Need for xenotransplantation in the treatment of type 1 diabetes
Authors: Seissler J. 
Published: February 2011

Type 1 diabetes (T1D) currently affects approximately 28 million patients with a rising incidence worldwide. Despite improvement of intensive insulin therapy, only a subgroup of patients reached near‐normal blood glucose control. Prospective studies have shown that 30–40% of patients with T1D are at risk to develop devastating micro‐ or macrovascular complications. In the intensive insulin treatment arm of DCCT/EDIC study the cumulative incidences of proliferative retinopathy, nephropathy and cardiovascular diseases were 21%, 9% and 9% after 30 years of diabetes, respectively [1]. In addition, about 15% of patients with a disease history of 20–25 years have the problem of hypoglycemia unawareness due to lack of hormonal counter‐regulation [2]. These serious complications lead to a significant reduction of life‐expectancy as compared to non‐diabetic individuals. Thus, there is an urgent need for more effective and durable management of diabetes.Transplantation of human beta cells using isolated islets or pancreas provided evidence that T1D can be cured by cell replacement therapies. Pancreas transplantation results in a significant reduction of vascular complication and reduced total mortality [3]. After islet cell transplantation 3‐year insulin independency, preserved graft function (detectable C‐peptide) and elimination of severe hypoglycemia have been reported in 23%, 52% and 70% by the collaborative islet transplant registry [4]. However, the total number of islet allografts (<100/years) and pancreas transplants (approximately 1800/year) worldwide is insufficient in relation to the number of potential recipients in whom islet/pancreas transplantation may be beneficial or even life‐saving.In the last years there have been impressive advances in the field of beta cell generation from induced pluripotent stem cells/embryonic stem cells and xenograft transplantation. It has been shown that novel immunosuppressive regimen can induce long‐lasting pig islet survival in nonhuman primates [5,6] and the use of fetal pig pancreas reduces immunogenicity [7]. Transgenic pigs expressing immunosuppressive and cytoprotective factors in beta cells have been generated. In addition, novel techniques of islet encapsulation in biochambers may allow long‐term islet function and pathogen‐free pig herds have been recently established to overcome the problem of zoonosis. The use of pig islets has additional advantages: (i) pig insulin is safe since it has been used for decades in the treatment of T1D; (ii) porcine pancreas is easily available on demand making it possible to reduce ischemia injury and pretreatment of recipients; (iii) pig islets do respond to glucose in a similar way as human islets. The last two points strongly favor pig islets as compared to neo‐beta cells derived from stem cells, which were reported to be not fully matured and possess the risk of tumor formation (teratomas) [8,9].The striking advances in pig islet transplantation suggest that it may be possible to overcome the major immunological barriers to pig islets in recipients so that clinical trials can be started in humans within the next years. Therefore, porcine islet xenografts may be the most realistic option to offer cell replacement therapy to a higher number of patients with T1D at risk for severe diabetes‐associated complications. When this approach is successful the large‐scale availability of pig islets would also open the window for other applications such as transplantation in insulin‐treated patients with type 2 diabetes in whom insulin resistance currently excludes islet cells transplantation due to the demand of high insulin levels/high number of islets.References1. Dcct/EdicResearch Group. Modern‐day clinical course of type 1 diabetes mellitus after 30 years’ duration: the diabetes control and complications trial/epidemiology of diabetes interventions and complications and Pittsburgh epidemiology of diabetes complications experience (1983–2005). Arch Intern Med 2009; 169: 1307–1316.2. Pedersen‐Bjergaard U, Pramming S, Heller SRet al. Severe hypoglycaemia in 1076 adult patients with type 1 diabetes: influence of risk markers and selection. Diabetes Metab Res Rev 2004; 20: 479–486.3. Sollinger HW, Odorico JS, Becker YTet al. One thousand simultaneous pancreas‐kidney transplants at a single center with 22‐year follow‐up. Ann Surg 2009 Aug 27. [Epub ahead of print]4. Alejandro R, Barton FB, Hering BJet al. 2008 Update from the collaborative islet transplant registry. Transplantation 2008; 86: 1783–1788.5. Hering BJ, Wijkstrom M, Graham MLet al. Prolonged diabetes reversal after intraportal xenotransplantation of wild‐type porcine islets in immunosuppressed nonhuman primates. Nat Med 2006; 12: 301–303.6. Cardona K, Korbutt GS, Milas Zet al. Long‐term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways. Nat Med 2006; 12: 304–306.7. Hecht G, Eventov‐Friedman S, Rosen Cet al. Embryonic pig pancreatic tissue for the treatment of diabetes in a nonhuman primate model. Proc Natl Acad Sci 2009; 106: 8659–8664.8. Kroon E, Martinson LA, Kadoya Ket al. Pancreatic endoderm derived from human embryonic stem cells generates glucose‐responsive insulin‐secreting cells in vivo. Nat Biotechnol 2008; 26: 443–452.9. Maehr R, Chen S, Snitow Met al. Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci 2009; 106: 15768–15773.