Insulin independence following isolated islet transplantation and single islet infusions

Abstract

Objective: To restore islet function in patients whose labile diabetes subjected them to frequent dangerous episodes of hypoglycemic unawareness, and to determine whether multiple transplants are always required to achieve insulin independence.

Summary background data: The recent report by the Edmonton group documenting restoration of insulin independence by islet transplantation in seven consecutive patients with type 1 diabetes differed from previous worldwide experience of only sporadic success. In the Edmonton patients, the transplanted islet mass critical for success was approximately more than 9,000 IEq/kg of recipient body weight and required two or three separate transplants of islets isolated from two to four cadaveric donors. Whether the success of the Edmonton group can be recapitulated by others, and whether repeated transplants using multiple donors will be a universal requirement for success have not been reported.

Methods: The authors report their treatment with islet transplantation of nine patients whose labile type 1 diabetes was characterized by frequent episodes of dangerous hypoglycemia.

Results: In each of the seven patients who have completed the treatment protocol (i.e., one or if necessary a second islet transplant), insulin independence has been achieved. In five of the seven patients only a single infusion of islets was required. To date, only one recipient has subsequently lost graft function, after an initially successful transplant. This patient suffered recurrent hyperglycemia 9 months after the transplant.

Conclusions: This report confirms the efficacy of the Edmonton immunosuppressive regimen and indicates that insulin independence can often be achieved by a single transplant of sufficient islet mass.

Figure 1. The number of IE’s isolated over time for 144 separate isolations is shown as a moving average of the last 10 preparations. The initiation of our center, the construction of a GMP isolation facility, the timing of IRB and IND approval, and the first clinical transplant are marked. The black trend line reveals improvement in yield with greater experience.

Figure 2. Shown is the cold ischemia time, from cross-clamp in the donor to initiation of the isolation procedure (blue bar) for the 15 isolations that have been transplanted. Red bars indicate the total ischemia time from cross-clamp to infusion of the preparation in the recipient. Three preparations (10, 12, and 14) were transiently maintained in vitro while a second isolation was performed. Total in vitro culture was 3, 5.5, and 9 hours, respectively.

Figure 3. Daily fasting glucose measurements and daily insulin requirements are shown for the patient who lost the majority of graft function at 9 months posttransplant. The need for reinstitution of insulin was heralded by a long period of gradually increasing fasting blood sugar levels.

Figure 4. Mean serum HgbA1c levels (%) are shown for patients who gained insulin independence before (n = 4) and 3 (n = 4), 6 (n = 4), 9 (n = 3), and 12 months (n = 2) posttransplant.

Figure 5. The percentage of patients experiencing various complications posttransplant. Leukopenia was defined as WBC less than 4.0. Anemia was defined as hemoglobin less than 11.8. Thrombocytopenia was defined as a platelet count below 150. Lipid elevations were defined as cholesterol more than 200. Only two patients required pharmacotherapy for persistent cholesterol elevation (resolved spontaneously in two patients, and immunosuppression was terminated in another).