International Trial of the Edmonton Protocol for Islet Transplantation
A.M. James Shapiro, M.D., Ph.D., Camillo Ricordi, M.D., Bernhard J. Hering, M.D., Hugh Auchincloss, M.D., Robert Lindblad, M.D., R. Paul Robertson, M.D., Antonio Secchi, M.D., Mathias D. Brendel, M.D., Thierry Berney, M.D., Daniel C. Brennan, M.D., Enrico Cagliero, M.D., Rodolfo Alejandro, M.D., Edmond A. Ryan, M.D., Barbara DiMercurio, R.N., Philippe Morel, M.D., Kenneth S. Polonsky, M.D., Jo-Anna Reems, Ph.D., Reinhard G. Bretzel, M.D., Federico Bertuzzi, M.D., Tatiana Froud, M.D., Raja Kandaswamy, M.D., David E.R. Sutherland, M.D., Ph.D., George Eisenbarth, M.D., Ph.D., Miriam Segal, Ph.D., Jutta Preiksaitis, M.D., Gregory S. Korbutt, Ph.D., Franca B. Barton, M.S., Lisa Viviano, R.N., Vicki Seyfert-Margolis, Ph.D., Jeffrey Bluestone, Ph.D., and Jonathan R.T. Lakey, Ph.D.
Background Islet transplantation offers the potential to improveglycemic control in a subgroup of patients with type 1 diabetesmellitus who are disabled by refractory hypoglycemia. We conductedan international, multicenter trial to explore the feasibilityand reproducibility of islet transplantation with the use ofa single common protocol (the Edmonton protocol).
Methods We enrolled 36 subjects with type 1 diabetes mellitus,who underwent islet transplantation at nine international sites.Islets were prepared from pancreases of deceased donors andwere transplanted within 2 hours after purification, withoutculture. The primary end point was defined as insulin independencewith adequate glycemic control 1 year after the final transplantation.
Results Of the 36 subjects, 16 (44%) met the primary end point,10 (28%) had partial function, and 10 (28%) had complete graftloss 1 year after the final transplantation. A total of 21 subjects(58%) attained insulin independence with good glycemic controlat any point throughout the trial. Of these subjects, 16 (76%)required insulin again at 2 years; 5 of the 16 subjects whoreached the primary end point (31%) remained insulin-independentat 2 years.
Conclusions Islet transplantation with the use of the Edmontonprotocol can successfully restore long-term endogenous insulinproduction and glycemic stability in subjects with type 1 diabetesmellitus and unstable control, but insulin independence is usuallynot sustainable. Persistent islet function even without insulinindependence provides both protection from severe hypoglycemiaand improved levels of glycated hemoglobin. (ClinicalTrials.govnumber, NCT00014911
[ClinicalTrials.gov]
.)
Source Information
From the University of Alberta, Edmonton, AB, Canada (A.M.J.S., E.A.R., J.P., G.S.K., J.R.T.L.); the University of Miami, Miami (C.R., R.A., T.F.); the University of Minnesota, Minneapolis (B.J.H., R.K., D.E.R.S., M.S.); Harvard Medical School, Boston (H.A., E.C.); the Emmes Corporation, Rockville, MD (R.L., F.B.B.); the University of Washington, Seattle (R.P.R., J.-A.R.); San Raffaele Scientific Institute, Milan (A.S., F.B.); Justus-Liebig University, Giessen, Germany (M.D.B., R.G.B.); the University of Geneva, Geneva (T.B., P.M.); Washington University, St. Louis (D.C.B., K.S.P.); the National Institute of Allergy and Infectious Diseases, Rockville, MD (B.D., L.V.); the Barbara Davis Center, University of Colorado, Boulder (G.E.); and the Immune Tolerance Network, San Francisco, and Bethesda, MD (H.A., V.S.-M., J.B.).
Address reprint requests to Dr. Shapiro at Clinical Islet Transplant Program, University of Alberta, 2000 College Plaza, 8215 112th St., Edmonton, AB T6G 2C8, Canada, or at shapiro{at}islet.ca.
Islet Transplantation
Meyer C., Vaksman A., Thompson D. M., Fung M. A., Warnock G. L., Shapiro A.M. J., Ricordi C., Hering B. J.
Extract |
Full Text |
PDF
N Engl J Med 2007;
356:963-965, Mar 1, 2007.
Correspondence
This article has been cited by other articles:
Tschen, S.-I., Dhawan, S., Gurlo, T., Bhushan, A.
(2009). Age-Dependent Decline in {beta}-Cell Proliferation Restricts the Capacity of {beta}-Cell Regeneration in Mice. Diabetes
58: 1312-1320
[Abstract][Full Text]
Kinkel, M. D., Sefton, E. M., Kikuchi, Y., Mizoguchi, T., Ward, A. B., Prince, V. E.
(2009). Cyp26 enzymes function in endoderm to regulate pancreatic field size. Proc. Natl. Acad. Sci. USA
106: 7864-7869
[Abstract][Full Text]
Guo, T., Hebrok, M.
(2009). Stem Cells to Pancreatic {beta}-Cells: New Sources for Diabetes Cell Therapy. Endocr. Rev.
30: 214-227
[Abstract][Full Text]
Kaddis, J. S., Olack, B. J., Sowinski, J., Cravens, J., Contreras, J. L., Niland, J. C.
(2009). Human Pancreatic Islets and Diabetes Research. JAMA
301: 1580-1587
[Abstract][Full Text]
Saudek, C. D.
(2009). Can Diabetes Be Cured?: Potential Biological and Mechanical Approaches. JAMA
301: 1588-1590
[Full Text]
Sancho-Bru, P, Najimi, M, Caruso, M, Pauwelyn, K, Cantz, T, Forbes, S, Roskams, T, Ott, M, Gehling, U, Sokal, E, Verfaillie, C M, Muraca, M
(2009). Stem and progenitor cells for liver repopulation: can we standardise the process from bench to bedside?. Gut
58: 594-603
[Abstract][Full Text]
Bottino, R., Criscimanna, A., Casu, A., He, J., Van der Windt, D. J., Rudert, W. A., Giordano, C., Trucco, M.
(2009). Recovery of Endogenous {beta}-Cell Function in Nonhuman Primates After Chemical Diabetes Induction and Islet Transplantation. Diabetes
58: 442-447
[Abstract][Full Text]
Heller, S. R.
(2008). Minimizing Hypoglycemia While Maintaining Glycemic Control in Diabetes. Diabetes
57: 3177-3183
[Full Text]
Imai, J., Katagiri, H., Yamada, T., Ishigaki, Y., Suzuki, T., Kudo, H., Uno, K., Hasegawa, Y., Gao, J., Kaneko, K., Ishihara, H., Niijima, A., Nakazato, M., Asano, T., Minokoshi, Y., Oka, Y.
(2008). Regulation of Pancreatic {beta} Cell Mass by Neuronal Signals from the Liver. Science
322: 1250-1254
[Abstract][Full Text]
Tateishi, K., He, J., Taranova, O., Liang, G., D'Alessio, A. C., Zhang, Y.
(2008). Generation of Insulin-secreting Islet-like Clusters from Human Skin Fibroblasts. J. Biol. Chem.
283: 31601-31607
[Abstract][Full Text]
Wei, L. H., Olafsen, T., Radu, C., Hildebrandt, I. J., McCoy, M. R., Phelps, M. E., Meares, C., Wu, A. M., Czernin, J., Weber, W. A.
(2008). Engineered Antibody Fragments with Infinite Affinity as Reporter Genes for PET Imaging. JNM
49: 1828-1835
[Abstract][Full Text]
Ackermann Misfeldt, A., Costa, R. H., Gannon, M.
(2008). {beta}-Cell Proliferation, but Not Neogenesis, Following 60% Partial Pancreatectomy Is Impaired in the Absence of FoxM1. Diabetes
57: 3069-3077
[Abstract][Full Text]
Lewis, E. C., Mizrahi, M., Toledano, M., DeFelice, N., Wright, J. L., Churg, A., Shapiro, L., Dinarello, C. A.
(2008). {alpha}1-Antitrypsin monotherapy induces immune tolerance during islet allograft transplantation in mice. Proc. Natl. Acad. Sci. USA
105: 16236-16241
[Abstract][Full Text]
Luo, X., Pothoven, K. L., McCarthy, D., DeGutes, M., Martin, A., Getts, D. R., Xia, G., He, J., Zhang, X., Kaufman, D. B., Miller, S. D.
(2008). ECDI-fixed allogeneic splenocytes induce donor-specific tolerance for long-term survival of islet transplants via two distinct mechanisms. Proc. Natl. Acad. Sci. USA
105: 14527-14532
[Abstract][Full Text]
Feller, J. M., Simpson, A. M., Nelson, M., Swan, M. A., O'Connell, P. J., Hawthorne, W. J., Tao, C., O'Brien, B. A.
(2008). Growth-Promoting Effect of Rh(D) Antibody on Human Pancreatic Islet Cells. J. Clin. Endocrinol. Metab.
93: 3560-3567
[Abstract][Full Text]
Merani, S., Truong, W., Emamaullee, J. A., Toso, C., Knudsen, L. B., Shapiro, A. M. J.
(2008). Liraglutide, a Long-Acting Human Glucagon-Like Peptide 1 Analog, Improves Glucose Homeostasis in Marginal Mass Islet Transplantation in Mice. Endocrinology
149: 4322-4328
[Abstract][Full Text]
Westermark, G. T., Westermark, P., Berne, C., Korsgren, O., the Nordic Network for Clinical Islet Transplantat,
(2008). Widespread Amyloid Deposition in Transplanted Human Pancreatic Islets. NEJM
359: 977-979
[Full Text]
Huang, X., Moore, D. J., Ketchum, R. J., Nunemaker, C. S., Kovatchev, B., McCall, A. L., Brayman, K. L.
(2008). Resolving the Conundrum of Islet Transplantation by Linking Metabolic Dysregulation, Inflammation, and Immune Regulation. Endocr. Rev.
29: 603-630
[Abstract][Full Text]
Oliver-Krasinski, J. M., Stoffers, D. A.
(2008). On the origin of the {beta} cell. Genes Dev.
22: 1998-2021
[Abstract][Full Text]
Emamaullee, J. A., Davis, J., Pawlick, R., Toso, C., Merani, S., Cai, S.-X., Tseng, B., Shapiro, A.M. J.
(2008). The Caspase Selective Inhibitor EP1013 Augments Human Islet Graft Function and Longevity in Marginal Mass Islet Transplantation in Mice. Diabetes
57: 1556-1566
[Abstract][Full Text]
Zhou, H., Zhang, T., Bogdani, M., Oseid, E., Parazzoli, S., Vantyghem, M.-C., Harmon, J., Slucca, M., Robertson, R. P.
(2008). Intrahepatic Glucose Flux as a Mechanism for Defective Intrahepatic Islet {alpha}-Cell Response to Hypoglycemia. Diabetes
57: 1567-1574
[Abstract][Full Text]
Cure, P., Pileggi, A., Alejandro, R., Ahmad, S. R., Swann, J., Bloomgren, G., Braun, D., Kolterman, O.
(2008). Exenatide and Rare Adverse Events. NEJM
358: 1969-1972
[Full Text]
Fraenkel, M., Ketzinel-Gilad, M., Ariav, Y., Pappo, O., Karaca, M., Castel, J., Berthault, M.-F., Magnan, C., Cerasi, E., Kaiser, N., Leibowitz, G.
(2008). mTOR Inhibition by Rapamycin Prevents {beta}-Cell Adaptation to Hyperglycemia and Exacerbates the Metabolic State in Type 2 Diabetes. Diabetes
57: 945-957
[Abstract][Full Text]
Fousteri, G., von Herrath, M.
(2008). First-Trimester Human Fetal Pancreas Transplantation for Type 1 Diabetes Treatment: An Alternative Approach for Achieving Long-Term Graft Survival?. Diabetes
57: 525-526
[Full Text]
Hadjiyanni, I., Baggio, L. L., Poussier, P., Drucker, D. J.
(2008). Exendin-4 Modulates Diabetes Onset in Nonobese Diabetic Mice. Endocrinology
149: 1338-1349
[Abstract][Full Text]
Brun, T., He, K. H. H., Lupi, R., Boehm, B., Wojtusciszyn, A., Sauter, N., Donath, M., Marchetti, P., Maedler, K., Gauthier, B. R.
(2008). The diabetes-linked transcription factor Pax4 is expressed in human pancreatic islets and is activated by mitogens and GLP-1. Hum Mol Genet
17: 478-489
[Abstract][Full Text]
Brun, T., Gauthier, B. R
(2008). A focus on the role of Pax4 in mature pancreatic islet {beta}-cell expansion and survival in health and disease. J Mol Endocrinol
40: 37-45
[Abstract][Full Text]
Zhao, M., Amiel, S. A, Christie, M. R, Muiesan, P., Srinivasan, P., Littlejohn, W., Rela, M., Arno, M., Heaton, N., Huang, G. C.
(2007). Evidence for the presence of stem cell-like progenitor cells in human adult pancreas. J Endocrinol
195: 407-414
[Abstract][Full Text]
Davani, B., Ikonomou, L., Raaka, B. M., Geras-Raaka, E., Morton, R. A., Marcus-Samuels, B., Gershengorn, M. C.
(2007). Human Islet-Derived Precursor Cells Are Mesenchymal Stromal Cells That Differentiate and Mature to Hormone-Expressing Cells In Vivo. Stem Cells
25: 3215-3222
[Abstract][Full Text]
Mutskov, V., Raaka, B. M., Felsenfeld, G., Gershengorn, M. C.
(2007). The Human Insulin Gene Displays Transcriptionally Active Epigenetic Marks in Islet-Derived Mesenchymal Precursor Cells in the Absence of Insulin Expression. Stem Cells
25: 3223-3233
[Abstract][Full Text]
Schlechte, J. A.
(2007). Update in Endocrinology. ANN INTERN MED
147: 563-572
[Full Text]
Onaca, N., Naziruddin, B., Matsumoto, S., Noguchi, H., Klintmalm, G. B., Levy, M. F.
(2007). Pancreatic Islet Cell Transplantation: Update and New Developments. Nutr Clin Pract
22: 485-493
[Abstract][Full Text]
Lee, Y., Ravazzola, M., Park, B.-H., Bashmakov, Y. K., Orci, L., Unger, R. H.
(2007). Metabolic Mechanisms of Failure of Intraportally Transplanted Pancreatic {beta}-Cells in Rats: Role of Lipotoxicity and Prevention by Leptin. Diabetes
56: 2295-2301
[Abstract][Full Text]
King, A. J.F., Fernandes, J. R., Hollister-Lock, J., Nienaber, C. E., Bonner-Weir, S., Weir, G. C.
(2007). Normal Relationship of {beta}- and Non {beta}-Cells Not Needed for Successful Islet Transplantation. Diabetes
56: 2312-2318
[Abstract][Full Text]
Su, D., Zhang, N., He, J., Qu, S., Slusher, S., Bottino, R., Bertera, S., Bromberg, J., Dong, H. H.
(2007). Angiopoietin-1 Production in Islets Improves Islet Engraftment and Protects Islets From Cytokine-Induced Apoptosis. Diabetes
56: 2274-2283
[Abstract][Full Text]
Cabric, S., Sanchez, J., Lundgren, T., Foss, A., Felldin, M., Kallen, R., Salmela, K., Tibell, A., Tufveson, G., Larsson, R., Korsgren, O., Nilsson, B.
(2007). Islet Surface Heparinization Prevents the Instant Blood-Mediated Inflammatory Reaction in Islet Transplantation. Diabetes
56: 2008-2015
[Abstract][Full Text]
Jiang, J., Au, M., Lu, K., Eshpeter, A., Korbutt, G., Fisk, G., Majumdar, A. S.
(2007). Generation of Insulin-Producing Islet-Like Clusters from Human Embryonic Stem Cells. Stem Cells
25: 1940-1953
[Abstract][Full Text]
Eisenbarth, G. S.
(2007). Update in Type 1 Diabetes. J. Clin. Endocrinol. Metab.
92: 2403-2407
[Abstract][Full Text]
Rickels, M. R., Kamoun, M., Kearns, J., Markmann, J. F., Naji, A.
(2007). Evidence for Allograft Rejection in an Islet Transplant Recipient and Effect on {beta}-Cell Secretory Capacity. J. Clin. Endocrinol. Metab.
92: 2410-2414
[Abstract][Full Text]
Eich, T., Eriksson, O., Lundgren, T., the Nordic Network for Clinical Islet Transplantat,
(2007). Visualization of Early Engraftment in Clinical Islet Transplantation by Positron-Emission Tomography. NEJM
356: 2754-2755
[Full Text]
Paget, M., Murray, H., Bailey, C. J, Downing, R.
(2007). Human islet isolation: semi-automated and manual methods. Diabetes and Vascular Disease Research
4: 7-12
[Abstract]
Meyer, C., Vaksman, A., Thompson, D. M., Fung, M. A., Warnock, G. L., Shapiro, A.M. J., Ricordi, C., Hering, B. J.
(2007). Islet transplantation.. NEJM
356: 963-964
[Full Text]
Rickels, M. R., Schutta, M. H., Mueller, R., Kapoor, S., Markmann, J. F., Naji, A., Teff, K. L.
(2007). Glycemic Thresholds for Activation of Counterregulatory Hormone and Symptom Responses in Islet Transplant Recipients. J. Clin. Endocrinol. Metab.
92: 873-879
[Abstract][Full Text]
Bertuzzi, F., Ricordi, C.
(2007). Prediction of Clinical Outcome in Islet Allotransplantation. Diabetes Care
30: 410-417
[Full Text]
Thomas, D. A., Stauffer, C., Zhao, K., Yang, H., Sharma, V. K., Szeto, H. H., Suthanthiran, M.
(2007). Mitochondrial Targeting with Antioxidant Peptide SS-31 Prevents Mitochondrial Depolarization, Reduces Islet Cell Apoptosis, Increases Islet Cell Yield, and Improves Posttransplantation Function. J. Am. Soc. Nephrol.
18: 213-222
[Abstract][Full Text]
(2006). Can We Cure Diabetes?. JWatch Pediatrics
2006: 1-1
[Full Text]
Tonks, A.
(2006). What's new in the other general journals. BMJ
333: 744-745
[Full Text]
Bromberg, J. S., LeRoith, D.
(2006). Diabetes cure--is the glass half full?. NEJM
355: 1372-1374
[Full Text]
Previous
