implantation was intraportal; iii) purity was >50%; and iv) anti-T cell induction therapy was used. The percent of patients that became insulin independent (>1 week) after receiving islet transplants fulfilling these "state of the art" criteria was closer to 35%.

Although the majority of patients with type 1 diabetes still failed to achieve insulin independence following "state of the art" islet allotransplantation procedures, in 80% of those cases C-peptide levels were above 1 ng/ml for over 1 month. Therefore, insulin dependence in the face of C-peptide secretion indicated that variables other than the mass of transplanted islets were critical factors affecting outcome. It became realized that an important variable that was different between the auto- and allotransplant settings, besides underlying autoimmunity, that accounted for the inferior results was the differential requirement for systemic immunosuppression. Some of these agents, corticosteroids in particular, impart a deleterious effect on the functional efficiency of islet grafts.23 Application of a new combination of maintenance agents without corticosteroids involving tacrolimus and sirolimus24,25 combined with an IL-2 receptor antagonist induction agent, and repeated infusions of purified islets, resulted in a dramatic breakthrough.

The clinical trial results reported by the University of Alberta group in Edmonton in July 2000 marked a turning point in the history of islet transplantation.26 Shapiro et al. transplanted an adequate mass of islets by performing sequential transplants of islets from 2 to 4 donors, reduced the metabolic demand placed on transplanted islets by avoiding glucocorticoids and high-dose calcineurin inhibitors, and prevented immunologic graft loss by administering the synergistic immunosuppressants sirolimus and tacrolimus. The Edmonton protocol included all of the "state-of-the-art" techniques associated with success, while also addressing many of the previously mentioned obstacles. The outcome resulted in restored normoglycemia and insulin independence in 7 of 7 type 1 diabetic patients who previously had labile diabetes and hypoglycemia unawareness.26 Recent publications of the Edmonton experience include 24 patients. The insulin independence rates are 87.5% at 1 year and 70% at 2 years.27 More detailed information on clinical outcomes and metabolic test results with the Edmonton protocol was published in 2 follow-up reports.28,29 The total experience through March 2003 exceeds 50 recipients.

Importantly, the validity of the Edmonton results has been strengthened by confirmatory findings reported by additional institutions, including diabetes reversal after islet transplants in patients with established kidney grafts30 and after transplants of islets prepared from a non-heart-beating donor.31 A consortium of islet transplant centers from North America and Europe, supported by the Immune Tolerance Network of the NIH, are also showing the reproducibility of the Edmonton results.

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Delicious Diabetic Recipes

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