Diabetes Cure — Is the Glass Half Full?
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《新英格兰医药杂志》
Nearly 80 years after the first clinical use of insulin, many important advances in the treatment of type 1 diabetes mellitus continue to be made. In this issue of the Journal, Shapiro et al.1 report on a multinational, prospective trial to disseminate the complicated knowledge and techniques required to prepare and transplant human islets and to evaluate the ability to provide a durable cure for a highly selected group of patients with type 1 diabetes.
It is important to realize how far this field has come in the past few years (Figure 1). Before 2000, the preceding two decades of islet transplantation had achieved an international 1-year rate of allograft survival of less than 2%. Then in 2000, a group that Shapiro headed at the University of Alberta in Edmonton, Canada, published a groundbreaking study2 in which they demonstrated that islet transplantation could result in what appeared to be a durable diabetes cure, with a 1-year graft survival of more than 80%. This study launched a new era in islet transplantation with what is now called the "Edmonton protocol." The Canadian investigators spurred a worldwide interest in replicating these promising results and disseminating this potentially important clinical service to more patients, with a protocol that might ultimately make islet-cell transplantation a routine procedure.
Figure 1. Milestones in the Treatment of Diabetes.
NPH denotes neutral protamine Hagedorn.
To this end, Shapiro et al. undertook an international, multicenter trial1 of islet transplantation using the Edmonton protocol. The trial teaches us several things. First, it is possible to conduct a large, multicenter, international trial in a young field in order to evaluate a complex and challenging means of technology. It is noteworthy that in order to recruit 36 patients, the investigators screened more than 2000 subjects for eligibility. Only 7% fulfilled the initial screening criteria, which included severe recurrent hypoglycemia, severe glycemic lability, progressive secondary complications, and the failure of conventional therapy. Second, many technical hurdles remain. Only 45% of islet isolations resulted in transplants, meaning that the majority of isolations were inadequate. Multiple islet infusions were also required: 31% of patients received a single infusion, 25% received two infusions, and 44% received three infusions, showing the difficulty of isolating and engrafting an adequate number of labile cells. Third, the clinical results were mixed. Of the 36 patients who entered the study, 44% attained the stringent primary end point of insulin independence, defined as a glycated hemoglobin value of less than 6.5%, a glucose level after an overnight fast not exceeding 140 mg per deciliter (7.8 mmol per liter) more than three times per week, and a 2-hour postprandial glucose level not exceeding 180 mg per deciliter (10 mmol per liter) more than four times per week. A total of 28% of patients had partial graft function, defined by a C-peptide level of 0.3 ng per milliliter or more and the requirement of insulin or inadequate glycemic control. Another 28% had complete graft loss. Analyzed another way, 58% of the subjects reached insulin independence at some point during the trial, but 76% had become insulin-dependent again by 2 years after transplantation.
In a recent study with similar findings,3 the Edmonton group reviewed the outcomes of their first 65 patients. The excellent initial results have been followed by disappointment, since only about 10% of recipients maintained insulin independence after 5 years. An unusual finding in the study by Shapiro et al.1 was that subjects with minimal residual islet function had no further severe hypoglycemic episodes, perhaps suggesting that even a small number of islets may be able to protect against this life-threatening complication.
The results can be seen according to the metaphor of the glass half full or half empty. The Edmonton protocol is clearly orders of magnitude better than previous attempts at islet transplantation. The study by Shapiro et al. shows that institutions all over the world can successfully perform the protocol with at least short-term results that are promising. The problem remains that the medium- to long-term results are not durable, so much more work is needed. Fortunately, there is no lack of targets for focused and high-yield research, including increasing the donor supply, new techniques for the isolation of islets, an improved understanding of islet-cell proliferation, marked improvements in the understanding of immunology, the use of new immunosuppressive drugs, and the development of trophic factors for islets and their progenitors. Additional work suggests that adult and embryonic stem cells may provide a source of islets.4,5 Xenotransplantation of islets from other species may also be tenable in the future.6 Thus, the study by Shapiro et al. offers hope that we will see improved outcomes in islet transplantation in the near future.
From a policy standpoint, the question remains whether islet transplantation should remain primarily a research initiative available to a small number of highly selected patients or whether the technology should be more broadly disseminated. In this respect, islet transplantation should be compared with other treatments. Whole-organ pancreas transplantation is significantly better than islet transplantation, with a rate of 5-year graft survival in the range of 50 to 70%, far in excess of the 10% rate of survival of islet grafts.7 With regard to conventional therapies and the avoidance of diabetic complications, the Diabetes Control and Complications Trial clearly demonstrated that tight metabolic control in type 1 diabetes results in a significant reduction in the development and progression of retinopathy, microalbuminuria and macroalbuminuria, and neuropathy. The follow-up Epidemiology of Diabetes Interventions and Complications study supported the idea that early intensive glycemic control has long-term benefits.8 The introduction of long-acting and rapid-acting insulin analogues, used in the basal-bolus paradigm, has markedly improved glycemic control.9 The use of such analogues, with continuous subcutaneous infusion pumps or as multiple daily injections, has had remarkable long-term results. Devices for monitoring blood glucose levels have become more advanced and are constantly being improved. Already in use are devices for continuous monitoring that read ambient blood glucose in real time, permitting immediate adjustment of the insulin dose.10 As new methods for noninvasive continuous monitoring advance, they will become the standard of care, assuming a reasonable cost. Another new development that may have an important effect on care is the closed-loop system, which combines continuous blood glucose monitoring, an algorithm for the conversion of glucose levels to insulin dose, and an insulin delivery device.11 The implications for glycemic control with the advent of these advanced techniques are that such therapy will be available to every patient, not just a select few.
The observation by Shapiro et al. that patients with even a small amount of residual islet function, as evidenced by a persistent level of C peptide, have a marked decrease in episodes of diabetic hypoglycemia is provocative. Does such a low level of insulin prevent this complication? And, if so, why? Do the immunosuppressive medications have an effect on intermediary metabolism? Is there engraftment of stem cells? Has the immunosuppression allowed for regrowth of endogenous pancreatic stem cells and islets? These important questions — many of which are the subjects of ongoing investigations — deserve more scrutiny.
Islet transplantation is at a crossroads. It is clear that poor long-term results, high costs, and the relatively high incidence of major and minor serious adverse events make it difficult to argue for expansion of islet transplantation to the general population. Nonetheless, the dramatic discoveries and successful dissemination of information in a relatively short period encourage us to believe these advances will continue apace. Additional research investments are likely to be high yield and to have a positive effect on many patients in the not-too-distant future.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Mount Sinai School of Medicine, New York.
References
Shapiro AMJ, Ricordi C, Hering BJ, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med 2006;355:1318-1330.
Shapiro AMJ, Lakey JRT, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343:230-238.
Ryan EA, Paty BW, Senior PA, et al. Five-year follow-up after clinical islet transplantation. Diabetes 2005;54:2060-2069.
Bonner-Weir S, Weir GC. New sources of pancreatic -cells. Nat Biotechnol 2005;23:857-861.
Hao E, Tyrberg B, Itkin-Ansari P, et al. Beta-cell differentiation from nonendocrine epithelial cells of the adult human pancreas. Nat Med 2006;12:310-316.
Hering BJ, Wijkstrom M, Graham ML, et al. Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nat Med 2006;12:301-303.
Cohen DJ, St Martin L, Christensen LL, Bloom RD, Sung RS. Kidney and pancreas transplantation in the United States, 1995-2004. Am J Transplant 2006;6:1153-1169.
Genuth S. Insights from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study on the use of intensive glycemic treatment to reduce the risk of complications of type 1 diabetes. Endocr Pract 2006;12:Suppl 1:34-41.
Gerich JE. Insulin glargine: long-acting basal insulin analog for improved metabolic control. Curr Med Res Opin 2004;20:31-37.
Garg S, Zisser H, Schwartz S, et al. Improvement in glycemic excursions with a transcutaneous, real-time continuous glucose sensor: a randomized controlled trial. Diabetes Care 2006;29:44-50.
Klonoff DC. Continuous glucose monitoring: roadmap for 21st century diabetes therapy. Diabetes Care 2005;28:1231-1239.(Jonathan S. Bromberg, M.D)
It is important to realize how far this field has come in the past few years (Figure 1). Before 2000, the preceding two decades of islet transplantation had achieved an international 1-year rate of allograft survival of less than 2%. Then in 2000, a group that Shapiro headed at the University of Alberta in Edmonton, Canada, published a groundbreaking study2 in which they demonstrated that islet transplantation could result in what appeared to be a durable diabetes cure, with a 1-year graft survival of more than 80%. This study launched a new era in islet transplantation with what is now called the "Edmonton protocol." The Canadian investigators spurred a worldwide interest in replicating these promising results and disseminating this potentially important clinical service to more patients, with a protocol that might ultimately make islet-cell transplantation a routine procedure.
Figure 1. Milestones in the Treatment of Diabetes.
NPH denotes neutral protamine Hagedorn.
To this end, Shapiro et al. undertook an international, multicenter trial1 of islet transplantation using the Edmonton protocol. The trial teaches us several things. First, it is possible to conduct a large, multicenter, international trial in a young field in order to evaluate a complex and challenging means of technology. It is noteworthy that in order to recruit 36 patients, the investigators screened more than 2000 subjects for eligibility. Only 7% fulfilled the initial screening criteria, which included severe recurrent hypoglycemia, severe glycemic lability, progressive secondary complications, and the failure of conventional therapy. Second, many technical hurdles remain. Only 45% of islet isolations resulted in transplants, meaning that the majority of isolations were inadequate. Multiple islet infusions were also required: 31% of patients received a single infusion, 25% received two infusions, and 44% received three infusions, showing the difficulty of isolating and engrafting an adequate number of labile cells. Third, the clinical results were mixed. Of the 36 patients who entered the study, 44% attained the stringent primary end point of insulin independence, defined as a glycated hemoglobin value of less than 6.5%, a glucose level after an overnight fast not exceeding 140 mg per deciliter (7.8 mmol per liter) more than three times per week, and a 2-hour postprandial glucose level not exceeding 180 mg per deciliter (10 mmol per liter) more than four times per week. A total of 28% of patients had partial graft function, defined by a C-peptide level of 0.3 ng per milliliter or more and the requirement of insulin or inadequate glycemic control. Another 28% had complete graft loss. Analyzed another way, 58% of the subjects reached insulin independence at some point during the trial, but 76% had become insulin-dependent again by 2 years after transplantation.
In a recent study with similar findings,3 the Edmonton group reviewed the outcomes of their first 65 patients. The excellent initial results have been followed by disappointment, since only about 10% of recipients maintained insulin independence after 5 years. An unusual finding in the study by Shapiro et al.1 was that subjects with minimal residual islet function had no further severe hypoglycemic episodes, perhaps suggesting that even a small number of islets may be able to protect against this life-threatening complication.
The results can be seen according to the metaphor of the glass half full or half empty. The Edmonton protocol is clearly orders of magnitude better than previous attempts at islet transplantation. The study by Shapiro et al. shows that institutions all over the world can successfully perform the protocol with at least short-term results that are promising. The problem remains that the medium- to long-term results are not durable, so much more work is needed. Fortunately, there is no lack of targets for focused and high-yield research, including increasing the donor supply, new techniques for the isolation of islets, an improved understanding of islet-cell proliferation, marked improvements in the understanding of immunology, the use of new immunosuppressive drugs, and the development of trophic factors for islets and their progenitors. Additional work suggests that adult and embryonic stem cells may provide a source of islets.4,5 Xenotransplantation of islets from other species may also be tenable in the future.6 Thus, the study by Shapiro et al. offers hope that we will see improved outcomes in islet transplantation in the near future.
From a policy standpoint, the question remains whether islet transplantation should remain primarily a research initiative available to a small number of highly selected patients or whether the technology should be more broadly disseminated. In this respect, islet transplantation should be compared with other treatments. Whole-organ pancreas transplantation is significantly better than islet transplantation, with a rate of 5-year graft survival in the range of 50 to 70%, far in excess of the 10% rate of survival of islet grafts.7 With regard to conventional therapies and the avoidance of diabetic complications, the Diabetes Control and Complications Trial clearly demonstrated that tight metabolic control in type 1 diabetes results in a significant reduction in the development and progression of retinopathy, microalbuminuria and macroalbuminuria, and neuropathy. The follow-up Epidemiology of Diabetes Interventions and Complications study supported the idea that early intensive glycemic control has long-term benefits.8 The introduction of long-acting and rapid-acting insulin analogues, used in the basal-bolus paradigm, has markedly improved glycemic control.9 The use of such analogues, with continuous subcutaneous infusion pumps or as multiple daily injections, has had remarkable long-term results. Devices for monitoring blood glucose levels have become more advanced and are constantly being improved. Already in use are devices for continuous monitoring that read ambient blood glucose in real time, permitting immediate adjustment of the insulin dose.10 As new methods for noninvasive continuous monitoring advance, they will become the standard of care, assuming a reasonable cost. Another new development that may have an important effect on care is the closed-loop system, which combines continuous blood glucose monitoring, an algorithm for the conversion of glucose levels to insulin dose, and an insulin delivery device.11 The implications for glycemic control with the advent of these advanced techniques are that such therapy will be available to every patient, not just a select few.
The observation by Shapiro et al. that patients with even a small amount of residual islet function, as evidenced by a persistent level of C peptide, have a marked decrease in episodes of diabetic hypoglycemia is provocative. Does such a low level of insulin prevent this complication? And, if so, why? Do the immunosuppressive medications have an effect on intermediary metabolism? Is there engraftment of stem cells? Has the immunosuppression allowed for regrowth of endogenous pancreatic stem cells and islets? These important questions — many of which are the subjects of ongoing investigations — deserve more scrutiny.
Islet transplantation is at a crossroads. It is clear that poor long-term results, high costs, and the relatively high incidence of major and minor serious adverse events make it difficult to argue for expansion of islet transplantation to the general population. Nonetheless, the dramatic discoveries and successful dissemination of information in a relatively short period encourage us to believe these advances will continue apace. Additional research investments are likely to be high yield and to have a positive effect on many patients in the not-too-distant future.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Mount Sinai School of Medicine, New York.
References
Shapiro AMJ, Ricordi C, Hering BJ, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med 2006;355:1318-1330.
Shapiro AMJ, Lakey JRT, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343:230-238.
Ryan EA, Paty BW, Senior PA, et al. Five-year follow-up after clinical islet transplantation. Diabetes 2005;54:2060-2069.
Bonner-Weir S, Weir GC. New sources of pancreatic -cells. Nat Biotechnol 2005;23:857-861.
Hao E, Tyrberg B, Itkin-Ansari P, et al. Beta-cell differentiation from nonendocrine epithelial cells of the adult human pancreas. Nat Med 2006;12:310-316.
Hering BJ, Wijkstrom M, Graham ML, et al. Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nat Med 2006;12:301-303.
Cohen DJ, St Martin L, Christensen LL, Bloom RD, Sung RS. Kidney and pancreas transplantation in the United States, 1995-2004. Am J Transplant 2006;6:1153-1169.
Genuth S. Insights from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study on the use of intensive glycemic treatment to reduce the risk of complications of type 1 diabetes. Endocr Pract 2006;12:Suppl 1:34-41.
Gerich JE. Insulin glargine: long-acting basal insulin analog for improved metabolic control. Curr Med Res Opin 2004;20:31-37.
Garg S, Zisser H, Schwartz S, et al. Improvement in glycemic excursions with a transcutaneous, real-time continuous glucose sensor: a randomized controlled trial. Diabetes Care 2006;29:44-50.
Klonoff DC. Continuous glucose monitoring: roadmap for 21st century diabetes therapy. Diabetes Care 2005;28:1231-1239.(Jonathan S. Bromberg, M.D)