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ADA/JDRF Type 1 Diabetes Sourcebook, Excerpt #14: Beta-Cell Replacement Therapy, Part 1 of 2

Anne Peters, MD, and Lori Laffel, MD, MPH, Editors
Jane Lee Chiang, MD, Managing Editor

ADA-JDRF-Type-1-Diabetes-Sourcebook-image

Andrew M. Posselt, MD, PhD, FACS, and Peter Stock, MD, PhD
The goal of curing type 1 diabetes (T1D) is best achieved with beta-cell replacement therapy because this allows physiologic blood glucose control. Currently, the only way to restore normal blood glucose levels in individuals with T1D without the associated risk of hypoglycemia is to replace the patient’s islets of Langerhans, which normally produce insulin but have been destroyed by an autoimmune reaction. This replacement can be achieved by either the transplantation of a whole pancreas or by the injection of islets of Langerhans, which are isolated from donor pancreata.1 Solid organ pancreas transplantation, particularly when performed in conjunction with a renal transplant in the uremic patient with diabetes, has become an increasingly successful procedure.2–4 Unfortunately, the procedure continues to carry significant perioperative morbidity and requires potent, long-term immunosuppression, and this has limited the target population to individuals who are <50 years old and who do not have significant cardiovascular disease.5,6

Pancreatic islet transplantation represents a minimally invasive alternative to vascularized whole organ transplantation. It offers a safer means of restoring euglycemia and insulin independence early in the course of diabetes, thereby preventing acute complications such as hypoglycemia, and long-term complications such as diabetic nephropathy, retinopathy, and neuropathy.7 The avoidance of the surgical complications associated with pancreas transplantation also significantly increases the safety and applicability of islet transplantation early in the course of diabetes. Unfortunately, multiple donors usually are required to isolate sufficient islets to achieve insulin independence, and islet function appears to wane over time.8–10 As with pancreas transplantation, lifelong aggressive immunosuppression is necessary to protect islets from the alloimmune and autoimmune responses of the host. Thus, the acceptability of clinical islet transplantation will in part depend on the development of less toxic immunosuppressive protocols and on the identification of alternative sources for donor islets, such as xenogeneic grafts and islets developed from stem cell progenitors. This chapter examines the history and current state of each beta-cell replacement option and provides a rational approach to the treatment of patients with T1D.

WHOLE ORGAN PANCREAS TRANSPLANTATION

The first successful pancreas transplant was performed at the University of Minnesota in 1966.11 For a number of years after this achievement, the applicability of the whole organ pancreas transplantation was hampered by both technical and immunologic factors. Pancreas grafts were frequently lost to thrombosis, rejection, bleeding, and anastomotic leaks at the donor duodenum.12 Over the past several years, however, advances in operative technique, perioperative management, and monitoring have resulted in significant improvements in graft and patient survival. In discussing outcomes, we will refer to graft survival and loss.3,5,13 Graft survival refers to the success of the graft and takes into account all possible causes of graft loss. Graft loss is a term that specifies the cause of graft failure (e.g., rejection, thrombosis, etc.).

Advances in immunosuppression have been an important component of the improved outcomes. New agents have allowed adequate suppression of the immune system without the chronic use of steroids, which are known to be toxic to beta-cells.14 For example, lymphocyte-depleting antibodies, such as antithymocyte globulin are now routinely used for induction therapy as well as for the treatment of acute episodes of cellular rejection.15 The introduction of sirolimus, an mTor inhibitor that has little nephrotoxicity, has improved renal allograft survival in patients with simultaneous pancreas and kidney (SPK) transplants by permitting reduction of tacrolimus dosing. With these new agents, rejection rates for SPK transplants have dropped from 80% to <20% in the past 10 years.16 The most recent national data for recipients of SPK transplants demonstrate a one-year and a five-year pancreatic graft survival of 87% and 72%, respectively (SRTR Annual Report, 2007).

Pancreas transplants alone (PTA) and pancreas after kidney (PAK) transplants traditionally have been less successful compared with SPK.13,15,17 Immunologic and technical factors play a role in this discrepancy. Because these patients do not suffer from the uremia associated with renal failure, their platelet function is not impaired, which places them at higher risk for thrombosis in the low-flow vessels of the pancreas. Treatment of these patients with heparin and dipyridamole in the perioperative period has decreased graft thrombosis rates; however, this has also increased bleeding risk significantly. In the past, PTA and PAK patients have experienced more graft loss because of rejection as compared with SPK recipients. In 1998, the University of Minnesota reported that one- and three-year rates of graft loss because of rejection were 2% and 6% for SPK transplants, 12% and 19% for PAK transplants, and 22% and 43% for PTA, respectively.5,18 Since then, improvements in monitoring (such as with protocol graft biopsies) and immunosuppression have resulted in pancreas graft survival rates of 85% and 52% at one year and five years, respectively, in patients receiving a pancreas only (PTA; SRTR Annual Report, 2007), results that are approaching those achieved in SPK.

Although pancreas transplantation can achieve long-term insulin-independence in >80% of patients and stabilizes some of the diabetes-associated complications such as retinopathy and neuropathy, it has significant limitations. First, the number of pancreata that are suitable for transplantation is quite low. Of the ~8,000 deceased donors in the U.S. annually, only ~1,400 (16%) are potentially suitable for whole organ transplantation.19 Second, because of the accelerated course of cardiovascular disease among patients with T1D, many patients who could benefit from the normal insulin physiology conferred by a pancreas transplant are poor candidates for this complex operation due to their underlying cardiovascular disease and resultant increased risk of perioperative complications.6,20 This perioperative cardiac risk coupled with the surgical complications that some patients experience have led researchers to look for other methods to restore beta-cell function in patients with diabetes. In the U.S., as with other organs, pancreas transplants are covered by insurance.

PANCREATIC ISLET TRANSPLANTATION

The pancreas is an organ with numerous functions, yet the function relevant to transplantation is its endocrine function in controlling blood glucose. Soon after the first successful whole organ pancreas transplant, researchers began to develop methods of transplanting isolated pancreatic islets rather than the entire organ. In theory, such a transplant would restore beta-cell function, while not requiring a physiologically stressful operation, and would eliminate the complications that can result from the nonendocrine portions of the gland (Fig. 4.1). In 1972, transplantation of isolated islets succeeded in treating hyperglycemia in a rat model of diabetes.21 Shortly afterward in 1974, islet transplantation was attempted in a patient with diabetes, although only brief, partial function was observed (Fig. 4.2).22 These early achievements raised hope that long-term insulin independence using islet transplantation was imminent; however, the ensuing decades failed to see the realization of the tremendous potential for islet cell transplants in achieving this goal. In 1999, the international registry at Giessen reported that of the 405 islet cell allotransplants performed, <10% were able to achieve and sustain insulin independence for >6 months.23

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Interestingly, patients who underwent islet autotransplants for indications other than diabetes had far better clinical outcomes than those who underwent islet allotransplants. In a series reported by the University of Minnesota, patients undergoing total or completion pancreatectomy for chronic pancreatitis with subsequent islet transplantation derived from their own tissue achieved insulin independence rates of >70%.24 One such patient was able to sustain insulin independence for >13 years without the need for immunosuppression.25,26 This was proof that islet transplantation could achieve long-lasting insulin independence. It also identified the immune response as an important barrier to clinical success in islet allotransplantion.

Multiple aspects of the islet transplant process were thought to contribute to the poor clinical outcomes observed in islet allotransplants; nonetheless, despite the general dysphoria surrounding islet allotransplantation, the groups at the University of Giessen and at the University of Alberta in Edmonton continued to work on the problem. This resulted in encouraging advances in the technical and immunologic aspects of islet transplantation.26,27 Studies of donor factors revealed that better islet yields could be obtained from patients with higher BMIs, and the importance of short cold ischemia times (<8 h) for pancreata destined for islet isolation was also evident.28,29 Ironically, the characteristics that make pancreata suitable for islet isolation (older donor, high BMI) also make them less desirable for whole organ transplantation, thus avoiding competition for organs and increasing overall organ utilization.

Improvements in the islet isolation process also had dramatic effects on islet yields and rates of insulin independence. The isolation process is extremely complex, and many of the steps are difficult to control (Fig. 4.3). Most important among these is the initial digestion of the exocrine tissue by enzymes that release the islets from the organ without destroying them. Historically, the purity and the activity of these enzymes were not well quantitated or standardized, and this resulted in inconsistent yields and highly variable results. Over the past few years, commercially available collagenase cocktails and neutral protease enzymes have become available, and although some variation still exists between lots, islet isolation centers are gaining more experience with these reagents and are able to achieve more consistent results.30,31 Other aspects of the islet isolation process, such as the separation, purification, and culture of the islets have been refined.32 These technical advancements have improved the islet yields obtained from each donor pancreas and have helped achieve insulin independence in up to 50% of patients after transplantation of islets from a single donor.33,34

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20. Nathan DM: Isolated pancreas transplantation for type 1 diabetes: a doctor’s dilemma. JAMA 290:2861–2863, 2003

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22. Sutherland DE: Pancreas and islet transplantation. II. Clinical trials. Diabe-tologia 20:435–450, 1981

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25. Sutherland DE, Radosevich DM, Bellin MD, et al.: Total pancreatec-tomy and islet autotransplantation for chronic pancreatitis. J Am Coll Surg 214:409–424, 2012; discussion 24-6

26. Bretzel RG: Current status and perspectives in clinical islet transplantation. J Hepatobiliary Pancreat Surg 7:370–373, 2000

27. Shapiro AM, Lakey JR, Ryan EA, et al.: Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppres-sive regimen. New Engl J Med 343:230–238, 2000

28. Tsujimura T, Kuroda Y, Kin T, et al.: Human islet transplantation from pan-creases with prolonged cold ischemia using additional preservation by the two-layer (UW solution/perfluorochemical) cold-storage method. Trans-plantation 74:1687–1691, 2002

29. Lakey JR, Burridge PW, Shapiro AM: Technical aspects of islet preparation and transplantation. Transplant Int 16:613–632, 2003

30. Balamurugan AN, Breite AG, Anazawa T, et al.: Successful human islet isola-tion and transplantation indicating the importance of class 1 collagenase and collagen degradation activity assay. Transplantation 89:954–961

31. Anazawa T, Balamurugan AN, Bellin M, et al.: Human islet isolation for autologous transplantation: comparison of yield and function using SERVA/Nordmark versus Roche enzymes. Am J Transplant 9:2383–2391, 2009

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33. Hering BJ, Kandaswamy R, Ansite JD, et al.: Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes. JAMA 293:830–835, 2005

34. Posselt AM, Szot GL, Frassetto LA, et al.: Islet transplantation in type 1 diabetic patients using calcineurin inhibitor-free immunosuppressive pro-tocols based on T-cell adhesion or costimulation blockade. Transplantation 90:1595–1601, 2010

Used with permission by the American Diabetes Association. Copyright © 2013 American Diabetes Association.

Please note: We are proud to have Dr. Anne Peters as a member of our Advisory Board member for Diabetes In Control, Inc.

 

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