Islet Transplantation in Seven Patients with Type 1 Diabetes Mellitus Using a Glucocorticoid-Free Immunosuppressive Regimen
A.M. James Shapiro, M.B., B.S., Jonathan R.T. Lakey, Ph.D., Edmond A. Ryan, M.D., Gregory S. Korbutt, Ph.D., Ellen Toth, M.D., Garth L. Warnock, M.D., Norman M. Kneteman, M.D., and Ray V. Rajotte, Ph.D.
Background Registry data on patients with type 1 diabetes mellituswho undergo pancreatic islet transplantation indicate that only8 percent are free of the need for insulin therapy at one year.
Methods Seven consecutive patients with type 1 diabetes anda history of severe hypoglycemia and metabolic instability underwentislet transplantation in conjunction with a glucocorticoid-freeimmunosuppressive regimen consisting of sirolimus, tacrolimus,and daclizumab. Islets were isolated by ductal perfusion withcold, purified collagenase, digested and purified in xenoprotein-freemedium, and transplanted immediately by means of a percutaneoustranshepatic portal embolization.
Results All seven patients quickly attained sustained insulinindependence after transplantation of a mean (±SD) isletmass of 11,547±1604 islet equivalents per kilogram ofbody weight (median follow-up, 11.9 months; range, 4.4 to 14.9).All recipients required islets from two donor pancreases, andone required a third transplant from two donors to achieve sustainedinsulin independence. The mean glycosylated hemoglobin valueswere normal after transplantation in all recipients. The meanamplitude of glycemic excursions (a measure of fluctuationsin blood glucose concentrations) was significantly decreasedafter the attainment of insulin independence (from 198±32mg per deciliter [11.1±1.8 mmol per liter] before transplantationto 119±37 mg per deciliter [6.7±2.1 mmol per liter]after the first transplantation and 51±30 mg per deciliter[2.8±1.7 mmol per liter] after the attainment of insulinindependence; P<0.001). There were no further episodes ofhypoglycemic coma. Complications were minor, and there wereno significant increases in lipid concentrations during follow-up.
Conclusions Our observations in patients with type 1 diabetesindicate that islet transplantation can result in insulin independencewith excellent metabolic control when glucocorticoid-free immunosuppressionis combined with the infusion of an adequate islet mass.
Source Information
From the SurgicalMedical Research Institute and the Department of Surgery (A.M.J.S., J.R.T.L., G.S.K., G.L.W., N.M.K., R.V.R.) and the Department of Medicine (E.A.R., E.T.), University of Alberta, Edmonton, Alta., Canada.
Address reprint requests to Dr. Shapiro at 2D4.37 Department of Surgery, University of Alberta Hospitals, Mackenzie Health Sciences Center, 8440 112 St., Edmonton, AB T6G 2B7, Canada, or at amjs{at}powersurfr.com.
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Zhang, N., Su, D., Qu, S., Tse, T., Bottino, R., Balamurugan, A.N., Xu, J., Bromberg, J. S., Dong, H. H.
(2006). Sirolimus Is Associated With Reduced Islet Engraftment and Impaired {beta}-Cell Function. Diabetes
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Quesada, I., Todorova, M. G., Alonso-Magdalena, P., Beltra, M., Carneiro, E. M., Martin, F., Nadal, A., Soria, B.
(2006). Glucose Induces Opposite Intracellular Ca2+ Concentration Oscillatory Patterns in Identified {alpha}- and {beta}-Cells Within Intact Human Islets of Langerhans. Diabetes
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Gillespie, K. M.
(2006). Type 1 diabetes: pathogenesis and prevention.. CMAJ
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Emamaullee, J. A., Shapiro, A.M. J.
(2006). Interventional Strategies to Prevent {beta}-Cell Apoptosis in Islet Transplantation.. Diabetes
55: 1907-1914
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Cozar-Castellano, I., Fiaschi-Taesch, N., Bigatel, T. A., Takane, K. K., Garcia-Ocana, A., Vasavada, R., Stewart, A. F.
(2006). Molecular Control of Cell Cycle Progression in the Pancreatic {beta}-Cell. Endocr. Rev.
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Mas, A., Montane, J., Anguela, X. M., Munoz, S., Douar, A. M., Riu, E., Otaegui, P., Bosch, F.
(2006). Reversal of Type 1 Diabetes by Engineering a Glucose Sensor in Skeletal Muscle. Diabetes
55: 1546-1553
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Ihm, S.-H., Matsumoto, I., Sawada, T., Nakano, M., Zhang, H. J., Ansite, J. D., Sutherland, D. E.R., Hering, B. J.
(2006). Effect of donor age on function of isolated human islets.. Diabetes
55: 1361-1368
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MacGregor, R. R., Williams, S. J., Tong, P. Y., Kover, K., Moore, W. V., Stehno-Bittel, L.
(2006). Small rat islets are superior to large islets in in vitro function and in transplantation outcomes. Am. J. Physiol. Endocrinol. Metab.
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Huurman, V. A.L., Kalpoe, J. S., van de Linde, P., Vaessen, N., Ringers, J., Kroes, A. C.M., Roep, B. O., De Fijter, J. W.
(2006). Choice of Antibody Immunotherapy Influences Cytomegalovirus Viremia in Simultaneous Pancreas-Kidney Transplant Recipients. Diabetes Care
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Lu, Y., Wang, Z., Zhu, M.
(2006). Human bone marrow mesenchymal stem cells transfected with human insulin genes can secrete insulin stably.. Annals of Clinical & Laboratory Science
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Dombrowski, F., Mathieu, C., Evert, M.
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Wang, H., Lee, S. S., Dell'Agnello, C., Tchipashvili, V., D'Avilla, J., Czismadia, E., Chin, B. Y., Bach, F. H.
(2006). Bilirubin Can Induce Tolerance to Islet Allografts. Endocrinology
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Thornley, T. B., Brehm, M. A., Markees, T. G., Shultz, L. D., Mordes, J. P., Welsh, R. M., Rossini, A. A., Greiner, D. L.
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Choi, Y. H., Lee, J. H., Yuk, S. H., Suh, S. H., Yoon, K.-H.
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[Abstract]
Toyofuku, A., Yasunami, Y., Nabeyama, K., Nakano, M., Satoh, M., Matsuoka, N., Ono, J., Nakayama, T., Taniguchi, M., Tanaka, M., Ikeda, S.
(2006). Natural Killer T-Cells Participate in Rejection of Islet Allografts in the Liver of Mice. Diabetes
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Battaglia, M., Stabilini, A., Draghici, E., Gregori, S., Mocchetti, C., Bonifacio, E., Roncarolo, M.-G.
(2006). Rapamycin and Interleukin-10 Treatment Induces T Regulatory Type 1 Cells That Mediate Antigen-Specific Transplantation Tolerance. Diabetes
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