Islet Transplantation at the Dresden Diabetes Center: Five Years’ Experience

Abstract

For the majority of patients with type 1 diabetes intensive insulin therapy is effective and safe for maintaining glycemia and minimizing diabetes-associated complications. However, a rare number of patients show highly labile metabolic control and experience repeated and unpredictable hypoglycemic episodes. Such condition is often caused by defective counterregulatory mechanisms and autonomous neuropathy. Patients are at high risk for severe acute and chronic complications, and quality of life is considerably impaired. For this small subset of patients, restoration of endogenous insulin secretion can substantially improve metabolic control and quality of life. In our experience, this is irrespective of insulin independency. Here, we report on our 5 years’ experience with implementing islet transplantation as a potential treatment option for type 1 diabetes. All patients were treated by long-term insulin pump therapy prior to enrolment. The main indication was severely unstable diabetes and repeated hypoglycemia. From 2008 to 2013, 10 patients have been transplanted with single islet infusion; mean follow-up time was 35 months. All patients show persistent graft function, stable glycemic control with a reduction in HbA1c in the absence of hypoglycemia. All patients are kept on minimal exogenous insulin. In conclusion, islet transplantation can be an excellent therapy for selected patients. Key prerequisite for success is a strict indication. The primary goal for islet transplantation should be stabile glycemia and prevention of hypoglycemia rather than insulin independence. In fact, maintaining minimal exogenous insulin may protect the islet graft from metabolic stress and even prolong islet graft function.

Key words

diabetes mellitus - hypoglycemia - unawareness - insulin deficiency

• References

• 1 Standards of medical care in diabetes 2014. Diabetes Care 2014; 37 (Suppl. 01) S14-S80
• 2 Jacqueminet S, Masseboeuf N, Rolland M, Grimaldi A, Sachon C. Limitations of the so-called “intensified” insulin therapy in type 1 diabetes mellitus. Diabetes Metab 2005; 31 (4 Pt 2) 4s45-4s50
• 3 Reichel A, Rietzsch H, Ludwig B, Rothig K, Moritz A, Bornstein SR. Self-adjustment of insulin dose using graphically depicted self-monitoring of blood glucose measurements in patients with type 1 diabetes mellitus. J Diabetes Sci Technol 2013; 7: 156-162
• 4 2007 Update on allogeneic islet transplantation from the Collaborative Islet Transplant Registry (CITR). Cell Transplant 2009; 18: 753-767
• 5 Barton FB, Rickels MR, Alejandro R, Hering BJ, Wease S, Naziruddin B, Oberholzer J, Odorico JS, Garfinkel MR, Levy M, Pattou F, Berney T, Secchi A, Messinger S, Senior PA, Maffi P, Posselt A, Stock PG, Kaufman DB, Luo X, Kandeel F, Cagliero E, Turgeon NA, Witkowski P, Naji A, O’Connell PJ, Greenbaum C, Kudva YC, Brayman KL, Aull MJ, Larsen C, Kay TW, Fernandez LA, Vantyghem MC, Bellin M, Shapiro AM. Improvement in outcomes of clinical islet transplantation: 1999–2010. Diabetes Care 2012; 35: 1436-1445
• 6 Ricordi C, Gray DW, Hering BJ, Kaufman DB, Warnock GL, Kneteman NM, Lake SP, London NJ, Socci C, Alejandro R, Zeng Y, Scharp DW, Viviani G, Falqui L, Tzakis A, Bretzel RG, Federlin K, Pozza G, James RFL, Rajotte RV, Di Carlo V, Morris PJ, Sutherland DER, Starzl TE, Mintz DH, Lacy PE. Islet isolation assessment in man and large animals. Acta Diabetol Lat 1990; 27: 185-195
• 7 Ryan EA, Paty BW, Senior PA, Bigam D, Alfadhli E, Kneteman NM, Lakey JR, Shapiro AM. Five-year follow-up after clinical islet transplantation. Diabetes 2005; 54: 2060-2069
• 8 Miller RG, Secrest AM, Sharma RK, Songer TJ, Orchard TJ. Improvements in the life expectancy of type 1 diabetes: the Pittsburgh Epidemiology of Diabetes Complications study cohort. Diabetes 2012; 61: 2987-2992
• 9 Steffes MW, Sibley S, Jackson M, Thomas W. Beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial. Diabetes Care 2003; 26: 832-836
• 10 Federlin K, Pozza G. Indications for clinical islet transplantation today and in the forseeable future – the diabetologist’s point of view. J Mol Med (Berl) 1999; 77: 148-152
• 11 Bouwens L. Beta cell regeneration. Curr Diabetes Rev 2006; 2: 3-9
• 12 Brennand K, Melton D. Slow and steady is the key to beta-cell replication. J Cell Mol Med 2009; 13: 472-487
• 13 Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, Young H, Richardson M, Smart NG, Cunningham J, Agulnick AD, D’Amour KA, Carpenter MK, Baetge EE. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 2008; 26: 443-452
• 14 Ludwig B, Ludwig S, Steffen A, Saeger HD, Bornstein SR. Islet versus pancreas transplantation in type 1 diabetes: competitive or complementary?. Curr Diab Rep 2010; 10: 506-511
• 15 McCall MD, Toso C, Baetge EE, Shapiro AM. Are stem cells a cure for diabetes?. Clin Sci (Lond) 2010; 118: 87-97
• 16 Schulz TC, Young HY, Agulnick AD, Babin MJ, Baetge EE, Bang AG, Bhoumik A, Cepa I, Cesario RM, Haakmeester C, Kadoya K, Kelly JR, Kerr J, Martinson LA, McLean AB, Moorman MA, Payne JK, Richardson M, Ross KG, Sherrer ES, Song X, Wilson AZ, Brandon EP, Green CE, Kroon EJ, Kelly OG, D’Amour KA, Robins AJ. A scalable system for production of functional pancreatic progenitors from human embryonic stem cells. PLoS One 2012; 7: e37004
• 17 Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126: 663-676
• 18 Weir GC, Cavelti-Weder C, Bonner-Weir S. Stem cell approaches for diabetes: towards beta cell replacement. Genome Med 2011; 3: 61
• 19 Zhang D, Jiang W, Liu M, Sui X, Yin X, Chen S, Shi Y, Deng H. Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells. Cell Res 2009; 19: 429-438
• 20 Sollinger HW, Odorico JS, Becker YT, D’Alessandro AM, Pirsch JD. One thousand simultaneous pancreas-kidney transplants at a single center with 22-year follow-up. Ann Surg 2009; 250: 618-630
• 21 Bromberg JS, Kaplan B, Halloran PF, Robertson RP. The islet transplant experiment: time for a reassessment. Am J Transplant 2007; 7: 2217-2218
• 22 Cravedi P, Mannon RB, Ruggenenti P, Remuzzi A, Remuzzi G. Islet transplantation: need for a time-out?. Nat Clin Pract Nephrol 2008; 4: 660-661
• 23 Lehmann R, Spinas GA, Moritz W, Weber M. Has time come for new goals in human islet transplantation?. Am J Transplant 2008; 8: 1096-1100
• 24 Thompson DM, Meloche M, Ao Z, Paty B, Keown P, Shapiro RJ, Ho S, Worsley D, Fung M, Meneilly G, Begg I, Al Mehthel M, Kondi J, Harris C, Fensom B, Kozak SE, Tong SO, Trinh M, Warnock GL. Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation 2011; 91: 373-378
• 25 Takita M, Matsumoto S, Shimoda M, Chujo D, Itoh T, Sorelle JA, Purcell K, Onaca N, Naziruddin B, Levy MF. Safety and tolerability of the T-cell depletion protocol coupled with anakinra and etanercept for clinical islet cell transplantation. Clin Transplant 2012; 26: E471-E484
• 26 Alejandro R, Barton FB, Hering BJ, Wease S. Update from the Collaborative Islet Transplant Registry. Transplantation 2008; 86: 1783-1788
• 27 Berney T, Johnson PR. Donor pancreata: evolving approaches to organ allocation for whole pancreas versus islet transplantation. Transplantation 2010; 90: 238-243
• 28 Collett D, Johnson R, Hudson A, Neuberger J. Organ allocation in the United Kingdom. Clin Transpl 2010; 24: 53-60
• 29 Ridgway DM, White SA, Kimber RM, Nicholson ML. Current practices of donor pancreas allocation in the UK: future implications for pancreas and islet transplantation. Transpl Int 2005; 18: 828-834