Islet Transplantation as a Treatment for Diabetes — A Work in Progress
http://www.100md.com
《新英格兰医药杂志》
In 1993 the Diabetes Control and Complications Trial (DCCT) established the modern standard of care for the medical management of type 1 diabetes mellitus.1 The DCCT randomly assigned 1441 patients to conventional or intensive treatment. The latter included multiple daily determinations of blood glucose levels at home by finger stick; combinations of daily injections of long-, intermediate-, and short-acting insulin; and dietary and psychological support. The clinical outcomes in terms of secondary complication rates were much better in the intensively treated group than in the conventionally treated group; thereafter, intensive treatment became the norm. More recent improvements in home glucose and glycosylated hemoglobin monitoring and insulin preparations have further enabled patients with diabetes to attain near-normal glycemic control without frequent episodes of hypoglycemia.
In addition to improving the ability of the medical community to control glycemia in patients with diabetes, the DCCT also provided a stronger rationale for the use of pancreas transplantation. Worldwide, the three-year organ-survival rate for simultaneous kidney and pancreas transplantation is approximately 70 to 80 percent,2 which is similar to the rates for most other types of organ transplantation. When successful, pancreas transplantation is particularly effective in patients with type 1 diabetes and autonomic insufficiency, who struggle with glycemic control, postural hypotension, gastroparesis, and diarrhea and have a dramatically shortened life span.3,4 Pancreas transplantation is more likely to result in normal glycosylated hemoglobin levels than is the intensive insulin-based approach to management prescribed in the DCCT. Long-term studies of motor, sensory, and autonomic neuropathy have demonstrated that these complications stabilize after pancreas transplantation,5 and native-kidney biopsies have shown a dramatic reversal of mesangial accumulation and basement-membrane thickening 10 years after the establishment of normal glucose levels by pancreas transplantation.6 Macrovascular complications are also stabilized by pancreas transplantation.7,8,9 Quality-of-life studies indicate that patients who undergo successful pancreas transplantation feel that the normalization of glucose levels and the freedom from daily insulin injections outweigh the problems caused by transplantation and its attendant immunosuppression.10,11,12,13,14
These favorable results were obtained in a highly selected group of patients who had major difficulties related to both achieving glycemic control and the disease itself and thus do not represent outcomes from randomized trials comparing medical management with pancreas transplantation. Nonetheless, the clinical outcomes of pancreas transplantation have been impressive enough for the American Diabetes Association to recommend in 2000 and again in 2003 that simultaneous pancreas transplantation should be considered at the time of kidney transplantation, that pancreas transplantation alone should be considered for patients with unacceptably poor metabolic control and quality of life despite optimal medical treatment, and that islet transplantation should still be considered an experimental procedure.
Success with pancreatic islet transplantation in series of patients far smaller than those involved in pancreas transplantation has led to optimism that islet transplantation may ultimately replace pancreas transplantation. Islet transplantation is a less demanding method of beta-cell replacement in that it does not involve major surgery, permits a lesser degree of immunosuppression, and is potentially less expensive for the recipient. Whether the physical and emotional costs are lower remains to be established, because there have been too few procedures for the complication rates associated with percutaneous liver puncture, anticoagulation, and immunosuppressive regimens to be determined. In this review, I will sketch the history of islet transplantation, describe the procedures of islet isolation and intrahepatic transplantation, consider the limitations of transplantation technology and the immunosuppressive drugs currently in use, compare the clinical outcomes of islet transplantation with those of pancreas transplantation, examine the definition of success, suggest avenues for future studies, and address the important problem of supply and demand.
History of Islet Transplantation from 1894 to 2000
The concept of transplanting pieces or extracts of pancreas in patients with diabetes is over a century old. The first known report appeared in 1894: Williams used minced sheep's pancreas and extracts of pancreas in glycerine for oral and subcutaneous therapy.15 This approach, audacious in retrospect, used sheep xenografts without immunosuppression and was reported as an overt failure. Virtually no subsequent effort was successful until 1972, when Ballinger and Lacy reported that islet isografts from normal rats could reverse streptozocin-induced diabetes in rats.16 By the 1980s successful transplantation of islet autografts17,18 and, in one instance, an islet allograft was reported in humans.19 In the autograft approach, a patient with unrelentingly painful, chronic pancreatitis and a poor quality of life undergoes complete pancreatectomy for pain relief. The removed pancreas is minced, digested with collagenase, and centrifuged to achieve a nonpurified preparation of islets that is infused into the patient's liver through the portal venous circulation within two hours after pancreatectomy. The islets lodge in the liver because they are too large to pass through the sinusoids. In 1992, Pyzdrowski et al.20 reported that 265,000 islets were sufficient to establish insulin independence. In 1995, Wahoff et al. reported an insulin-independence rate of 74 percent two years after autologous islet transplantation in 14 patients who had undergone total pancreatectomy and who had received a portal-vein infusion of more than 300,000 islets (the normal pancreas has roughly 1 million islets).21
In the 1980s, reports of successful allogeneic islet transplantation in patients with type 1 diabetes with the use of conventional immunosuppression and purified human islets from cadaveric donors began to appear19,22,23,24,25,26,27,28,29,30,31,32,33,34,35 (Table 1), but internationally, the overall rates of success were reported as less than 10 percent.36 In 2000, Shapiro et al. reported 100 percent success in seven patients.35 This high rate may have been due to the many differences in their approach as compared with previous techniques — there were restrictions on recipients' body weights, the immunosuppressive regimen was modified by the addition of sirolimus and low-dose tacrolimus together with avoidance of corticosteroids, patients received the anticytokine drug daclizumab, and multiple infusions of islets from different donors were used to attain a transplanted islet mass sufficient to achieve normal glucose levels and independence from exogenous insulin.
Table 1. Synopsis of Reports of Successful Islet Transplantation in Patients with Type 1 Diabetes.
Can Islet Yields Be Improved?
Paul Langerhans identified pancreatic islets in 1869, describing them as discrete islands or islets surrounded by pancreatic exocrine tissue37 — hence, the term "islets of Langerhans." The islets make up approximately 2 to 3 percent of the total pancreatic volume. Islets have a portal circulation, with blood flowing from beta to alpha to delta cells,38,39 as well as afferents from the central nervous system, which regulate secretion of these cells' hormones. The alpha, beta, delta, and PP cells secrete glucagon, insulin, somatostatin, and pancreatic polypeptide, respectively. Alpha and beta cells are exquisitely sensitive to glucose, which stimulates the beta cell and inhibits the alpha cell, thereby maintaining blood glucose levels within a narrow range. The principal actions of insulin promote the entry of glucose into tissues and decrease hepatic gluconeogenesis, whereas glucagon principally stimulates hepatic glycogenolysis when hypoglycemia threatens.
Modern islet-isolation technology involves the procurement of a healthy pancreas from a brain-dead donor whose heart is beating, although recent success has been reported with the use of cadaveric donors.40 The pancreas is procured with the use of the same techniques that are used to procure a pancreas for whole-organ transplantation. The pancreatic duct is cannulated, and collagenase is infused to separate islets from exocrine and ductal tissue.41 Subsequently, islets are purified by density–gradient centrifugation. The final product is evaluated for purity and viability before it is transported to the angiography suite for transplantation (Figure 1).
Figure 1. The Process of Islet Transplantation.
A pancreas is obtained from a donor. The pancreas is digested with collagenase to free the islets from surrounding exocrine tissue. The freed islets, containing mostly beta and alpha cells, are purified by density–gradient centrifugation to remove remaining exocrine cellular debris. The purified islets are infused into a catheter that has been placed percutaneously through the liver into the portal vein, whence they travel to the liver sinusoids.
Although relatively simple to describe, the process of islet isolation for transplantation is complicated. The health of and the medications used by the potential donor, the care with which the surgical team removes the pancreas, and the timeliness of transportation to the laboratory are important variables. Improvements in transport of the pancreas are being attempted by advocates of the "two-layer method," which sandwiches the pancreas between a bottom layer of perfluorodecalin saturated with oxygen and a top layer of University of Wisconsin preservation solution.42,43,44,45 Once the pancreas reaches the laboratory, four to six hours is required for complete processing and quality assessment of the islets.
Critics46 of this approach question the need for the purification step because it adds time, can cause the loss of 30 to 50 percent of islets, and traumatizes the remaining islets that are harvested. They point out that unpurified islets are used successfully in autologous transplantation and that purification removes pancreatic-duct stem cells that might give rise to new islets after transplantation.47 Proponents of purification respond by arguing that purification yields a much smaller tissue volume, which is thus less likely to cause portal hypertension. Culturing the islets after isolation would allow them to recover before transplantation48,49 and would decrease travel demands for recipients, who must currently arrive at the transplantation site within hours after notification.
Is the Liver the Optimal Site for Islet Infusion?
The liver, spleen, kidney capsule, testes, brain, peritoneal cavity, and omentum have all been considered as potential sites of islet infusion. The liver is by far the most commonly used site because of the early successes with autologous islet transplants. However, although autologous islets are infused intraoperatively directly into the hepatic portal venous circulation under direct view, islet allografts are infused percutaneously into the portal vein. Potential complications of an infusion into the liver include bleeding, portal venous thrombosis, and portal hypertension. Although portal blood pressure is monitored during the procedure and anticoagulant agents are used to prevent clotting, anticoagulation can promote hepatic bleeding at the sites of the percutaneous needle punctures. Furthermore, intrahepatic islets may be exposed to environmental toxins and potentially toxic prescribed medications absorbed from the gastrointestinal tract and delivered into the portal vein. Ironically, all commonly used immunosuppressive drugs have been reported to have adverse effects on pancreatic beta cells50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68 (Table 2). In addition, the antiproliferative effects of sirolimus may theoretically be disadvantageous both for angiogenesis in newly transplanted islets69,70 and for islet neogenesis from ductal stem cells.47
Table 2. Mechanisms of the Adverse Effects of Immunosuppressant Drugs on Beta Cells.
Finally, intrahepatic islets are unable to release glucagon during hypoglycemia20,71,72,73 (Figure 2 and Figure 3). Yet, though intrahepatic islets fail to respond to hypoglycemia, they appear to contain healthy alpha cells that process and secrete glucagon, as indicated by their response to intravenous arginine.20,71,72 Since not all recipients remain insulin-independent for the rest of their lives, they may become at risk for hypoglycemia and thus would benefit from having a glucagon response.
Figure 2. Lack of Glucagon Responses during Hypoglycemia Induced by Hypoglycemic, Hyperinsulinemic Clamping in Patients with Type 1 Diabetes Who Underwent Successful Transplantation of Intrahepatic Allografts.
During the study, insulin is infused at a steady rate and glucose at a decreasing rate so that glucose levels gradually reach 40 mg per deciliter. Reprinted from Paty et al.,73 with the permission of the publisher. P<0.05 for the comparison of glucagon levels at 0 and 180 minutes for the controls and for the comparison between the levels at 180 minutes in the controls and the levels in subjects with type 1 diabetes who underwent islet transplantation and those who did not.
Figure 3. Glucagon Responses in Pancreatectomized Dogs That Have Received Autologous Islets during Hypoglycemia Induced by Hypoglycemic, Hyperinsulinemic Clamping (Panel A) and Intravenous (IV) Arginine (Panel B).
In Panel A, glucagon responses remain intact when autologous islets are placed in the peritoneal cavity but not when they are placed in the liver. During the study, insulin is infused at a steady rate and glucose at a decreasing rate so that glucose levels gradually reach 40 mg per deciliter. In Panel B, glucagon responses remain intact after the intravenous infusion of arginine whether autologous islets are placed in the peritoneal cavity or in the liver. Reprinted from Gupta et al.,72 with the permission of the publisher.
In view of these problems, it is reasonable to consider the use of nonhepatic sites. It might also be possible to infuse unpurified islet preparations into nonhepatic sites, which would eliminate the trauma to and losses of islets caused by purification. Potential alternative sites include the peritoneal cavity and omentum, both of which have been used successfully in animal models and shown to be safe for humans.74,75
Clinical Outcomes, 2001 to 2003
Since the initial report35 from Edmonton, Alberta, Canada, many transplantation centers throughout the world have initiated corticosteroid-free protocols.76 Although the results of other studies are beginning to appear,77,78 in most instances, success rates have not yet been published. The Immune Tolerance Network has organized a nine-center trial designed to evaluate the reproducibility of the Edmonton results in 36 recipients. Preliminary information presented at the 2003 American Transplant Congress suggests robust success rates at more experienced centers, but much lower rates at less experienced centers.79 In addition, several patients who became insulin-independent after transplantation have withdrawn from the study because of unacceptable side effects of the immunosuppressive drugs.
The largest, most recent update on the clinical outcomes of the Edmonton experience was published in 2002.80 The authors reported 54 islet infusions in 30 recipients with type 1 diabetes and provided detailed follow-up data on 17 consecutive patients, all of whom became insulin-independent, with mean (±SE) glycosylated hemoglobin values of 6.1±0.8 percent after receiving a minimum of 9000 islets per kilogram of body weight, or 630,000 islets for a 70-kg person. Typically, two separate infusions of islets from two pancreata were used an average of one month apart. Four of six patients were insulin-independent for more than two years, but two of the four had impaired glucose tolerance. Fourteen of the initial 17 recipients no longer had hypoglycemic reactions. The adverse effects of the procedure included five bleeding episodes related to percutaneous puncture of the liver in 50 procedures, three transfusions, and one partial thrombosis of the portal vein with hepatic subcapsular hemorrhage caused by anticoagulant therapy that required transfusion and surgery. Transiently elevated liver-enzyme levels, hypercholesterolemia, further increases in creatinine levels in patients with preexisting renal disease, increased proteinuria in patients with preexisting proteinuria, increases in the doses of antihypertensive drugs, and the need for retinal laser photocoagulation were among the other complications. No deaths or life-threatening infections occurred.
The interpretation of these results is complicated by the fact that the Edmonton trial design did not include a similar and concurrent control cohort. Since the observation period before transplantation was not as long or as intense as the observation period after transplantation, extensive paired analyses of pretransplantation and post-transplantation clinical data are not possible. Whether two islet infusions a month apart are essential is unresolved, since recipients were not randomly assigned to receive either one infusion or two. Relevant data from studies of autologous islet transplantation suggest that islets continually regain function up to three months after infusion81 (Figure 4). Nonetheless, one can conclude that in the hands of the Edmonton group, islet transplantation is relatively safe and efficacious in eliminating the need for exogenous insulin and in preventing recurrent hypoglycemia, albeit at a cost of a roughly 10 percent incidence of liver bleeding related to the procedure. The initial graft survival rate of 80 percent with the use of islets from multiple donors compares favorably with that of successful pancreas transplantation4 and successful autologous islet transplantation.21 Whether or not the long-term survival of allografts will equal that of autologous grafts is unknown. Autologous grafts can function successfully for many years after transplantation. A recipient of one such autologous graft was reported to have normal fasting glucose and glycosylated hemoglobin levels 13 years after transplantation82 and remains insulin-independent 16 years later. However, recipients of islet allografts face the additional risk of recurrent autoimmune diabetes,83,84 as well as of side effects from treatment with immunosuppressive drugs that are potentially lethal to beta cells.
Figure 4. Acute Insulin Responses to Intravenous (IV) Glucose in a Nondiabetic Patient with Chronic Pancreatitis before and at Various Times after Pancreatectomy and Receipt of an Intrahepatic Islet Autograft.
The insulin response did not become substantial until the second month after transplantation, and it increased even more by the third month. Reprinted from Robertson et al.,75 with the permission of the publisher.
Defining Success
A major problem in judging the success of islet transplantation lies in the definition of success. The typical candidate has recurrent hypoglycemia with poor recognition of the resulting symptoms and abnormal glycosylated hemoglobin values. Although the first two issues can be resolved by lessening the intensity of insulin management,85,86,87 this approach increases glycosylated hemoglobin values. The use of a rigorous definition of success means recipients no longer use insulin, do not have hypoglycemia and poor recognition of symptoms, and have normal preprandial and postprandial glucose levels and glycosylated hemoglobin values for prolonged periods. The use of a more flexible definition means that the main problems that resulted in transplantation in the first place — frequent hypoglycemia with poor symptom recognition, a poor quality of life, and abnormal glycosylated hemoglobin values — have been solved. The more flexible view allows the use of oral hypoglycemic drugs and residual impaired glucose tolerance and is supported by some experts in the field,88 but not all.
Putting aside definitions of success, an equally important consideration is the cost–benefit ratio of islet transplantation, in both personal and financial terms. In addition to the clinical complications of the procedure, patients pay a personal price for using immunosuppressive drugs because of their adverse effects. In defense of islet transplantation, all types of allogeneic transplantation carry a risk of adverse effects related to immunosuppressive drugs and the financial cost of islet transplantation is less than that of pancreas transplantation. On the other hand, pancreas transplantation is more efficient, since it typically involves only a single procedure and quickly results in normal glucose and glycosylated hemoglobin values. A comparison of these two procedures illustrates another important difference. Whole pancreata are most often used for patients with renal failure who simultaneously receive kidney transplants. The increase in the quality of life, satisfaction with the procedure, and tolerance of adverse drug effects are likely to be greater among recipients of combined pancreas and kidney transplants than recipients of an islet transplant alone, because the former group of patients is typically more ill to begin with. This outcome leads many clinicians to conclude that simultaneous kidney and islet transplantation or islet transplantation after kidney transplantation is the preferred approach, rather than the transplantation of islets, in patients without renal failure. The combined procedures are used for the sicker patients, and the issue regarding the burden of immunosuppressive drugs can be finessed because patients scheduled for kidney transplantation know that they must receive these drugs.
The Next Generation of Research Studies
Although the prospect of islet transplantation as a treatment for diabetes is exciting, there are no data that allow firm conclusions to be drawn about who should receive this therapy. Continuing improvements in the medical management of diabetes invalidate the use of data from historical controls, even those obtained in the DCCT. Controlled studies are needed to evaluate the efficacy and complications of islet transplantation. If randomization is not possible, a case–control approach that includes patients who qualify for but decline to undergo the procedure could be used. Subgroups should be stratified according to the secondary complications of diabetes and to whether islets are transplanted alone or in conjunction with a kidney. Allowances must also be made for the further development of procurement and laboratory techniques for the isolation of islets, as well as the development of new immunosuppressive drugs that are less toxic to beta cells.
Problems of Supply and Demand
Demand for islet transplantation far exceeds the number of islets available. Even if the procedure is limited to adults with type 1 diabetes who have recurrent hypoglycemia and poor symptom recognition, there are not enough pancreata to meet the need. The relatives of patients with diabetes often ask whether they can donate part of the pancreas, a practice performed successfully, primarily at the University of Minnesota, for the purposes of segmental pancreas transplantation.89 However, postoperative complications of pancreatitis and pancreatic pseudocyst, although infrequent, represent major risks to the donors. The most frequent issue for donors is the potential for diabetes. Donors are excluded if they are obese or have abnormal glucose tolerance or islet-cell antibodies, or if less than 10 years has lapsed since the onset of diabetes in the potential recipient. By the first year after hemipancreatectomy, almost all donors still have normal fasting glucose levels but 25 percent have oral glucose-tolerance results that are diagnostic of diabetes.90 Long-term follow-up for one to two decades indicates that fasting hyperglycemia is more likely to develop in donors who become obese and insulin-resistant.91
The pressure to create an adequate supply of islets has led to extensive basic-science research into the potential use of islet surrogates. These include islet expansion, encapsulated islet xenografts, human islet-cell lines, and embryonic stem cells. The concept that expanding islets is feasible was strengthened by a report that digested pancreatic tissue from which islets had been removed could be expanded as a monolayer of epithelial cells that formed ductal cysts from which islet-like clusters of endocrine cells budded.47 However, these results cannot be taken entirely at face value, because the pancreatic tissue was positive for insulin messenger RNA and insulin. Many investigators have advocated the use of xenografts, usually pig islets. Although there have been reports of success,92,93 none have reported consistent success with the use of this approach to transplant islets across species.
The establishment of human beta-cell lines has been a goal, because this method might provide unlimited quantities of cells for transplantation. De la Tour et al. reported that transformed, differentiated human beta cells were capable of secreting insulin in response to glucose in vivo.94 The reproducibility of these results and the demonstration that such cell lines are stable await confirmation by other investigators. Pluripotent embryonic stem cells have reportedly been converted into insulin-secreting cells,95,96,97,98,99 but the reproducibility of these results has been questioned.100 Very promising results have been reported with the use of monoclonal antibodies to induce tolerance and antitoxins directed against components of the allogeneic response system in primates,101,102,103,104 but no successful experiment has yet been reported in recipients of human islets.
Conclusions
The dream that began in 1972 of transplanting islets to patients with diabetes to restore normoglycemia and to eliminate the need for insulin injections remains a work in progress. Many important problems must be solved before islet transplantation can take its place as a conventional therapeutic option. The worldwide success rate of pancreas transplantation renders it the more effective procedure, especially since it uses only one donated organ. Practical issues, such as the huge losses of islets during isolation and purification, the clinical complications associated with the use of the hepatic site, adverse reactions to immunosuppressive drugs, and insufficient supply, require resolution. Until then, only specialized centers should carry out islet transplantation. Information about the long-term benefits of transplantation with respect to the secondary complications of diabetes has only recently begun to emerge.105 Nonetheless, it is clear the remaining problems should be resolvable through the use of currently available scientific methods. The good news is that the rates of successful islet transplantation are increasing, and each such success is teaching us valuable lessons about improving beta-cell replacement in patients with diabetes.
Supported by a grant (RO1 39994) from the National Institutes of Health.
Source Information
From the Pacific Northwest Research Institute and the Division of Metabolism, Endocrinology, and Nutrition, Departments of Medicine and Pharmacology, University of Washington School of Medicine, Seattle.
Address reprint requests to Dr. Robertson at the Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122, or at rpr@pnri.org.
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Gillison SL, Bartlett ST, Curry DL. Inhibition by cyclosporine of insulin secretion -- a beta cell-specific alteration of islet tissue function. Transplantation 1991;52:890-895.
Ricordi C, Zeng YJ, Alejandro R, et al. In vivo effect of FK506 on human pancreatic islets. Transplantation 1991;52:519-522.
Strasser S, Alejandro R, Shapiro ET, Ricordi C, Todo S, Mintz DH. Effect of FK506 on insulin secretion in normal dogs. Metabolism 1992;41:64-67.
Ishizuka J, Gugliuzza KK, Wassmuth Z, et al. Effects of FK506 and cyclosporine on dynamic insulin secretion from isolated dog pancreatic islets. Transplantation 1993;56:1486-1490.
Fabian MC, Lakey JR, Rajotte RV, Kneteman NM. The efficacy and toxicity of rapamycin in murine islet transplantation: in vitro and in vivo studies. Transplantation 1993;56:1137-1142.
Redmon JB, Olson LK, Armstrong MB, Greene MJ, Robertson RP. Effects of tacrolimus (FK506) on human insulin gene expression, insulin mRNA levels, and insulin secretion in HIT-T15 cells. J Clin Invest 1996;98:2786-2793.
Meredith M, Li G, Metz SA. Inhibition of calcium-induced insulin secretion from intact HIT-T15 or INS-1 beta cells by GTP depletion. Biochem Pharmacol 1997;53:1873-1882.
Davani B, Khan A, Hult M, et al. Type 1 11beta-hydroxysteroid dehydrogenase mediates glucocorticoid activation and insulin release in pancreatic islets. J Biol Chem 2000;275:34841-34844.
Paty BW, Harmon JS, Marsh CL, Robertson RP. Inhibitory effects of immunosuppressive drugs on insulin secretion from HIT-T15 drugs and Wistar rat islets. Transplantation 2002;73:353-357.
Oetjen E, Baun D, Beimesche S, et al. Inhibition of human insulin gene transcription by the immunosuppressive drugs cyclosporin A and tacrolimus in primary, mature islets of transgenic mice. Mol Pharmacol 2003;63:1289-1295.
Oetjen E, Grapentin D, Blume R, et al. Regulation of human insulin gene transcription by the immunosuppressive drugs cyclosporin A and tacrolimus at concentrations that inhibit calcineurin activity and involving the transcription factor CREB. Naunyn Schmiedebergs Arch Pharmacol 2003;367:227-236.
Carlsson PO, Palm F, Mattsson G. Low revascularization of experimentally transplanted human pancreatic islets. J Clin Endocrinol Metab 2002;87:5418-5423.
Hirshberg B, Mog S, Patterson N, Leconte J, Harlan DM. Histopathological study of intrahepatic islets transplanted in the nonhuman primate model using Edmonton protocol immunosuppression. J Clin Endocrinol Metab 2002;87:5424-5429.
Kendall DM, Teuscher AU, Robertson RP. Defective glucagon secretion during sustained hypoglycemia following successful islet allo- and autotransplantation in humans. Diabetes 1997;46:23-27.
Gupta V, Wahoff DC, Rooney DP, et al. The defective glucagon response from transplanted intrahepatic pancreatic islets during hypoglycemia is transplantation site-determined. Diabetes 1997;46:28-33.
Paty BW, Ryan EA, Shapiro AM, Lakey JR, Robertson RP. Intrahepatic islet transplantation in type 1 diabetic patients does not restore hypoglycemic hormonal counterregulation or symptom recognition after insulin independence. Diabetes 2002;51:3428-3434.
Kin T, Korbutt GS, Rajotte RV. Survival and metabolic function of syngeneic rat islet grafts transplanted in the omental pouch. Am J Transplant 2003;3:281-285.
Robertson RP, Lafferty KJ, Haug CE, Weil R III. Effect of human fetal pancreas transplantation on secretion of C-peptide and glucose tolerance in type I diabetics. Transplant Proc 1987;19:2354-2356.
Shapiro J. Eighty years after insulin: parallels with modern islet transplantation. CMAJ 2002;167:1398-1400.
Markmann JF, Deng S, Huang X, et al. Insulin independence following isolated islet transplantation and single islet infusions. Ann Surg 2003;237:741-749.
Hirshberg B, Rother KI, Digon BJ III, et al. Benefits and risks of solitary islet transplantation for type 1 diabetes using steroid-sparing immunosuppression: the National Institutes of Health experience. Diabetes Care 2003;26:3288-3295.
Ault A. Edmonton's islet success tough to duplicate elsewhere. Lancet 2003;361:2054-2054.
Ryan EA, Lakey JR, Paty BW, et al. Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes 2002;51:2148-2157.
Robertson RP, Kendall D. Islet transplantation 2003: questions about its future. Curr Opin Endocrinol Diabetes 2003;10:128-32.
Robertson RP, Lanz KJ, Sutherland DE, Kendall DM. Prevention of diabetes for up to 13 years by autoislet transplantation after pancreatectomy for chronic pancreatitis. Diabetes 2001;50:47-50.
Jaeger C, Brendel MD, Hering BJ, Eckhard M, Bretzel RG. Progressive islet graft failure occurs significantly earlier in autoantibody-positive than in autoantibody-negative IDDM recipients of intrahepatic islet allografts. Diabetes 1997;46:1907-1910.
Bosi E, Braghi S, Maffi P, et al. Autoantibody response to islet transplantation in type 1 diabetes. Diabetes 2001;50:2464-2471.
Dagogo-Jack S, Rattarasarn C, Cryer PE. Reversal of hypoglycemia unawareness, but not defective glucose counterregulation, in IDDM. Diabetes 1994;43:1426-1434.
Fanelli CG, Epifano L, Rambotti AM, et al. Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and magnitude of most of neuroendocrine responses to, symptoms of, and cognitive function during hypoglycemia in intensively treated patients with short-term IDDM. Diabetes 1993;42:1683-1689.
Davis M, Mellman M, Friedman S, Chang CJ, Shamoon H. Recovery of epinephrine response but not hypoglycemic symptom threshold after intensive therapy in type 1 diabetes. Am J Med 1994;97:535-542.
Luzi L, Perseghin G, Brendel MD, et al. Metabolic effects of restoring partial beta-cell function after islet allotransplantation in type 1 diabetic patients. Diabetes 2001;50:277-282.
Sutherland DE, Gruessner RW, Dunn DL, et al. Lessons learned from more than 1,000 pancreas transplants at a single institution. Ann Surg 2001;233:463-501.
Kendall DM, Sutherland DER, Najarian JS, Goetz FC, Robertson RP. Effects of hemipancreatectomy on insulin secretion and glucose tolerance in healthy humans. N Engl J Med 1990;322:898-903.
Robertson RP, Lanz KJ, Sutherland DE, Seaquist ER. Relationship between diabetes and obesity 9 to 18 years after hemipancreatectomy and transplantation in donors and recipients. Transplantation 2002;73:736-741.
Sun Y, Ma X, Zhou D, Vacek I, Sun AM. Normalization of diabetes in spontaneously diabetic cynomologus monkeys by xenografts of microencapsulated porcine islets without immunosuppression. J Clin Invest 1996;98:1417-1422.
Lanza RP, Butler DH, Borland KM, et al. Xenotransplantation of canine, bovine, and porcine islets in diabetic rats without immunosuppression. Proc Natl Acad Sci U S A 1991;88:11100-11104.
de la Tour D, Halvorsen T, Demeterco C, et al. Beta-cell differentiation from a human pancreatic cell line in vitro and in vivo. Mol Endocrinol 2001;15:476-483.
Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R. Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 2001;292:1389-1394.
Soria B, Skoudy A, Martin F. From stem cells to beta cells: new strategies in cell therapy of diabetes mellitus. Diabetologia 2001;44:407-415.
Assady S, Maor G, Amit M, Itskovitz-Elder J, Skorecki KL, Tzukerman M. Insulin production by human embryonic stem cells. Diabetes 2001;50:1691-1697.
Zulewski H, Abraham EJ, Gerlach MJ, et al. Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes 2001;50:521-533.
Hori Y, Rulifson IC, Tsai BC, Heit JJ, Cahoy JD, Kim SK. Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells. Proc Natl Acad Sci U S A 2002;99:16105-16110.
Rajagopal J, Anderson WJ, Kume S, Martinez OI, Melton DA. Insulin staining of ES cell progeny from insulin uptake. Science 2003;299:363-363.
Kenyon NS, Fernandez LA, Lehmann R, et al. Long-term survival and function of intrahepatic islet allografts in baboons treated with humanized anti-CD154. Diabetes 1999;48:1473-1481.
Kenyon NS, Chatzipetrou M, Masetti M, et al. Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154. Proc Natl Acad Sci U S A 1999;96:8132-8137.
Contreras JL, Eckhoff DE, Cartner S, et al. Long-term functional islet mass and metabolic function after xenoislet transplantation in primates. Transplantation 2000;69:195-201.
Thomas JM, Contreras JL, Smyth CA, et al. Successful reversal of streptozotocin-induced diabetes with stable allogeneic islet function in a preclinical model of type 1 diabetes. Diabetes 2001;50:1227-1236.
Fiorina P, Folli F, Bertuzzi F, et al. Long-term beneficial effect of islet transplantation on diabetic macro-/microangiopathy in type 1 diabetic kidney-transplanted patients. Diabetes Care 2003;26:1129-1136.
Related Letters:
Islet Transplantation as a Treatment for Diabetes
Harlan D. M., Rother K. I., Robertson R. P.(R. Paul Robertson, M.D.)
In addition to improving the ability of the medical community to control glycemia in patients with diabetes, the DCCT also provided a stronger rationale for the use of pancreas transplantation. Worldwide, the three-year organ-survival rate for simultaneous kidney and pancreas transplantation is approximately 70 to 80 percent,2 which is similar to the rates for most other types of organ transplantation. When successful, pancreas transplantation is particularly effective in patients with type 1 diabetes and autonomic insufficiency, who struggle with glycemic control, postural hypotension, gastroparesis, and diarrhea and have a dramatically shortened life span.3,4 Pancreas transplantation is more likely to result in normal glycosylated hemoglobin levels than is the intensive insulin-based approach to management prescribed in the DCCT. Long-term studies of motor, sensory, and autonomic neuropathy have demonstrated that these complications stabilize after pancreas transplantation,5 and native-kidney biopsies have shown a dramatic reversal of mesangial accumulation and basement-membrane thickening 10 years after the establishment of normal glucose levels by pancreas transplantation.6 Macrovascular complications are also stabilized by pancreas transplantation.7,8,9 Quality-of-life studies indicate that patients who undergo successful pancreas transplantation feel that the normalization of glucose levels and the freedom from daily insulin injections outweigh the problems caused by transplantation and its attendant immunosuppression.10,11,12,13,14
These favorable results were obtained in a highly selected group of patients who had major difficulties related to both achieving glycemic control and the disease itself and thus do not represent outcomes from randomized trials comparing medical management with pancreas transplantation. Nonetheless, the clinical outcomes of pancreas transplantation have been impressive enough for the American Diabetes Association to recommend in 2000 and again in 2003 that simultaneous pancreas transplantation should be considered at the time of kidney transplantation, that pancreas transplantation alone should be considered for patients with unacceptably poor metabolic control and quality of life despite optimal medical treatment, and that islet transplantation should still be considered an experimental procedure.
Success with pancreatic islet transplantation in series of patients far smaller than those involved in pancreas transplantation has led to optimism that islet transplantation may ultimately replace pancreas transplantation. Islet transplantation is a less demanding method of beta-cell replacement in that it does not involve major surgery, permits a lesser degree of immunosuppression, and is potentially less expensive for the recipient. Whether the physical and emotional costs are lower remains to be established, because there have been too few procedures for the complication rates associated with percutaneous liver puncture, anticoagulation, and immunosuppressive regimens to be determined. In this review, I will sketch the history of islet transplantation, describe the procedures of islet isolation and intrahepatic transplantation, consider the limitations of transplantation technology and the immunosuppressive drugs currently in use, compare the clinical outcomes of islet transplantation with those of pancreas transplantation, examine the definition of success, suggest avenues for future studies, and address the important problem of supply and demand.
History of Islet Transplantation from 1894 to 2000
The concept of transplanting pieces or extracts of pancreas in patients with diabetes is over a century old. The first known report appeared in 1894: Williams used minced sheep's pancreas and extracts of pancreas in glycerine for oral and subcutaneous therapy.15 This approach, audacious in retrospect, used sheep xenografts without immunosuppression and was reported as an overt failure. Virtually no subsequent effort was successful until 1972, when Ballinger and Lacy reported that islet isografts from normal rats could reverse streptozocin-induced diabetes in rats.16 By the 1980s successful transplantation of islet autografts17,18 and, in one instance, an islet allograft was reported in humans.19 In the autograft approach, a patient with unrelentingly painful, chronic pancreatitis and a poor quality of life undergoes complete pancreatectomy for pain relief. The removed pancreas is minced, digested with collagenase, and centrifuged to achieve a nonpurified preparation of islets that is infused into the patient's liver through the portal venous circulation within two hours after pancreatectomy. The islets lodge in the liver because they are too large to pass through the sinusoids. In 1992, Pyzdrowski et al.20 reported that 265,000 islets were sufficient to establish insulin independence. In 1995, Wahoff et al. reported an insulin-independence rate of 74 percent two years after autologous islet transplantation in 14 patients who had undergone total pancreatectomy and who had received a portal-vein infusion of more than 300,000 islets (the normal pancreas has roughly 1 million islets).21
In the 1980s, reports of successful allogeneic islet transplantation in patients with type 1 diabetes with the use of conventional immunosuppression and purified human islets from cadaveric donors began to appear19,22,23,24,25,26,27,28,29,30,31,32,33,34,35 (Table 1), but internationally, the overall rates of success were reported as less than 10 percent.36 In 2000, Shapiro et al. reported 100 percent success in seven patients.35 This high rate may have been due to the many differences in their approach as compared with previous techniques — there were restrictions on recipients' body weights, the immunosuppressive regimen was modified by the addition of sirolimus and low-dose tacrolimus together with avoidance of corticosteroids, patients received the anticytokine drug daclizumab, and multiple infusions of islets from different donors were used to attain a transplanted islet mass sufficient to achieve normal glucose levels and independence from exogenous insulin.
Table 1. Synopsis of Reports of Successful Islet Transplantation in Patients with Type 1 Diabetes.
Can Islet Yields Be Improved?
Paul Langerhans identified pancreatic islets in 1869, describing them as discrete islands or islets surrounded by pancreatic exocrine tissue37 — hence, the term "islets of Langerhans." The islets make up approximately 2 to 3 percent of the total pancreatic volume. Islets have a portal circulation, with blood flowing from beta to alpha to delta cells,38,39 as well as afferents from the central nervous system, which regulate secretion of these cells' hormones. The alpha, beta, delta, and PP cells secrete glucagon, insulin, somatostatin, and pancreatic polypeptide, respectively. Alpha and beta cells are exquisitely sensitive to glucose, which stimulates the beta cell and inhibits the alpha cell, thereby maintaining blood glucose levels within a narrow range. The principal actions of insulin promote the entry of glucose into tissues and decrease hepatic gluconeogenesis, whereas glucagon principally stimulates hepatic glycogenolysis when hypoglycemia threatens.
Modern islet-isolation technology involves the procurement of a healthy pancreas from a brain-dead donor whose heart is beating, although recent success has been reported with the use of cadaveric donors.40 The pancreas is procured with the use of the same techniques that are used to procure a pancreas for whole-organ transplantation. The pancreatic duct is cannulated, and collagenase is infused to separate islets from exocrine and ductal tissue.41 Subsequently, islets are purified by density–gradient centrifugation. The final product is evaluated for purity and viability before it is transported to the angiography suite for transplantation (Figure 1).
Figure 1. The Process of Islet Transplantation.
A pancreas is obtained from a donor. The pancreas is digested with collagenase to free the islets from surrounding exocrine tissue. The freed islets, containing mostly beta and alpha cells, are purified by density–gradient centrifugation to remove remaining exocrine cellular debris. The purified islets are infused into a catheter that has been placed percutaneously through the liver into the portal vein, whence they travel to the liver sinusoids.
Although relatively simple to describe, the process of islet isolation for transplantation is complicated. The health of and the medications used by the potential donor, the care with which the surgical team removes the pancreas, and the timeliness of transportation to the laboratory are important variables. Improvements in transport of the pancreas are being attempted by advocates of the "two-layer method," which sandwiches the pancreas between a bottom layer of perfluorodecalin saturated with oxygen and a top layer of University of Wisconsin preservation solution.42,43,44,45 Once the pancreas reaches the laboratory, four to six hours is required for complete processing and quality assessment of the islets.
Critics46 of this approach question the need for the purification step because it adds time, can cause the loss of 30 to 50 percent of islets, and traumatizes the remaining islets that are harvested. They point out that unpurified islets are used successfully in autologous transplantation and that purification removes pancreatic-duct stem cells that might give rise to new islets after transplantation.47 Proponents of purification respond by arguing that purification yields a much smaller tissue volume, which is thus less likely to cause portal hypertension. Culturing the islets after isolation would allow them to recover before transplantation48,49 and would decrease travel demands for recipients, who must currently arrive at the transplantation site within hours after notification.
Is the Liver the Optimal Site for Islet Infusion?
The liver, spleen, kidney capsule, testes, brain, peritoneal cavity, and omentum have all been considered as potential sites of islet infusion. The liver is by far the most commonly used site because of the early successes with autologous islet transplants. However, although autologous islets are infused intraoperatively directly into the hepatic portal venous circulation under direct view, islet allografts are infused percutaneously into the portal vein. Potential complications of an infusion into the liver include bleeding, portal venous thrombosis, and portal hypertension. Although portal blood pressure is monitored during the procedure and anticoagulant agents are used to prevent clotting, anticoagulation can promote hepatic bleeding at the sites of the percutaneous needle punctures. Furthermore, intrahepatic islets may be exposed to environmental toxins and potentially toxic prescribed medications absorbed from the gastrointestinal tract and delivered into the portal vein. Ironically, all commonly used immunosuppressive drugs have been reported to have adverse effects on pancreatic beta cells50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68 (Table 2). In addition, the antiproliferative effects of sirolimus may theoretically be disadvantageous both for angiogenesis in newly transplanted islets69,70 and for islet neogenesis from ductal stem cells.47
Table 2. Mechanisms of the Adverse Effects of Immunosuppressant Drugs on Beta Cells.
Finally, intrahepatic islets are unable to release glucagon during hypoglycemia20,71,72,73 (Figure 2 and Figure 3). Yet, though intrahepatic islets fail to respond to hypoglycemia, they appear to contain healthy alpha cells that process and secrete glucagon, as indicated by their response to intravenous arginine.20,71,72 Since not all recipients remain insulin-independent for the rest of their lives, they may become at risk for hypoglycemia and thus would benefit from having a glucagon response.
Figure 2. Lack of Glucagon Responses during Hypoglycemia Induced by Hypoglycemic, Hyperinsulinemic Clamping in Patients with Type 1 Diabetes Who Underwent Successful Transplantation of Intrahepatic Allografts.
During the study, insulin is infused at a steady rate and glucose at a decreasing rate so that glucose levels gradually reach 40 mg per deciliter. Reprinted from Paty et al.,73 with the permission of the publisher. P<0.05 for the comparison of glucagon levels at 0 and 180 minutes for the controls and for the comparison between the levels at 180 minutes in the controls and the levels in subjects with type 1 diabetes who underwent islet transplantation and those who did not.
Figure 3. Glucagon Responses in Pancreatectomized Dogs That Have Received Autologous Islets during Hypoglycemia Induced by Hypoglycemic, Hyperinsulinemic Clamping (Panel A) and Intravenous (IV) Arginine (Panel B).
In Panel A, glucagon responses remain intact when autologous islets are placed in the peritoneal cavity but not when they are placed in the liver. During the study, insulin is infused at a steady rate and glucose at a decreasing rate so that glucose levels gradually reach 40 mg per deciliter. In Panel B, glucagon responses remain intact after the intravenous infusion of arginine whether autologous islets are placed in the peritoneal cavity or in the liver. Reprinted from Gupta et al.,72 with the permission of the publisher.
In view of these problems, it is reasonable to consider the use of nonhepatic sites. It might also be possible to infuse unpurified islet preparations into nonhepatic sites, which would eliminate the trauma to and losses of islets caused by purification. Potential alternative sites include the peritoneal cavity and omentum, both of which have been used successfully in animal models and shown to be safe for humans.74,75
Clinical Outcomes, 2001 to 2003
Since the initial report35 from Edmonton, Alberta, Canada, many transplantation centers throughout the world have initiated corticosteroid-free protocols.76 Although the results of other studies are beginning to appear,77,78 in most instances, success rates have not yet been published. The Immune Tolerance Network has organized a nine-center trial designed to evaluate the reproducibility of the Edmonton results in 36 recipients. Preliminary information presented at the 2003 American Transplant Congress suggests robust success rates at more experienced centers, but much lower rates at less experienced centers.79 In addition, several patients who became insulin-independent after transplantation have withdrawn from the study because of unacceptable side effects of the immunosuppressive drugs.
The largest, most recent update on the clinical outcomes of the Edmonton experience was published in 2002.80 The authors reported 54 islet infusions in 30 recipients with type 1 diabetes and provided detailed follow-up data on 17 consecutive patients, all of whom became insulin-independent, with mean (±SE) glycosylated hemoglobin values of 6.1±0.8 percent after receiving a minimum of 9000 islets per kilogram of body weight, or 630,000 islets for a 70-kg person. Typically, two separate infusions of islets from two pancreata were used an average of one month apart. Four of six patients were insulin-independent for more than two years, but two of the four had impaired glucose tolerance. Fourteen of the initial 17 recipients no longer had hypoglycemic reactions. The adverse effects of the procedure included five bleeding episodes related to percutaneous puncture of the liver in 50 procedures, three transfusions, and one partial thrombosis of the portal vein with hepatic subcapsular hemorrhage caused by anticoagulant therapy that required transfusion and surgery. Transiently elevated liver-enzyme levels, hypercholesterolemia, further increases in creatinine levels in patients with preexisting renal disease, increased proteinuria in patients with preexisting proteinuria, increases in the doses of antihypertensive drugs, and the need for retinal laser photocoagulation were among the other complications. No deaths or life-threatening infections occurred.
The interpretation of these results is complicated by the fact that the Edmonton trial design did not include a similar and concurrent control cohort. Since the observation period before transplantation was not as long or as intense as the observation period after transplantation, extensive paired analyses of pretransplantation and post-transplantation clinical data are not possible. Whether two islet infusions a month apart are essential is unresolved, since recipients were not randomly assigned to receive either one infusion or two. Relevant data from studies of autologous islet transplantation suggest that islets continually regain function up to three months after infusion81 (Figure 4). Nonetheless, one can conclude that in the hands of the Edmonton group, islet transplantation is relatively safe and efficacious in eliminating the need for exogenous insulin and in preventing recurrent hypoglycemia, albeit at a cost of a roughly 10 percent incidence of liver bleeding related to the procedure. The initial graft survival rate of 80 percent with the use of islets from multiple donors compares favorably with that of successful pancreas transplantation4 and successful autologous islet transplantation.21 Whether or not the long-term survival of allografts will equal that of autologous grafts is unknown. Autologous grafts can function successfully for many years after transplantation. A recipient of one such autologous graft was reported to have normal fasting glucose and glycosylated hemoglobin levels 13 years after transplantation82 and remains insulin-independent 16 years later. However, recipients of islet allografts face the additional risk of recurrent autoimmune diabetes,83,84 as well as of side effects from treatment with immunosuppressive drugs that are potentially lethal to beta cells.
Figure 4. Acute Insulin Responses to Intravenous (IV) Glucose in a Nondiabetic Patient with Chronic Pancreatitis before and at Various Times after Pancreatectomy and Receipt of an Intrahepatic Islet Autograft.
The insulin response did not become substantial until the second month after transplantation, and it increased even more by the third month. Reprinted from Robertson et al.,75 with the permission of the publisher.
Defining Success
A major problem in judging the success of islet transplantation lies in the definition of success. The typical candidate has recurrent hypoglycemia with poor recognition of the resulting symptoms and abnormal glycosylated hemoglobin values. Although the first two issues can be resolved by lessening the intensity of insulin management,85,86,87 this approach increases glycosylated hemoglobin values. The use of a rigorous definition of success means recipients no longer use insulin, do not have hypoglycemia and poor recognition of symptoms, and have normal preprandial and postprandial glucose levels and glycosylated hemoglobin values for prolonged periods. The use of a more flexible definition means that the main problems that resulted in transplantation in the first place — frequent hypoglycemia with poor symptom recognition, a poor quality of life, and abnormal glycosylated hemoglobin values — have been solved. The more flexible view allows the use of oral hypoglycemic drugs and residual impaired glucose tolerance and is supported by some experts in the field,88 but not all.
Putting aside definitions of success, an equally important consideration is the cost–benefit ratio of islet transplantation, in both personal and financial terms. In addition to the clinical complications of the procedure, patients pay a personal price for using immunosuppressive drugs because of their adverse effects. In defense of islet transplantation, all types of allogeneic transplantation carry a risk of adverse effects related to immunosuppressive drugs and the financial cost of islet transplantation is less than that of pancreas transplantation. On the other hand, pancreas transplantation is more efficient, since it typically involves only a single procedure and quickly results in normal glucose and glycosylated hemoglobin values. A comparison of these two procedures illustrates another important difference. Whole pancreata are most often used for patients with renal failure who simultaneously receive kidney transplants. The increase in the quality of life, satisfaction with the procedure, and tolerance of adverse drug effects are likely to be greater among recipients of combined pancreas and kidney transplants than recipients of an islet transplant alone, because the former group of patients is typically more ill to begin with. This outcome leads many clinicians to conclude that simultaneous kidney and islet transplantation or islet transplantation after kidney transplantation is the preferred approach, rather than the transplantation of islets, in patients without renal failure. The combined procedures are used for the sicker patients, and the issue regarding the burden of immunosuppressive drugs can be finessed because patients scheduled for kidney transplantation know that they must receive these drugs.
The Next Generation of Research Studies
Although the prospect of islet transplantation as a treatment for diabetes is exciting, there are no data that allow firm conclusions to be drawn about who should receive this therapy. Continuing improvements in the medical management of diabetes invalidate the use of data from historical controls, even those obtained in the DCCT. Controlled studies are needed to evaluate the efficacy and complications of islet transplantation. If randomization is not possible, a case–control approach that includes patients who qualify for but decline to undergo the procedure could be used. Subgroups should be stratified according to the secondary complications of diabetes and to whether islets are transplanted alone or in conjunction with a kidney. Allowances must also be made for the further development of procurement and laboratory techniques for the isolation of islets, as well as the development of new immunosuppressive drugs that are less toxic to beta cells.
Problems of Supply and Demand
Demand for islet transplantation far exceeds the number of islets available. Even if the procedure is limited to adults with type 1 diabetes who have recurrent hypoglycemia and poor symptom recognition, there are not enough pancreata to meet the need. The relatives of patients with diabetes often ask whether they can donate part of the pancreas, a practice performed successfully, primarily at the University of Minnesota, for the purposes of segmental pancreas transplantation.89 However, postoperative complications of pancreatitis and pancreatic pseudocyst, although infrequent, represent major risks to the donors. The most frequent issue for donors is the potential for diabetes. Donors are excluded if they are obese or have abnormal glucose tolerance or islet-cell antibodies, or if less than 10 years has lapsed since the onset of diabetes in the potential recipient. By the first year after hemipancreatectomy, almost all donors still have normal fasting glucose levels but 25 percent have oral glucose-tolerance results that are diagnostic of diabetes.90 Long-term follow-up for one to two decades indicates that fasting hyperglycemia is more likely to develop in donors who become obese and insulin-resistant.91
The pressure to create an adequate supply of islets has led to extensive basic-science research into the potential use of islet surrogates. These include islet expansion, encapsulated islet xenografts, human islet-cell lines, and embryonic stem cells. The concept that expanding islets is feasible was strengthened by a report that digested pancreatic tissue from which islets had been removed could be expanded as a monolayer of epithelial cells that formed ductal cysts from which islet-like clusters of endocrine cells budded.47 However, these results cannot be taken entirely at face value, because the pancreatic tissue was positive for insulin messenger RNA and insulin. Many investigators have advocated the use of xenografts, usually pig islets. Although there have been reports of success,92,93 none have reported consistent success with the use of this approach to transplant islets across species.
The establishment of human beta-cell lines has been a goal, because this method might provide unlimited quantities of cells for transplantation. De la Tour et al. reported that transformed, differentiated human beta cells were capable of secreting insulin in response to glucose in vivo.94 The reproducibility of these results and the demonstration that such cell lines are stable await confirmation by other investigators. Pluripotent embryonic stem cells have reportedly been converted into insulin-secreting cells,95,96,97,98,99 but the reproducibility of these results has been questioned.100 Very promising results have been reported with the use of monoclonal antibodies to induce tolerance and antitoxins directed against components of the allogeneic response system in primates,101,102,103,104 but no successful experiment has yet been reported in recipients of human islets.
Conclusions
The dream that began in 1972 of transplanting islets to patients with diabetes to restore normoglycemia and to eliminate the need for insulin injections remains a work in progress. Many important problems must be solved before islet transplantation can take its place as a conventional therapeutic option. The worldwide success rate of pancreas transplantation renders it the more effective procedure, especially since it uses only one donated organ. Practical issues, such as the huge losses of islets during isolation and purification, the clinical complications associated with the use of the hepatic site, adverse reactions to immunosuppressive drugs, and insufficient supply, require resolution. Until then, only specialized centers should carry out islet transplantation. Information about the long-term benefits of transplantation with respect to the secondary complications of diabetes has only recently begun to emerge.105 Nonetheless, it is clear the remaining problems should be resolvable through the use of currently available scientific methods. The good news is that the rates of successful islet transplantation are increasing, and each such success is teaching us valuable lessons about improving beta-cell replacement in patients with diabetes.
Supported by a grant (RO1 39994) from the National Institutes of Health.
Source Information
From the Pacific Northwest Research Institute and the Division of Metabolism, Endocrinology, and Nutrition, Departments of Medicine and Pharmacology, University of Washington School of Medicine, Seattle.
Address reprint requests to Dr. Robertson at the Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122, or at rpr@pnri.org.
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