Acta Diabetologica

, Volume 51, Issue 5, pp 833–843 | Cite as

Five-year follow-up of patients with type 1 diabetes transplanted with allogeneic islets: the UIC experience

  • Meirigeng Qi
  • Katie Kinzer
  • Kirstie K. Danielson
  • Joan Martellotto
  • Barbara Barbaro
  • Yong Wang
  • James T. Bui
  • Ron C. Gaba
  • Grace Knuttinen
  • Raquel Garcia-Roca
  • Ivo Tzvetanov
  • Andrew Heitman
  • Maureen Davis
  • James J. McGarrigle
  • Enrico Benedetti
  • Jose OberholzerEmail author
Original Article


This report summarizes a 5-year phase 1/2 allogeneic islet transplantation clinical trial conducted at the University of Illinois at Chicago (UIC). Ten patients were enrolled in this single center, open label, and prospective trial in which patients received 1–3 transplants. The first four subjects underwent islet transplantation with the Edmonton immunosuppressive regimen and the remaining six subjects received the UIC immunosuppressive protocol (Edmonton plus etanercept and exenatide). All 10 patients achieved insulin independence after 1–3 transplants. At 5 years of follow-up, 6 of the initial 10 patients were free of exogenous insulin. During the follow-up period, 7 of the 10 patients maintained positive C-peptide levels and a composite hypoglycemic score of 0. Most patients maintained HbA1c levels <6.0 % (42.1 mmol/mol) and a significantly improved β-score. In conclusion, this study demonstrated long-term islet graft function without using T cell depleting induction, with an encouraging outcome that includes 60 % of patients remaining insulin independent after 5 years of initial transplantation.


Type 1 diabetes Islet transplantation Immunosuppression Insulin independence 



University of Illinios at Chicago


Mycophenolate mofetil


Islet equivalents


Collaborate islet transplant registry


Tumor necrosis factor


Glucagon-like peptide-1


Mixed meal test


Oral glucose tolerance test


Intravenous glucose tolerance test


Glucagon stimulation test


Urine albumin and creatinine ratio



This work was supported by funding from the College of Medicine, University of Illinois at Chicago. J.O. and J. M. were supported by the Islet Cell Resources Center NIH grant (5 U42 RR023245-02), the Christopher Family Foundation, and the Efroymson Foundation. The subjects are evaluated at the UIC Clinical Research Center, which is supported by the University of Illinois at Chicago Center for Clinical and Translational Science (Award Number UL1RR029879) from the National Center for Research Resources. Data acquisition aided by the CITR, Emmes corporation. The islet program was supported by the Chicago Diabetes Project, and the Washington Square Health Foundation.

Conflict of interest

Meirigeng Qi, Katie Kinzer, Kirstie K. Danielson, Joan Martellotto, Barbara Barbaro, Yong Wang, James T. Bui, Ron C. Gaba, Grace Knuttinen, Raquel Garcia-Roca, Ivo Tzvetanov, Andrew Heitman, Maureen Davis, James J. McGarrigle, Enrico Benedetti, and Jose Oberholzer declare that they have no conflict of interest.

Ethical disclosure

All human studies have been reviewed by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in an appropriate version of the 1964 Declaration of Helsinki.

Human and animal rights disclosure

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5).

Informed consent disclosure

Informed consent was obtained from all patients for being included in the study.


  1. 1.
    Ricordi C (2003) Islet transplantation: a brave new world. Diabetes 52(7):1595–1603PubMedCrossRefGoogle Scholar
  2. 2.
    Bertuzzi F, Ricordi C (2007) Beta-cell replacement in immunosuppressed recipients: old and new clinical indications. Acta Diabetol 44(4):171–176PubMedCrossRefGoogle Scholar
  3. 3.
    Barton FB, Rickels MR, Alejandro R, Hering BJ, Wease S, Naziruddin B, Oberholzer J, Odorico JS, Garfinkel MR, Levy M, Pattou F, Berney T, Secchi A, Messinger S, Senior PA, Maffi P, Posselt A, Stock PG, Kaufman DB, Luo X, Kandeel F, Cagliero E, Turgeon NA, Witkowski P, Naji A, O’Connell PJ, Greenbaum C, Kudva YC, Brayman KL, Aull MJ, Larsen C, Kay TW, Fernandez LA, Vantyghem MC, Bellin M, Shapiro AM (2012) Improvement in outcomes of clinical islet transplantation: 1999–2010. Diabetes Care 35(7):1436–1445PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    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(4):230–238PubMedCrossRefGoogle Scholar
  5. 5.
    Ryan EA, Paty BW, Senior PA, Bigam D, Alfadhli E, Kneteman NM, Lakey JRT, Shapiro AMJ (2005) Five-year follow-up after clinical islet transplantation. Diabetes 54(7):2060–2069PubMedCrossRefGoogle Scholar
  6. 6.
    Bellin MD, Barton FB, Heitman A, Harmon JV, Kandaswamy R, Balamurugan AN, Sutherland DE, Alejandro R, Hering BJ (2012) Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. Am J Transplant 12(6):1576–1583PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Shapiro AM, Hao EG, Lakey JR, Yakimets WJ, Churchill TA, Mitlianga PG, Papadopoulos GK, Elliott JF, Rajotte RV, Kneteman NM (2001) Novel approaches toward early diagnosis of islet allograft rejection. Transplantation 71(12):1709–1718PubMedCrossRefGoogle Scholar
  8. 8.
    Vergani A, Fotino C, D’Addio F, Tezza S, Podetta M, Gatti F, Chin M, Bassi R, Molano RD, Corradi D, Gatti R, Ferrero ME, Secchi A, Grassi F, Ricordi C, Sayegh MH, Maffi P, Pileggi A, Fiorina P (2013) Effect of the purinergic inhibitor oxidized ATP in a model of islet allograft rejection. Diabetes 62(5):1665–1675PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Jalili RB, Forouzandeh F, Rezakhanlou AM, Hartwell R, Medina A, Warnock GL, Larijani B, Ghahary A (2010) Local expression of indoleamine 2,3 dioxygenase in syngeneic fibroblasts significantly prolongs survival of an engineered three-dimensional islet allograft. Diabetes 59(9):2219–2227PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Monti P, Scirpoli M, Maffi P, Ghidoli N, De Taddeo F, Bertuzzi F, Piemonti L, Falcone M, Secchi A, Bonifacio E (2008) Islet transplantation in patients with autoimmune diabetes induces homeostatic cytokines that expand autoreactive memory T cells. J Clin Invest 118(5):1806–1814PubMedPubMedCentralGoogle Scholar
  11. 11.
    Huang G, Wang X, Li Z, Li H, Li X, Zhou Z (2012) Insulin autoantibody could help to screen latent autoimmune diabetes in adults in phenotypic type 2 diabetes mellitus in Chinese. Acta Diabetol 49(5):327–331PubMedCrossRefGoogle Scholar
  12. 12.
    Nir T, Melton DA, Dor Y (2007) Recovery from diabetes in mice by beta cell regeneration. J Clin Invest 117(9):2553–2561PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Gillard P, Ling Z, Mathieu C, Crenier L, Lannoo M, Maes B, Roep B, Gorus F, Pipeleers D, Keymeulen B (2008) Comparison of sirolimus alone with sirolimus plus tacrolimus in type 1 diabetic recipients of cultured islet cell grafts. Transplantation 85(2):256–263PubMedCrossRefGoogle Scholar
  14. 14.
    Laugharne M, Cross S, Richards S, Dawson C, Ilchyshyn L, Saleem M, Mathieson P, Smith R (2007) Sirolimus toxicity and vascular endothelial growth factor release from islet and renal cell lines. Transplantation 83(12):1635–1638PubMedCrossRefGoogle Scholar
  15. 15.
    Bellin MD, Barton FB, Heitman A, Harmon JV, Kandaswamy R, Balamurugan AN, Sutherland DE, Alejandro R, Hering BJ (2012) Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. Am J Transplant 12(6):1576–1583PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Ngo A, Sutherland DE, Beilman GJ, Bellin MD (2014) Deterioration of glycemic control after corticosteroid administration in islet autotransplant recipients: a cautionary tale. Acta Diabetol 51(1):141–145PubMedCrossRefGoogle Scholar
  17. 17.
    Gangemi A, Salehi P, Hatipoglu B, Martellotto J, Barbaro B, Kuechle JB, Qi M, Wang Y, Pallan P, Owens C, Bui J, West D, Kaplan B, Benedetti E, Oberholzer J (2008) Islet transplantation for brittle type 1 diabetes: the UIC protocol. Am J Transplant 8(6):1250–1261PubMedCrossRefGoogle Scholar
  18. 18.
    Qi M, Barbaro B, Wang S, Wang Y, Hansen M, Oberholzer J (2009) Human pancreatic islet isolation: Part I: digestion and collection of pancreatic tissue. J Vis Exp (27). doi: 10.3791/1125
  19. 19.
    Qi M, Barbaro B, Wang S, Wang Y, Hansen M, Oberholzer J (2009) Human pancreatic islet isolation: Part II: purification and culture of human islets. J Vis Exp (27). doi: 10.3791/1343
  20. 20.
    Soltani SM, O’Brien TD, Loganathan G, Bellin MD, Anazawa T, Tiwari M, Papas KK, Vickers SM, Kumaravel V, Hering BJ, Sutherland DE, Balamurugan AN (2013) Severely fibrotic pancreases from young patients with chronic pancreatitis: evidence for a ductal origin of islet neogenesis. Acta Diabetol 50(5):807–814PubMedCrossRefGoogle Scholar
  21. 21.
    Koh A, Imes S, Kin T, Dinyari P, Malcolm A, Toso C, Shapiro AM, Senior P (2010) Supplemental islet infusions restore insulin independence after graft dysfunction in islet transplant recipients. Transplantation 89(3):361–365PubMedCrossRefGoogle Scholar
  22. 22.
    Lehmann R, Spinas GA, Moritz W, Weber M (2008) Has time come for new goals in human islet transplantation? Am J Transplant 8(6):1096–1100PubMedCrossRefGoogle Scholar
  23. 23.
    Teuscher AU, Kendall DM, Smets YF, Leone JP, Sutherland DE, Robertson RP (1998) Successful islet autotransplantation in humans: functional insulin secretory reserve as an estimate of surviving islet cell mass. Diabetes 47(3):324–330PubMedCrossRefGoogle Scholar
  24. 24.
    Ryan EA, Shandro T, Green K, Paty BW, Senior PA, Bigam D, Shapiro AM, Vantyghem MC (2004) Assessment of the severity of hypoglycemia and glycemic lability in type 1 diabetic subjects undergoing islet transplantation. Diabetes 53(4):955–962PubMedCrossRefGoogle Scholar
  25. 25.
    Ryan EA, Paty BW, Senior PA, Lakey JR, Bigam D, Shapiro AM (2005) Beta-score: an assessment of beta-cell function after islet transplantation. Diabetes Care 28(2):343–347PubMedCrossRefGoogle Scholar
  26. 26.
    Justesen TI, Petersen JL, Ekbom P, Damm P, Mathiesen ER (2006) Albumin-to-creatinine ratio in random urine samples might replace 24-h urine collections in screening for micro- and macroalbuminuria in pregnant woman with type 1 diabetes. Diabetes Care 29(4):924–925PubMedCrossRefGoogle Scholar
  27. 27.
    Salehi P, Stull MA, Martellotto J, Gangemi A, Hatipoglu B, Benedetti E, Oberholzer J (2009) Case report: diabetic myonecrosis of the neck complicated by infection in an islet transplanted patient. J Diabetes Complications 23(2):140–142PubMedCrossRefGoogle Scholar
  28. 28.
    Froud T, Faradji RN, Pileggi A, Messinger S, Baidal DA, Ponte GM, Cure PE, Monroy K, Mendez A, Selvaggi G, Ricordi C, Alejandro R (2008) The use of exenatide in islet transplant recipients with chronic allograft dysfunction: safety, efficacy, and metabolic effects. Transplantation 86(1):36–45PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Faradji RN, Tharavanij T, Messinger S, Froud T, Pileggi A, Monroy K, Mineo D, Baidal DA, Cure P, Ponte G, Mendez AJ, Selvaggi G, Ricordi C, Alejandro R (2008) Long-term insulin independence and improvement in insulin secretion after supplemental islet infusion under exenatide and etanercept. Transplantation 86(12):1658–1665PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Johnson JA, Kotovych M, Ryan EA, Shapiro AM (2004) Reduced fear of hypoglycemia in successful islet transplantation. Diabetes Care 27(2):624–625PubMedCrossRefGoogle Scholar
  31. 31.
    Huurman VA, van der Torren CR, Gillard P, Hilbrands R, van der Meer-Prins EP, Duinkerken G, Gorus FK, Claas FH, Keymeulen B, Roelen DL, Pipeleers DG, Roep BO (2012) Immune responses against islet allografts during tapering of immunosuppression—a pilot study in 5 subjects. Clin Exp Immunol. doi: 10.1111/j.1365-2249.2011.04605 PubMedCentralGoogle Scholar
  32. 32.
    Smith RN, Kent SC, Nagle J, Selig M, Iafrate AJ, Najafian N, Hafler DA, Auchincloss H, Orban T, Cagliero E (2008) Pathology of an islet transplant 2 years after transplantation: evidence for a nonimmunological loss. Transplantation 86(1):54–62PubMedCrossRefGoogle Scholar
  33. 33.
    Westermark GT, Westermark P, Berne C, Korsgren O (2008) Widespread amyloid deposition in transplanted human pancreatic islets. N Engl J Med 359(9):977–979PubMedCrossRefGoogle Scholar
  34. 34.
    Ponte GM, Baidal DA, Romanelli P, Faradji RN, Poggioli R, Cure P, Froud T, Selvaggi G, Pileggi A, Ricordi C, Alejandro R (2007) Resolution of severe atopic dermatitis after tacrolimus withdrawal. Cell Transplant 16(1):23–30PubMedCrossRefGoogle Scholar
  35. 35.
    Bumbea V, Kamar N, Ribes D, Esposito L, Modesto A, Guitard J, Nasou G, Durand D, Rostaing L (2005) Long-term results in renal transplant patients with allograft dysfunction after switching from calcineurin inhibitors to sirolimus. Nephrol Dial Transplant 20(11):2517–2523PubMedCrossRefGoogle Scholar
  36. 36.
    Liew A, Chiang GS, Vathsala A (2009) Factors associated with proteinuria in renal transplant recipients treated with sirolimus. Transpl Int 22(3):313–322PubMedCrossRefGoogle Scholar
  37. 37.
    Senior PA, Zeman M, Paty BW, Ryan EA, Shapiro AM (2007) Changes in renal function after clinical islet transplantation: four-year observational study. Am J Transplant 7(1):91–98PubMedCrossRefGoogle Scholar
  38. 38.
    Kaplan B, Schold J, Srinivas T, Womer K, Foley DP, Patton P, Howard R, Meier-Kriesche HU (2004) Effect of sirolimus withdrawal in patients with deteriorating renal function. Am J Transplant 4(10):1709–1712PubMedCrossRefGoogle Scholar
  39. 39.
    Senior PA, Paty BW, Cockfield SM, Ryan EA, Shapiro AM (2005) Proteinuria developing after clinical islet transplantation resolves with sirolimus withdrawal and increased tacrolimus dosing. Am J Transplant 5(9):2318–2323PubMedCrossRefGoogle Scholar
  40. 40.
    Olack BJ, Swanson CJ, Flavin KS, Phelan D, Brennan DC, White NH, Lacy PE, Scharp DW, Poindexter N, Mohanakumar T (1997) Sensitization to HLA antigens in islet recipients with failing transplants. Transplant Proc 29(4):2268–2269PubMedCrossRefGoogle Scholar
  41. 41.
    Campbell PM, Senior PA, Salam A, Labranche K, Bigam DL, Kneteman NM, Imes S, Halpin A, Ryan EA, Shapiro AM (2007) High risk of sensitization after failed islet transplantation. Am J Transplant 7(10):2311–2317PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2014

Authors and Affiliations

  • Meirigeng Qi
    • 1
  • Katie Kinzer
    • 1
  • Kirstie K. Danielson
    • 1
  • Joan Martellotto
    • 1
  • Barbara Barbaro
    • 1
  • Yong Wang
    • 1
  • James T. Bui
    • 2
  • Ron C. Gaba
    • 2
  • Grace Knuttinen
    • 2
  • Raquel Garcia-Roca
    • 1
  • Ivo Tzvetanov
    • 1
  • Andrew Heitman
    • 3
  • Maureen Davis
    • 1
  • James J. McGarrigle
    • 1
  • Enrico Benedetti
    • 1
  • Jose Oberholzer
    • 1
    Email author
  1. 1.Division of Transplantation, Department of SurgeryUniversity of Illinois at ChicagoChicagoUSA
  2. 2.Department of RadiologyUniversity of Illinois at ChicagoChicagoUSA
  3. 3.The Emmes Corporation RockvilleRockvilleUSA

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