Islet Cell Transplantation: Can It Facilitate Insulin Independence?

Do islet cells hold promise in treating diabetes? Islet cells are groupings of hormone-secreting cells in the pancreas that are responsible for several endocrine functions including the production of insulin. Pancreatic islets contain four different types of cells including: insulin-producing beta cells, glucagon-releasing alpha cells, somatostatin-producing delta cells and cells that contain polypeptides (PP cells). Each individual islet contains approximately 1,000 of these four types of cells.    In islet cell transplantation procedures, surgeons use enzymes to extract islet cells, typically from the pancreata of multiple deceased donors, in order to collect an ample amount of cells that can be immediately injected into the recipient’s liver. The surgeon would make an injection through the portal vein of the liver in order to facilitate easy access and maintain a minimal level of invasiveness. The cells remain in the liver, attach themselves to new blood vessels and begin to produce insulin from that location.1    After a period of acclimation in the recipient’s system, the transplanted cells produce insulin and regulate the patient’s blood glucose level. As a result, the need for an insulin injection regimen or total pancreas transplant could be eliminated.2 This procedure has gained considerable attention in the medical community due to its extreme potential for benefit to people with diabetes. However, significant advancements are still necessary in order for islet cell treatment to become a comprehensive cure for diabetes mellitus type 1, in which insulin production is absent.    Healthy glucose levels are crucial in decreasing the risk of common complications of diabetes mellitus. These complications include nerve, eye and limb degeneration, particularly of the foot. Typically, one attains euglycemia through a regimen of insulin injections, which are not ideal due to the pain involved and their relative inconvenience. Elimination of a shot regimen is of particular interest for juvenile patients who struggle with the considerable burden and responsibility involved in this glucose regulation method.

Weighing The Pros And Cons Of Islet Cell Transplantation

Islet cell transplantation, on the other hand, involves one surgical procedure usually performed with a local anesthetic, and can result in self-production of insulin by the recipient’s system for up to five years.3 The minimally invasive nature of this surgical option is preferred over the more elaborate procedure of total pancreatic transplantation. In addition to establishing possible insulin independence for a number of years, islet cell therapy may help control glycated HbA1c and decrease the recurrence of hypoglycemia.4    Although current literature expresses optimism about the validity of islet cell transplantation as a solution for glycemic control, researchers are also realistic about the current limitations of this therapy. Significant advances are needed in order for this treatment course to become widely available and successful in establishing normaglycemia.    The limited availability of donor islet cells and the rejection of these transplanted tissues by the recipient’s immune system are the two most serious challenges to islet cell transplantation. Approximately 1 million islet cells are needed for transplantation to be successful. As a result, two or more donors are usually needed per recipient, thus limiting the availability of ample transplantation material. The extraction process itself is relatively inefficient as well and contributes to the difficulty of obtaining islet cells for recipients.    After the islet cells are collected and transplanted into a recipient, the patient’s immune system often attacks the foreign islet cells. Researchers have developed a method using contrast agents and magnetic resonance imaging (MRI) to assess the degree of rejection of the transplanted cells, and determine the success of the transplant.5 Beta cells of the pancreas, which are responsible for the production of insulin, are particularly at risk for attack by the immune system as well as by infectious agents or toxic materials involved in diabetes mellitus type I.6 As a result, one would use immunosuppressant drugs in tandem with islet cell transplantation to minimize rejection of foreign cell material which, in turn, hampers the patient’s ability to fight infection and disease.    Another unfortunate and ironic result of immunosuppressant therapy is the decreased function of the recipient’s own limited supply of islet cells. Radical pharmaceutical developments are needed to create immunosuppressant drugs that act only to assist in the acceptance of donor islet cells instead of suppressing the recipient’s entire immune system.    Researchers have utilized gene transfection, or the injection of foreign DNA into a cell to alter its properties, to strengthen beta cells’ defense from an attack on the immune system.6 We need a better clinical understanding of how cells protect themselves from attack by the immune system before this technique can significantly increase the effectiveness of beta cell replacement.6 An additional concern is the fact that immunosuppressive therapy negatively impacts renal function. Accordingly, this therapy would be limited to those with healthy kidneys.

A Closer Look At The Edmonton Protocol

Islet cell transplantation can be categorized into two different eras: before and after the Edmonton Protocol. The protocol was developed in the 1990s and the first patient was treated under its statutes in 1999. This special course of treatment introduced pivotal changes to the world of islet cell transplantation. Total pancreatic transplantation was the preferred surgical procedure for long-term glucose control before the Edmonton Protocol revolutionized islet cell transplantation.2 Insulin independence in patients with type 1 diabetes one year after islet cell transplantation rose from 20 percent to nearly 80 percent after the Edmonton Protocol became the standard of care.3,7    Advancements in how islets are isolated, purified and extracted from donors, using a mixture of enzymes called Liberase™, factor into the success of the protocol. Better adjunctive immunosuppressive drugs, such as sirolimus and tacrolimus, and the monoclonal antibody drug daclizumab (Zenapax, Roche U.S. Pharmaceuticals), also contribute to the protocol’s success.2,8 Additionally, changes in the transportation of the donor pancreatic islets as well as the amount of cells transplanted into the recipient also contribute to the increased insulin independence rates.2,8    However, even with the advances involved in the Edmonton Protocol, problems still exist with successful, long-term islet cell transplantation. Some researchers question the efficacy of sirolimus, a drug of choice of the protocol, as an effective immunosuppressant for islet cell transplantation as the drug may potentially impede the growth of pancreatic ductal cells and minimize the secretion of insulin.9 Furthermore, the long-term outcome of islet cell transplantation is still quite dismal. In 2006, one study claimed only 10 percent of transplanted patients were insulin independent after five years.3 Although there is hope with recent advances, the outcome of islet transplantation is still not a permanent solution for type 1 diabetes.

In Conclusion

The most crucial area for improvement of islet cell transplantation is in the development of immunosuppressant drugs that minimize system-wide immunosuppression while fostering better acceptance of transplanted islet cells. Perhaps the most promising possibility is the potential use of stem cells to eliminate problems with availability of islet cells.7,8 Nevertheless, the development of cells — that produce insulin like the beta cells of the pancreas — from stem cells will undoubtedly be the subject of continued research.    Clearly, at this point, islet cell transplantation is not a practical cure for those diagnosed with diabetes. However, this type of advanced therapy and research represent the great strides that have been made to discover methods of establishing insulin independence for patients with diabetes. Ms. Kaylor is a Research Intern at Georgetown University Hospital in Washington, DC. Dr. Steinberg (pictured at left) is an Assistant Professor in the Department of Plastic Surgery at the Georgetown University School of Medicine in Washington, D.C.
 

References:

References 1.    Hopkins Tanne J. New technique improves safety of islet cell transplantation. BMJ. 2005 Dec 3;331(7528):1290. 2.    Lakey JR, Mirbolooki M, Shapiro AM. Current status of clinical islet cell transplantation. Methods Mol Biol. 2006;333:47-104. Review. 3.    Balamurugan AN, Bottino R, Giannoukakis N, Smetanka C. Prospective and challenges of islet transplantation for the therapy of autoimmune diabetes. Pancreas. 2006 Apr;32(3):231-43. Review. 4.    Bertuzzi F, Marzorati S, Secchi A. Islet cell transplantation. Curr Mol Med. 2006 Jun;6(4):369-74. Review. 5.    Evgenov NV, Medarova Z, Pratt J, Pantazopoulos P, Leyting S, Bonner-Weir S, Moore A. In vivo imaging of immune rejection in transplanted pancreatic islets. Diabetes. 2006 Sep;55(9):2419-28. 6.    Bloch K, Vardi P. Toxin-based selection of insulin-producing cells with improved defense properties for islet cell transplantation. Diabetes Metab Res Rev. 2005 May-Jun;21(3):253-61. Review. 7.    Bretzel RG, Eckhard M, Brendel MD. Pancreatic islet and stem cell transplantation: new strategies in cell therapy of diabetes mellitus. Panminerva Med. 2004 Mar;46(1):25-42. Review. 8.    Ridgway DM, White SA, Nicholson ML, Kimber RM. Pancreatic islet cell transplantation: progress in the clinical setting. Treat Endocrinol. 2003;2(3):173-89. Review. 9.    Bussiere CT, Lakey JR, Shapiro AM, Korbutt GS. The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells. Diabetologia. 2006 Oct;49(10):2341-9. Epub 2006 Aug 9.