Islet transplantation can restore endogenous ␤-cell function to subjects with type 1 diabetes. Sixty-five patients received an islet transplant in Edmonton as of 1 November 2004. Their mean age was 42.9 ؎ 1.2 years, their mean duration of diabetes was 27.1 ؎ 1.3 years, and 57% were women. The main indication was problematic hypoglycemia. Forty-four patients completed the islet transplant as defined by insulin independence, and three further patients received >16,000 islet equivalents (IE)/kg but remained on insulin and are deemed complete. Those who became insulin independent received a total of 799,912 ؎ 30,220 IE (11,910 ؎ 469 IE/kg). Five subjects became insulin independent after one transplant. Fifty-two patients had two transplants, and 11 subjects had three transplants. In the completed patients, 5-year follow-up reveals that the majority S ustained C-peptide production and successful insulin independence after pancreatic islet transplantation in type 1 diabetic patients was reported over 4 years ago by the Edmonton group (1). This reality became possible with the use of newer, more potent immunosuppressive agents, the avoidance of corticosteroids, and high-quality islet preparations, although typically two islet infusions were necessary to attain insulin independence. Over this period, other centers have been able to replicate the initial success of the Edmonton Protocol with further refinements in technique (2-5), and islet transplantation is increasingly being used (6 -8).However, the need for ongoing immunosuppressive therapy and the scarcity of donor islets have precluded the widespread adoption of islet transplantation. The main indications for solitary islet transplantation have been frequent recurrent hypoglycemia or labile glucose values that have defied optimization of medical therapy. An additional hoped for, but unproven, benefit has been stabilization or improvement of diabetes complications with the achievement of stable good glycemic control. Now, 5 years after the first islet transplant was performed with the Edmonton Protocol, we have had the opportunity to review the outcomes in terms of C-peptide secretion, insulin independence, correction of hypoglycemia and lability, acute complications encountered, chronic problems related to immunsuppressive therapy, and some assessment of the effect on diabetes complications. RESEARCH DESIGN AND METHODSAs of 1 November 2004, 65 patients have received islet transplants at the University of Alberta. Four other subjects were transplanted as part of the Immune Tolerance Network trial of islet transplantation and will be reported independently. One further subject was transplanted with a preparation from a pediatric donor that had many trapped islets. This subject had primary nonfunction of the graft, and the data from this patient are not included in this report. At the time of the transplant, the mean age of the 65 patients was 42.9 Ϯ 1.2 years, their duration of diabetes was 27.1 Ϯ 1.3 years, and 57% were women. Their median weight was 68.5 kg (interq...

Clinical pancreatic islet transplantation can be considered one of the safest and least invasive transplant procedures. Remarkable progress has occurred in both the technical aspects of islet cell processing and the outcomes of clinical islet transplantation. With >1,500 patients treated since 2000, this therapeutic strategy has moved from a curiosity to a realistic treatment option for selected patients with type 1 diabetes mellitus (that is, those with hypoglycaemia unawareness, severe hypoglycaemic episodes and glycaemic lability). This Review outlines the techniques required for human islet isolation, in vitro culture before the transplant and clinical islet transplantation, and discusses indications, optimization of recipient immunosuppression and management of adjunctive immunomodulatory and anti-inflammatory strategies. The potential risks, long-term outcomes and advances in treatment after the transplant are also discussed to further move this treatment towards becoming a more widely available option for patients with type 1 diabetes mellitus and eventually a potential cure.

Clinical islet transplantation is gaining acceptance as a potential therapy, particularly for subjects who have labile diabetes or problems with hypoglycemic awareness. The risks of the procedure and long-term outcomes are still not fully known. We have performed 54 islet transplantation procedures on 30 subjects and have detailed follow-up in 17 consecutive Edmonton protocol-treated subjects who attained insulin independence after transplantation of adequate numbers of islets. Subjects were assessed pretransplant and followed prospectively posttransplant for immediate and long-term complications related to the procedure or immunosuppressive therapy. The 17 patients all became insulin independent after a minimum of 9,000 islets/kg were transplanted. Of 15 consecutive patients with at least 1 year of follow-up after the initial transplant, 12 (80%) were insulin independent at 1 year. In 14 subjects who have maintained demonstrable C-peptide secretion, glucose control has been stable and glycemic lability and problems with hypoglycemic reactions have been corrected. After 2 of the 54 procedures, some thrombosis was detected in the portal vein circulation. Five subjects had bleeding related to the percutaneous portal vein access procedures: three required transfusion alone, and in one subject, who had a partial thrombosis of the portal vein, an expanding intrahepatic and subscapular hemorrhage occurred while on anticoagulation, requiring transfusion and surgery. Elevated liver function test results were found in 46% of subjects but resolved in all. Complications related to the therapy have been hypercholesterolemia requiring statin therapy in 65%; a rise in creatinine in two patients, both of whom had preexisting renal disease; a rise in protein in four, all of whom had preexisting proteinuria; and antihypertensive therapy increased or started in 53%. Three of the 17 patients have required retinal laser photocoagulation. There have been no cases of posttransplant lymphoproliferative disorder or cytomegalovirus infection, and no deaths. The acute insulin response to arginine correlated better with transplanted islet mass than acute insulin response to glucose (AIR g ) and area under the curve for insulin (AUC i ), but the AIR g and AUC i were more closely related to glycemic control. The AUC i directly posttransplant was lower in those who eventually became C-peptide deficient. Our results, with a maximum follow-up of 34 months, indicate that prolonged insulin independence can be achieved after islet transplantation. There are some risks associated acutely with the procedure, and hypercholesterolemia and hypertension are treatable concerns on longer-term follow-up. All patients with persisting C-peptide secretion have had a resolution of both glycemic lability and problems with hypoglycemic reactions. Apart from the rise in serum creatinine in two subjects, no serious consequences of immunosuppressive therapy have been encountered. Islet transplantation is a reasonable option in those with severe problems with glyce...

No abstract

Currently, the major indications for solitary islet transplantation are recurrent severe hypoglycemia and labile glucose control. Quantifying these problems remains subjective. We have developed a scoring system for both hypoglycemia and glycemic lability, established normative data, and used them in patients who have undergone islet transplantation. A composite hypoglycemic score (HYPO score) was devised based on the frequency, severity, and degree of unawareness of the hypoglycemia. In addition, using 4 weeks of glucose records, a lability index (LI) was calculated based on the change in glucose levels over time and compared with a clinical assessment of glycemic lability. A mean amplitude of glycemic excursions (MAGE) was also calculated based on 2 consecutive days of seven readings each day. These scores were determined in 100 randomly selected subjects with type 1 diabetes from our general clinic to serve as a control group and in patients before and after islet transplantation. The mean age of the control diabetic subjects was 38.4 ؎ 1.3 years (؎SE), with a duration of diabetes of 21.5 ؎ 1.1 years. The median HYPO score in the control subjects was 143 (25th to 75th interquartile range: 46 -423). The LI in the diabetic control subjects was 223 (25th to 75th interquartile range: 130 -329 mmol/l 2 /h ⅐ week ؊1 ). The LI correlated much more closely than the MAGE with the clinical assessment of lability. A HYPO score of >1,047 (90th percentile) or an LI >433 mmol/l 2 / h ⅐ week ؊1 (90th percentile) indicated serious problems with hypoglycemia or glycemic lability, respectively. The islet transplant patients (n ‫؍‬ 51) were 42.1 ؎ 1.4 years old, with a duration of diabetes of 25.7 ؎ 1.4 years. Islet transplant patients had a mean HYPO score of 1,234 ؎ 184 pretransplant, which was significantly higher than that of the control subjects (P < 0.001), which became negligible posttransplantation with the elimination of hypoglycemia. The median LI pretransplant was 497 mmol/l 2 /h ⅐ week ؊1 (25th to 75th interquartile range: 330 -692), significantly higher than that of control subjects (P < 0.001), and fell to 40 (25th to 75th interquartile range: 14 -83) within a month after the final transplant. In those who had lost graft function, the LI rose again. The HYPO score and LI provide measures of the extent of problems with hypoglycemia and glycemic lability, respectively, complement the clinical assessment of the problems with glucose control before islet transplantation, and will allow comparison of selection of subjects for transplants between centers. Diabetes 53:955-962, 2004 P atients with type 1 diabetes have to balance the risks of long-term hyperglycemia and its consequences versus the acute risk of hypoglycemia. The Diabetes Control and Complications Trial has confirmed that achieving strict glycemic control is worthwhile but comes with the price of a threefold increased risk of severe hypoglycemia (1). In addition to long-term consequences (2), such hypoglycemia comes with costs in the short term as evidenced...