matsuoka K, Shibata T, Kasai Y, Maekawa T, Shapiro J, Tanaka K (2005) Insulin independence after living-donor distal pancreatectomy and islet allotransplantation. Lancet 365:1642–1644PubMedGoogle Scholar
  82. 82.
    Evans RW (2001) Coming to terms with reality: why xenotransplantation is a necessity. In: Platt JL (ed) Xenotransplantation. ASM, Washington, DC. pp 29–51Google Scholar
  83. 83.
    Brown J, Danilovs JA, Clark WR, Mullen YS (1984) Fetal pancreas as a donor organ. World J Surg 8:152–157PubMedGoogle Scholar
  84. 84.
    Korsgren O (1991) Xenotransplantation of fetal porcine islet-like cell clusters in diabetes mellitus: an experimental and clinical study. Acta Univ Upsal 295:1–40Google Scholar
  85. 85.
    Korsgren O, Sandler S, Landström A, Jansson L, Andersson A (1988) Large-scale production of fetal porcine pancreatic islet-like cell clusters. An experimental tool for studies of islet cell differentiation and xenotransplantation. Transplantation 45:509–514PubMedGoogle Scholar
  86. 86.
    Korsgren O, Jansson L, Eizirik D, Andersson A (1991) Functional and morphological differentiation of fetal porcine islet-like cell clusters after transplantation into nude mice. Diabetologia 34:379–386PubMedGoogle Scholar
  87. 87.
    Liu X, Federlin KF, Bretzel RG, Hering BJ, Brendel MD (1991) Persistent reversal of diabetes by transplantation of fetal pig proislets into nude mice. Diabetes 40:858–866PubMedGoogle Scholar
  88. 88.
    Liu X, Brendel MD, Hering BJ, Bretzel RG, Federlin K (1992) Comparison of the potency of fetal pig pancreatic proislets and fragments to reverse diabetes. Transplant Proc 24:987PubMedGoogle Scholar
  89. 89.
    Liu X, Brendel MD, Klitscher D, Brandhorst H, Hering BJ, Federlin KF, Bretzel RG (1993) Successful cryopreservation of fetal porcine proislets. Cryobiology 30:262–271PubMedGoogle Scholar
  90. 90.
    Liu X, Brendel MD, Brandhorst D, Brandhorst H, Hering BJ, Federlin K, Bretzel RG (1994) Reversal of diabetes in nude mice by transplantation of cryopreserved fetal porcine proislets. Transplant Proc 26:707–708PubMedGoogle Scholar
  91. 91.
    Bretzel RG, Liu X, Hering BJ, Brendel M, Federlin K (1995) Cryopreservation transplantation and susceptibility to diabetogenic agents of fetal porcine proislets. Xenotransplantation 2:133–138CrossRefGoogle Scholar
  92. 92.
    Bach FH, Fishman JA, Daniels N, Proimos J, Anderson B, Carpenter CB, Forrow L, Robson SC, Fineberg HV (1998) Uncertainty in xenotransplantation: individual benefit versus collective risk. Nat Med 4:141–144PubMedGoogle Scholar
  93. 93.
    Patience C, Takeuchi Y, Weiss RA (1997) Infection of human cells by an endogenous retrovirus of pigs. Nat Med 3:275–276Google Scholar
  94. 94.
    Martin U, Kiessig V, Blusch JH, Haverich A, von der Helm K, Herden T, Steinhoff G (1998) Expression of pig endogenous retrovirus by primary porcine endothelial cells and infection of human cells. Lancet 352:666–667Google Scholar
  95. 95.
    Van der Laan LJ, Lockey C, Griffeth BC, Frasier FS, Wilson CA, Onions DE, Hering BJ, Long Z, Otto E, Torbett BE, Salomon DR (2000) Infection by porcine endogenous retroviruses after islet xenotransplantation in SCID mice. Nature 407:90–94PubMedGoogle Scholar
  96. 96.
    Deng YM, Tuch BE, Rawlinson WD (2000) Transmission of porcine endogenous retroviruses in severe combined immunodeficient mice xenotransplanted with fetal porcine pancreatic cells. Transplantation 70:1010–1016PubMedGoogle Scholar
  97. 97.
    Heneine W, Tibell A, Switzer WM, Sandstrom P, Rosales GV, Mathews A, Korsgren O, Chapman LE, Folks TM, Groth CG (1998) No evidence of infection with porcine endogenous retrovirus in recipients of porcine islet-cell xenografts. Lancet 352:695–699PubMedGoogle Scholar
  98. 98.
    Paradis K, Langford G, Long Z, Heneine W, Sandstrom P, Switzer WM, Chapman LE, Lockey C, Onions D, Otto E (1999) Search for cross-species transmission of porcine endogenous retrovirus in patients treated with living pig tissue. Science 285:1236–1241PubMedGoogle Scholar
  99. 99.
    Valdes R (2002) Xenotransplantation trials. Lancet 359:2281PubMedGoogle Scholar
  100. 100.
    Birmingham K (2002) Skepticism surrounds diabetes xenograft experiment. Nat Med 8:1047PubMedGoogle Scholar
  101. 101.
    Soria B, Skoudy A, Martin F (2001) From stem cells to beta cells:new strategies in cell therapy of diabetes mellitus. Diabetologia 44:407–415PubMedGoogle Scholar
  102. 102.
    Edlund H (1958) Transcribing the pancreas. Diabetes 47:1817–1823Google Scholar
  103. 103.
    Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF (1997) Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat genet 15:106–110PubMedGoogle Scholar
  104. 104.
    Apelqvist A, Li H, Sommer L, Beatus P, Anderson DJ, Honjo T, Hrabe de Angelis M, Lendahl U, Edlund H (1999) Notch signalling controls pancreatic cell differentiation. Nature 400:877–881PubMedGoogle Scholar
  105. 105.
    Gradwohl G, Dierich A, Le Meur M, Guillemot F (2000) Neurogenin 3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci USA 97:1607–1611PubMedGoogle Scholar
  106. 106.
    Sosa-Pineda B, Chowdhury K, Torres M, Oliver G, Gruss P (1997) The Pax 4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature 386:399–402PubMedGoogle Scholar
  107. 107.
    Wilson ME, Scheel D, German MS (2003) Gene expression cascades in pancreatic development. Mech Dev 120:65–80PubMedGoogle Scholar
  108. 108.
    Soria B, Roche E, Berna G, Leon-Quinto T, Reig JA, Martin F (2000) Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes 49:157–162PubMedGoogle Scholar
  109. 109.
    Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R (2001) Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 292:1389–1394PubMedGoogle Scholar
  110. 110.
    Assady S, Maor G, Amit M, Itskovitz-Eldor J, Skorecki KL, Tzukerman M (2001) Insulin production by human embryonic stem cells. Diabetes 50:1691–1697PubMedGoogle Scholar
  111. 111.
    Zulewski H, Abraham EJ, Gerlach MJ, Daniel PB, Moritz W, Müller B, Vallejo M, Thomas MK, Habener JF (2001) Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes 50:521–525PubMedGoogle Scholar
  112. 112.
    Ramiya VK, Maraist M, Arfors KE, Schatz DA, Peck AB, Cornelius JG (2000) Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells. Nat Med 6:278–282PubMedGoogle Scholar
  113. 113.
    Bonner-Weir S, Taneja M, Weir GC, Tatarkiewicz K, Song KH, Sharma A, O’Neil JJ (2000) In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci USA 97:7999–8004PubMedGoogle Scholar
  114. 114.
    Rafaeloff R, Pittenger GL, Barlow SW, Qin XF, Yan B, Rosenberg L, Duguid WP, Vinik AI (1997) Cloning and sequencing of the pancreatic islet neogenesis in hamsters. J Clin Invest 99:2100–2109PubMedCrossRefGoogle Scholar
  115. 115.
    Ghofaili KA, Eung M, Ao Z, Meloche M, Shapiro RJ, Warnock GL, Elahi D, Meneilly GS, Thompson DM (2007) Effect of exenatide on beta cell function after islet transplantation in type 1 diabetes. Transplantation 83:24-28PubMedGoogle Scholar
  116. 116.
    Soria B, Andreu E, Berna G, Fuentes E, Gil A, Leon-Quinto T, Martin F, Montanya E, Nadal A, Reig JA, Ripoll C, Roche E, Sanchez-Andres JV, Segura J (2000) Engineering pancreatic islets. Eur J Physiol 440:1-18Google Scholar
  117. 117.
    Cheung AT, Dayanandan B, Lewis JT, Korbutt GS, Rajotte RV, Bryer-Ash M, Boylan MO, Wolfe MM, Kieffer TJ (2000) Glucose-dependent insulin release from genetically engineered K cells. Science 290:1959–1962PubMedGoogle Scholar
  118. 118.
    Ferber S, Halkin A, Cohen H, Ber I, Einav Y, Goldberg I, Barshack I, Seijffers R, Kopolovic J, Kaiser N, Karasik A (2000) Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat Med 6:568–572PubMedGoogle Scholar
  119. 119.
    Yang L, Li S, Hatch H, Ahrens K, Cornelius JG, Petersen BE, Peck AB (2002) In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells. Proc Natl Acad Sci USA 99:8078–8083PubMedGoogle Scholar
  120. 120.
    Ber I, Shternhall K, Perl S, Ohanuna Z, Goldberg I, Barshack I, Benvenisti-Zarum L, Meivar-Levy I, Ferber S (2003) Functional, persistent, and extended liver to pancreas transdifferentiation. J Biol Chem 278:31950–31957PubMedGoogle Scholar
  121. 121.
    Horb ME, Shen CN, Tosh D, Slack JM (2003) Experimental conversion of liver to pancreas. Curr Biol 13:105–115PubMedGoogle Scholar
  122. 122.
    Kojima H, Fujimiya M, Matsumura K, Younan P, Imaeda H, Maeda M, Chan L (2003) NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Nat Med 9:596–603PubMedGoogle Scholar
  123. 123.
    Lee HC, Kim SJ, Kim KS, Shin HC, Yoon JW (2000) Remission in models of type 1 diabetes by gene therapy using a single-chain insulin analogue. Nature 408:483–488PubMedGoogle Scholar
  124. 124.
    Shaw JAM, Delday MI, Hart AW, Docherty K (2002) Secretion of bioactive human insulin following plasmid-mediated gene transfer to non-neuroendocrine cell lines, primary cultures and rat skeletal muscle in vivo. J Endocrinol 172:653–672PubMedGoogle Scholar
  125. 125.
    Riu E, Mas A, Ferre T, Pujol A, Gros L, Otaegui P, Montoliu L, Bosch F (2002) Counteraction of type 1 diabetic alterations by engineering skeletal muscle to produce insulin: insights from transgenic mice. Diabetes 51:704–711PubMedGoogle Scholar
  126. 126.
    Jahr H, Wagner S, Brendel M, Bretzel RG (2005) Gastrin-induced insulin production in hepatocyteG2 cells. Diabetologia 48 (suppl 1):A153Google Scholar
  127. 127.
    Kahn A (2000) Converting hepatocytes to β-cells—a new approach for diabetes? Nat Med 6:505–506PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Reinhard G. Bretzel
    • 1
  • Henning Jahr
    • 1
  • Michael Eckhard
    • 1
  • Isabel Martin
    • 1
  • Daniel Winter
    • 1
  • Mathias D. Brendel
    • 1
  1. 1.Third Medical Department and PoliclinicUniversity Hospital Giessen and Marburg GmbHGiessenGermany

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