Long-Term Immunosuppression After Solitary Islet Transplantation Is Associated With Preserved C-Peptide Secretion for More Than a Decade
Open accessAbstract
We report on two patients with type 1 diabetes (T1D) after solitary islet transplantation in 2001. They received steroid-sparing immunosuppression (daclizumab, sirolimus, and tacrolimus according to the Edmonton protocol). Both patients became insulin independent for 2 years: Patient A, a 42-year-old female with a 12-year history of T1D, received two islet infusions; patient B, a 53-year-old female with a 40-year T1D history, received one islet infusion. Pretransplant, both had undetectable C-peptide concentrations and frequent and severe hypoglycemia. Pretransplant, hemoglobin A1c (HbA1c) was 7.8% and 8.8% and insulin requirements were 0.47 and 0.33 units/kg/day, respectively. Posttransplant, C-peptide levels remained detectable while immunosuppression was continued, but decreased over time. Insulin was re-started 2 years posttransplant in both patients. Since patient A's glycemia and insulin requirements trended toward pretransplant levels, immunosuppression was discontinued after 13 years. This resulted in a sudden cessation of C-peptide secretion. Patient B continues on immunosuppression, has better HbA1c, and half the insulin requirement compared to pretransplant. Both patients no longer experience severe hypoglycemia. Herein, we document blood glucose concentrations over time (>30 000 measurements per patient) and β cell function based on C-peptide secretion. Despite renewed insulin dependence, both patients express satisfaction with having undergone the procedure.
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Immunosuppressive drugs used for whole organ transplants can successfully retain graft viability but can have serious side-effects, including an increased risk of infection and cancer as well as less severe but uncomfortable symptoms.
“While these drugs can successfully retain graft viability, they also can have serious side-effects, including an increased risk of infection and cancer as well as less severe but uncomfortable symptoms.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [80]
The Case Reports > Complications section describes immunosuppression-related mouth ulcers, a cellulitis episode requiring hospitalization and antibiotics, and declining renal function. The Discussion and Patient A report support preservation of islet graft function during immunosuppression, but the paper does not address increased cancer risk or establish an increased infection risk in whole-organ transplant recipients. Page numbers are unavailable in our copy. (LLM, conf=0.87)
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Cites
Five-Year Follow-Up After Clinical Islet Transplantation
Ryan, E. A., Paty, B. W., Senior, P. A., Bigam, D., Alfadhli, E., Kneteman, N. M., Lakey, J. R. T., & Shapiro, A. M. J. (2005) · Diabetes · doi:10.2337/diabetes.54.7.2060 · Cited by 1,641 · cited 2× · see citing works
“The Edmonton protocol raised the hope for sustained insulin independence, but 5 years after islet transplantation, only 10% of patients remained insulin free (1).”
Improvement in outcomes of clinical islet transplantation: 1999–2010
Barton, F. B., Rickels, M. R., Alejandro, R., Hering, B. J., Wease, S., Naziruddin, B., Oberholzer, J., Odorico, J. S., Garfinkel, M. R., Levy, M., et al. (2012) · Diabetes Care · doi:10.2337/dc12-0063 · Cited by 725 · cited 2× · see citing works
“The mechanism is unknown but has been postulated to involve (1) lower insulin doses and (2) increased endogenous glucose production via lactate gluconeogenesis and decreased systemic glucose disposal (18).”
Bellin, M. D., Barton, F. B., Heitman, A., Harmon, J. V., Kandaswamy, R., Balamurugan, A. N., Sutherland, D. E. R., Alejandro, R., & Hering, B. J. (2012) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2011.03977.x · Cited by 350 · cited 1× · see citing works
“HLA matching may play a role in preservation of functional islets, demonstrated by two cases (13,15) with encouraging outcomes of 10- and 13-year insulin independence.”
Hirshberg, B., Rother, K. I., Digon, B. J., Lee, J. S., Gaglia, J. L., Hines, K., Read, E. J., Chang, R., Wood, B. J., & Harlan, D. M. (2003) · Diabetes Care · doi:10.2337/diacare.26.12.3288 · Cited by 164 · see citing works
Self-citationWarnock, G. L., Thompson, D. M., Meloche, R. M., Shapiro, R. J., Ao, Z., Keown, P. A., Johnson, J. D., Verchere, C. B., Partovi, N., Begg, I. S., et al. (2008) · Transplantation · doi:10.1097/tp.0b013e318190b052 · Cited by 157 · see citing works
Shapiro, A. M. J. (2012) · The review of diabetic studies : RDS · doi:10.1900/rds.2012.9.385 · Cited by 131 · cited 1× · see citing works
“However, the overall number of islet transplant recipients has remained small with just over 1000 patientsworldwide (5).”
Quality of Life After Islet Transplantation
Poggioli, R., Faradji, R. N., Ponte, G., Betancourt, A., Messinger, S., Baidal, D. A., Froud, T., Ricordi, C., & Alejandro, R. (2005) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2005.01174.x · Cited by 128 · cited 1× · see citing works
“Another clinically important outcome is resolution of severe hypoglycemia (16,17).”
Qi, M., Kinzer, K., Danielson, K. K., Martellotto, J., Barbaro, B., Wang, Y., Bui, J. T., Gaba, R. C., Knuttinen, G., Garcia-Roca, R., et al. (2014) · Acta Diabetologica · doi:10.1007/s00592-014-0627-6 · Cited by 96 · see citing works
Cure, P., Pileggi, A., Froud, T., Messinger, S., Faradji, R., Baidal, D., Cardani, R., Curry, A., Poggioli, R., Pugliese, A., et al. (2008) · Transplantation · doi:10.1097/tp.0b013e318166a27b · Cited by 91 · cited 1× · see citing works
“Another clinically important outcome is resolution of severe hypoglycemia (16,17).”
Berney, T., Ferrari‐Lacraz, S., Bühler, L. H., Oberholzer, J., Marangon, N., Philippé, J., Villard, J., & Morel, P. (2008) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2008.02481.x · Cited by 76 · see citing works
Thompson, D. M., Begg, I. S., Harris, C., Ao, Z., Fung, M. A., Meloche, R. M., Keown, P. A., Meneilly, G. S., Shapiro, R. J., Ho, S. G. F., et al. (2008) · Transplantation · doi:10.1097/tp.0b013e318172ca07 · Cited by 75 · see citing works
Liu, E. H., Digon, B. J., Hirshberg, B., Chang, R., Wood, B. J., Neeman, Z., Kam, A. W., WESLEY, R. A., Polly, S. M., Hofmann, R. M., et al. (2009) · Diabetologia · doi:10.1007/s00125-009-1342-7 · Cited by 56 · see citing works
Self-citationNaziruddin, B., Wease, S., Stablein, D., Barton, F. B., Berney, T., Rickels, M. R., & Alejandro, R. (2011) · Cell Transplantation · doi:10.3727/096368911x612468 · Cited by 51 · see citing works
Sirolimus-Induced Interstitial Pneumonitis in an Islet Transplant Recipient
Digon, B. J., Rother, K. I., Hirshberg, B., & Harlan, D. M. (2003) · Diabetes Care · doi:10.2337/diacare.26.11.3191 · Cited by 47 · see citing works
Self-citationTreating diabetes with islet transplantation: lessons from the past decade in Lille.
Vantyghem, M., Defrance, F., Quintin, D., Leroy, C., Raverdi, V., Prévost, G., Caiazzo, R., Kerr-Conte, J., Glowacki, F., Hazzan, M., et al. (2014) · Diabetes & Metabolism · doi:10.1016/j.diabet.2013.10.003 · Cited by 46 · cited 1× · see citing works
“More recently, a 5-year insulin-independence rate of 50% has been documented (3,4).”
Clinical relevance of circulating donor-specific HLA antibodies
Claas, F. H. J. (2010) · Current Opinion in Organ Transplantation · doi:10.1097/mot.0b013e32833b9c38 · Cited by 41 · cited 1× · see citing works
“It has been shown previously (20,21) that withdrawal of immunosuppression, including the potent T cell inhibitor tacrolimus, within 3 years of a failing islet transplant increases anti-donor HLA antibody formation (22).”
Fasano, R. M., Mamcarz, E. K., Adams, S. D., Jerussi, T., Sugimoto, K., Tian, X., Flegel, W. A., & Childs, R. W. (2014) · British Journal of Haematology · doi:10.1111/bjh.12890 · Cited by 32 · see citing works
Self-citationAng, M., Meyer, C., Brendel, M. D., Bretzel, R. G., & Linn, T. (2013) · Diabetologia · doi:10.1007/s00125-013-3120-9 · Cited by 26 · cited 1× · see citing works
“The mechanism is unknown but has been postulated to involve (1) lower insulin doses and (2) increased endogenous glucose production via lactate gluconeogenesis and decreased systemic glucose disposal (18).”
Huurman, V. A. L., van der Torren, C. R., Gillard, P., Hilbrands, R., van der Meer-Prins, E. P. M. W., Duinkerken, G., Gorus, F., Claas, F. H. J., Keymeulen, B., Roelen, D. L., et al. (2012) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2012.04605.x · Cited by 24 · cited 1× · see citing works
“Furthermore, immunosuppression tapering has been inversely related to C-peptide secretion in functional grafts (23).”
Transplanted Human Pancreatic Islets After Long-Term Insulin Independence
Müller, Y. D., Gupta, S., Morel, P., Borot, S., Bettens, F., Truchetet, M., Villard, J., Seebach, J. D., Holmberg, D., Toso, C., et al. (2013) · American Journal of Transplantation · doi:10.1111/ajt.12138 · Cited by 21 · see citing works
Organ procurement organization (OPO), best practices
Bollinger, R. R., Heinrichs, D., Seem, D. L., Rosendale, J. D., Johnson, K., & Metzger, R. A. (2001) · Clinical Transplantation · doi:10.1034/j.1399-0012.2001.00003.x · Cited by 21 · cited 2× · see citing works
“HLA antigens of recipients and donors had been determined at the time of transplantation (Organ Procurement Organizations) (9).”
Immune Antibody Monitoring Predicts Outcome in Islet Transplantation
Shapiro, A. M. J. (2013) · Diabetes · doi:10.2337/db13-0019 · Cited by 11 · cited 1× · see citing works
“More recently, a 5-year insulin-independence rate of 50% has been documented (3,4).”
Hilbrands, R., Gillard, P., van der Torren, C. R., Ling, Z., Verheyden, S. J., Jacobs‐Tulleneers‐Thevissen, D., Roep, B. O., Claas, F. H. J., Demanet, C. J., Gorus, F., et al. (2013) · Transplantation · doi:10.1097/tp.0b013e3182977afc · Cited by 11 · cited 1× · see citing works
“It has been shown previously (20,21) that withdrawal of immunosuppression, including the potent T cell inhibitor tacrolimus, within 3 years of a failing islet transplant increases anti-donor HLA antibody formation (22).”
Renal and vascular benefits of C-peptide: Molecular mechanisms of C-peptide action
Nordquist, L. (2008) · Biologics · doi:10.2147/btt.s3221 · Cited by 10 · see citing works
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Cited by
Sorted by citations
Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes
Hogrebe, N. J., Ishahak, M., & Millman, J. R. (2023) · Cell Stem Cell · doi:10.1016/j.stem.2023.04.002 · Cited by 210 · see citing works
Vantyghem, M.-C., Chetboun, M., Gmyr, V., Jannin, A., Espiard, S., Le Mapihan, K., Raverdy, V., Delalleau, N., Machuron, F., Hubert, T., et al. (2019) · Diabetes Care · doi:10.2337/dc19-0401 · Cited by 105 · see citing works
Pham-Hua, D., Padgett, L. E., Xue, B., Anderson, B. M., Zeiger, M., Barra, J. M., Bethea, M. M., Hunter, C. S., Kozlovskaya, V., Kharlampieva, E., et al. (2017) · Biomaterials · doi:10.1016/j.biomaterials.2017.03.002 · Cited by 84 · see citing works
Lablanche, S., Borot, S., Wojtusciszyn, A., Skaare, K., Penfornis, A., Malvezzi, P., Badet, L., Thivolet, C. H., Morélon, E., Buron, F., et al. (2021) · American Journal of Transplantation · doi:10.1111/ajt.16637 · Cited by 50 · see citing works
Vo, P., Purev, E., West, K. A., McDuffee, E. C., Worthy, T., Cook, L., Hawks, G., Wells, B., Shalabi, R. A., Flegel, W. A., et al. (2020) · British Journal of Haematology · doi:10.1111/bjh.16385 · Cited by 31 · see citing works
“We tested HLA antibodies and antigens, compliant with the regulations under the Clinical Laboratory Improvement Amendments, as described previously (Fasano et al., 2014; Goldspiel et al., 2014; Blau et al., 2015; Sissung et al., 2017).”
MethodSelf-citationIslet Cell Transplantion: Update on Current Clinical Trials
Schuetz, C., & Markmann, J. F. (2016) · Current Transplantation Reports · doi:10.1007/s40472-016-0103-z · Cited by 27 · see citing works
Cell therapies for pancreatic beta-cell replenishment
Okere, B., Lucaccioni, L., Dominici, M., & Iughetti, L. (2016) · Italian Journal of Pediatrics · doi:10.1186/s13052-016-0273-4 · Cited by 25 · see citing works
“Recently, long term follow up of two patients treated with Islet transplant according to the Edmond protocol in 2001 were reported as insulin-independent for two years [5], while the all the 10 patients described by Qui et al.”
BackgroundHe, Y., Xu, Z., Zhou, M., Wu, M., Chen, X., Wang, S., Qiu, K., Cai, Y., Fu, H., Chen, B., et al. (2016) · Journal of Diabetes Research · doi:10.1155/2016/4157313 · Cited by 21 · see citing works
“Whether islet transplantation can regulate the secretion of C-peptide is also a vital issue [37].”
BackgroundQu, Z., Lou, Q., Cooper, D. K. C., Pu, Z., Lu, Y., Chen, J., Ni, Y., Zhan, Y., Chen, J., Li, Z., et al. (2021) · Xenotransplantation · doi:10.1111/xen.12678 · Cited by 12 · see citing works
A critical review on therapeutic approaches of CRISPR-Cas9 in diabetes mellitus
Bora, J., Dey, A., Lyngdoh, A. R., Dhasmana, A., Ranjan, A., Kishore, S., Rustagi, S., Tuli, H., Chauhan, A., Rath, P., et al. (2023) · Naunyn-Schmiedeberg's Archives of Pharmacology · doi:10.1007/s00210-023-02631-1 · Cited by 13 · see citing works
“Only 10% of patients remained insulin-dependent 5 years following islet transplantation, even though transplantation is beneficial in controlling certain T1DM patients (Blau et al. 2015).”
BackgroundCoombe, L., Kadri, A., Martinez, J. F., Tatachar, V., & Gallicano, G. I. (2018) · Europe PMC (PubMed Central) · Cited by 8 · see citing works
Li, Z.-F., Kang, Y., & Niu, Y.-Y. (2026) · Animal Models and Experimental Medicine · doi:10.1002/ame2.70211 · Cited by 1 · see citing works
“103,104 Two principal strategies have been proposed to address this challenge.”
Therapeutic applications of CRISPR-Cas9 in diabetes mellitus: a perspective review
Bora, J., Malik, S., Kishore, S., Rustagi, S., Ahmad, F., Fagoonee, S., Pellicano, R., & Haque, S. (2024) · Minerva Biotechnology and Biomolecular Research · doi:10.23736/s2724-542x.23.02996-6 · Cited by 1 · see citing works
Mycophenolate mofetil/sirolimus/tacrolimus
(2015) · Reactions Weekly · doi:10.1007/s40278-015-10596-y
Lü, J., Kim, H., Zhu, J., Martin, C., Zhang, J., Polavarapu, V., Lacko, L. A., Ariyachet, C., Dattoli, A. A., Liu, T., et al. (2025) · Stem Cell Reports · doi:10.1016/j.stemcr.2025.102708
- Authors
- Blau, J. E., Abegg, M. R., Flegel, W. A., Zhao, X., Harlan, D. M., & Rother, K. I.
- Affiliations
- National Institutes of Health (US)
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Rother, K.I.
- Venue
- American Journal of Transplantation
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 15
- Issue
- 11
- Pages
- 2995-3001
- ISSN
- 1600-6135 (ISSN-L)
- PMC
- PMC5158099
- OpenAlex
- W1855140684
- Cited by
- 15
- References
- 24
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 3 · 2015: 1
- FWCI
- 2.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal of Transplantation (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Intramural Research Program
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- islet transplantation, type 1 diabetes, long-term immunosuppression, C-peptide secretion, beta-cell function, daclizumab, rapamycin, tacrolimus, Edmonton protocol, insulin independence, hypoglycemia, insulin requirement
- MeSH terms
- Adult, Blood Glucose, C-Peptide, Diabetes Mellitus, Type 1, Female, Follow-Up Studies, Humans, Immunosuppression Therapy, Middle Aged, Monitoring, Physiologic, Postoperative Care, Quality of Life, Sampling Studies, Severity of Illness Index, Time Factors, Islets of Langerhans Transplantation, Treatment Outcome, Patient Satisfaction, Risk Assessment
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