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Successful Islet Transplantation Continued Insulin Reserve Provides Long-Term Glycemic Control Edmond A. Ryan,1 Jonathan R.T. Lakey,2,3 Breay W. Paty,1 Sharleen Imes,4 Gregory S. Korbutt,3 Norman M. Kneteman,2 David Bigam,2 Ray V. Rajotte,3 and A.M. James Shapiro2 Clinical islet transplantation is gaining acceptance as a apy in 65%; a rise in creatinine in two patients, both of potential therapy, particularly for subjects who have whom had preexisting renal disease; a rise in protein in labile diabetes or problems with hypoglycemic aware- four, all of whom had preexisting proteinuria; and anti- ness. The risks of the procedure and long-term out- hypertensive therapy increased or started in 53%. Three comes are still not fully known. We have performed 54 of the 17 patients have required retinal laser photoco- islet transplantation procedures on 30 subjects and agulation. There have been no cases of posttransplant have detailed follow-up in 17 consecutive Edmonton lymphoproliferative disorder or cytomegalovirus infec- protocol–treated subjects who attained insulin indepen- tion, and no deaths. The acute insulin response to dence after transplantation of adequate numbers of arginine correlated better with transplanted islet mass islets. Subjects were assessed pretransplant and fol- than acute insulin response to glucose (AIRg) and area lowed prospectively posttransplant for immediate and under the curve for insulin (AUCi), but the AIRg and long-term complications related to the procedure or AUCi were more closely related to glycemic control. The immunosuppressive therapy. The 17 patients all became AUCi directly posttransplant was lower in those who insulin independent after a minimum of 9,000 islets/kg eventually became C-peptide deficient. Our results, were transplanted. Of 15 consecutive patients with at with a maximum follow-up of 34 months, indicate that least 1 year of follow-up after the initial transplant, 12 prolonged insulin independence can be achieved after (80%) were insulin independent at 1 year. In 14 sub- islet transplantation. There are some risks associated jects who have maintained demonstrable C-peptide se- acutely with the procedure, and hypercholesterolemia cretion, glucose control has been stable and glycemic and hypertension are treatable concerns on longer-term lability and problems with hypoglycemic reactions have follow-up. All patients with persisting C-peptide secre- been corrected. After 2 of the 54 procedures, some tion have had a resolution of both glycemic lability and thrombosis was detected in the portal vein circulation. problems with hypoglycemic reactions. Apart from the Five subjects had bleeding related to the percutaneous rise in serum creatinine in two subjects, no serious portal vein access procedures: three required transfu- consequences of immunosuppressive therapy have been sion alone, and in one subject, who had a partial throm- encountered. Islet transplantation is a reasonable op- bosis of the portal vein, an expanding intrahepatic and tion in those with severe problems with glycemic lability subscapular hemorrhage occurred while on anticoagula- or hypoglycemia. Diabetes 51:2148–2157, 2002 tion, 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 ther- nterest in islet transplantation has increased enor- mously, because of the improved success rates with newer immunosuppressive regimens and islet prep- From the 1Department of Medicine, Clinical Islet Transplant Program, Uni- aration techniques (1,2). After our early results, versity of Alberta and Capital Health Authority, Edmonton, Alberta, Canada; I many other centers are now initiating islet transplant the 2Department of Surgery, Clinical Islet Transplant Program, University of Alberta and Capital Health Authority, Edmonton, Alberta, Canada; the 3Sur- programs (3,4). A favorable outcome depends primarily on gical Medical Research Institute, Clinical Islet Transplant Program, University having excellence in harvesting human islets, appropriate of Alberta and Capital Health Authority, Edmonton, Alberta, Canada; and the 4Capital Health Authority, Edmonton, Alberta, Canada. immunosuppression regimens, and medical expertise in Address correspondence and reprint requests to Edmond A. Ryan, Clinical selecting patients and in follow-up. Although successful Islet Transplant Program, 2000 College Plaza, 8215 112th St., Edmonton, AB, islet transplant programs are relatively new, the concept Canada T6G 2C8. E-mail: [email protected]. Received for publication 11 February 2002 and accepted in revised form 4 of transplanting islets rather than the whole pancreas is April 2002. attractive because of its technical ease and the ability to N.M.K. served as a consultant for Wyeth on structuring clinical trials with transplant early in the course of the disease. The early Sirolimus in liver transplantation. promise of islet transplantation is now a reality, but the AIRarg, acute insulin response to arginine; AIRg, acute insulin response to glucose; AUC, area under the curve; AUCC-p, area under the curve for process still carries potential risks. C-peptide; AUCi, area under the curve for insulin; CBC, complete blood count; CMV, cytomegalovirus; GAD, glutamic acid decarboxylase; HOMA, homeosta- In deciding whether it is worthwhile to undergo the risk sis model assessment; ICA, islet cell antigen; IE, islet equivalents; IVGTT, of immunosuppression for labile diabetes or concerns intravenous glucose tolerance test; KG, glucose disposal; LFT, liver function with hypoglycemia, it is important to be aware of the test; MAGE, mean amplitude of glycemic excursion; OGTT, oral glucose tolerance test; PTLD, posttransplant lymphoproliferative disorder; WBC, problems and outcomes in the long term. The simplest white blood cell count. measure of success is insulin independence, which must 2148 DIABETES, VOL. 51, JULY 2002 E.A. RYAN AND ASSOCIATES be judged in the context of glycemic control. However, X-ray, dental exam, and electrocardiogram. Further cardiac tests were per- other parameters have to be assessed, including the risks formed if it was believed they were required. Screening was done for cytomegalovirus (CMV) IgG, Epstein-Barr nuclear antigen IgG, varicella-zoster associated with both the procedure and immunosuppres- IgG, hepatitis, syphilis, toxoplasmosis, and HIV. Lymphocytotoxic antibody sion, the improvement in glycemic lability, the eradication screens were performed. All patients were screened for C-peptide status with of problems with hypoglycemia, the effect of transplanta- determination of glucose and C-peptide levels before and 90 min after tion on long-term diabetes complications, and finally, the ingestion of a standard mixed meal. economic costs involved. In addition, early measures of Transplant procedures. Islets were prepared as previously described (3,6– success of the transplant other than the absolute measure 8). Briefly, human cadaveric pancreata were removed from brain-dead multi- organ donors following in situ vascular flushing with cold University of of insulin independence would be helpful to assess func- Wisconsin solution and transported to Edmonton. On arrival at the laboratory, tion and outcomes. Measures of insulin release after the the pancreatic duct was cannulated and liberase enzyme (Boehringer Mann- secretagogues glucose or arginine have been suggested heim, Indianapolis, IN) (8) was perfused. The pancreas was enzymatically and but not formally studied in the setting of successful mechanically dissociated before the islets were separated on a refrigerated ϭ allotransplantation. Cobe 2991 centrifuge (Cobe BCT, Lakewood, CO). A group of pancreata (n 14) were preserved for a period of 2–3 h with a two-layer (University of As of 1 January 2002, we performed 54 procedures as Wisconsin/perfluorochemical) cold storage method, as the retrieval results for part of our islet transplant program, and these serve to situations of longer cold ischemic time appear to improve islet recovery with delineate issues related to the procedure. Seventeen sub- this modification (T. Tsujimura, Y. Kuroda, T. Kin, J.G. Avila, R.V.R., G.S.K., jects have completed the Edmonton protocol and are the E.A.R., A.M.J.S., J.R.T.L., unpublished observations). In addition, in some basis of this report of longer-term outcomes. Our results cases, isolated islets were cultured at 22°C for up to a maximum of 12 h before transplantation (n ϭ 14) to facilitate timing of islet infusion. This did not demonstrate the ability to stabilize labile diabetes and appear to adversely affect viability, as measured in vitro after transplantation greatly improve problems with hypoglycemia. The better (3). Islet numbers were quantified in duplicate using an islet standard diameter measure of insulin reserve appears to be the insulin of 150 ␮m (9). Once the islets were obtained, the patient was admitted and response after intravenous glucose. (for the Edmonton protocol) had the following tests: CBC, chest X-ray, LFTs, and coagulation screen. The patient was then brought to the Radiology Department, and portal vein cannulation was performed. Typically, a size 4F RESEARCH DESIGN AND METHODS catheter is now used to minimize the risk of bleeding, and with this a Gelfoam Thirty consecutive patients had islet transplantation, for a total of 54 plug is not required as previously reported (4). Once the portal vein was procedures.

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