Intramuscular islet transplantation promotes restored islet vascularity

In a recent publication, we reported that islets transplanted to mouse striated muscle became revascularized with intra-islet vessel densities comparable to native islets. Revascularization of islet grafts was completely dependent on recruited Gr-1+ leukocytes. Diabetic mice cured by transplantation of 300 islets into muscle handled glucose tolerance tests as healthy controls, whereas mice cured by intraportal islet transplantation into the liver had increased blood glucose values during the load. The translational impact of these observations were confirmed by magnetic resonance imaging of autotransplanted islets in the forearm muscle of pancreactomized patients, and higher blood perfusion of the grafts compared to adjacent muscle were found. In summary, the striated muscle is a promising site for islet transplantation which promotes full revascularization of implanted grafts. The proangiogenic role of recruited leukocytes during engraftment needs to be further characterized, and considered for immune suppression treatments.     

Clinical islet transplantation

Achieving stable metabolic control in patients with type 1 diabetes mellitus (T1DM) is highly desirable and may contribute to delaying and/or preventing the development of secondary complications. Transplantation of pancreatic islets represents a viable option for the treatment of patients with unstable T1DM with frequent severe hypoglycemia and hypoglycemia unawareness. The benefits of the transplant include improvement of glycemic control, prevention of severe hypoglycemia and amelioration of quality of life. The success of future clinical trials will depend on the implementation of an integrated therapeutic approach combining strategies to maximize islet availability and engraftment with those aiming at safely modulating the recipients' immunity to afford long-term function. The steady progress of recent years in islet cell processing and patient management after transplantation justify great optimism for the years to come.     

Clinical islet transplantation

Type 1 diabetes affects over 1 million persons in the United States, with over 30,000 new cases diagnosed annually. Transplantation of new insulin-producing β cells, in the form of the whole pancreas or isolated islets, has been shown to ameliorate the disease by eliminating the need for exogenous insulin and normalizing glycosylated hemoglobin levels. Islet transplants are a particularly attractive form of therapy because they are a minimally invasive procedure and are more likely to be scaled-up to treat the large numbers of people affected by diabetes. Currently, only a handful of programs have been successful in the endeavor. Nevertheless, the early clinical experience strongly demonstrates that islet transplantation is an effective treatment strategy in select patients with type 1 diabetes. To scale up this therapy and use it earlier in the disease and for more people, the shortage of suitable donor tissue must be solved and the requirement of lifelong immunosuppression must be minimized.     

Pancreatic and islet transplantation

Diabetes mellitus is the most devastating chronic disease of all time. This review discusses the current therapies for type 1 diabetes that are predicated on the restoration of insulin secretion by transplantation. Recent developments in vascularized pancreas transplantation have led to a dramatic increase in the number of these procedures performed worldwide, with over 10,000 cases reported currently to the International Pancreas Transplant Registry. Although the procedure contributes to a significant improvement in quality of life, compared with traditional insulin therapy, it still suffers from a number of shortcomings, including a persistently high postoperative morbidity rate and the requirement of long-term immunosuppression. Islet transplantation is therefore being pursued actively as an equally efficient means of restoring normoglycemia, but without the attendant morbidity of the whole-organ procedure, and hopefully with a significantly reduced need for immunosuppression.     

Pancreas and islet transplantation

Clinical islet allotransplantation has been a safe, but largely unsuccessful enterprise. It has been difficult to apply techniques that might overcome the islet yield and allograft rejection problems encountered in animal experiments. Over the past decade only 4 of 74 attempts at islet transplantation have been followed by long term withdrawal of exogenous insulin therapy, and there are problems with intrepretation of the outcome in each of theses cases, as discussed in the preceding section. In the islet allograft situation, the failures may have been for technical or for immunological reasons. In the autograft situation, rejection could not occur and the failures were clearly technical. The success rate with islet autografts gives some indication as to what might be achieved with islet allotransplantation if rejection could be prevented in the latter situation. The islet autotransplant experience is not entirely predictative, however, for two reasons: 1) the uncertainty over the contribution of the pancreatic remnant to carbohydrate metabolism when less than the total pancreatectomy is done; 2) the increased difficulty with liberating islets from diseased, fibrotic pancreases. For both islet allo- and autotransplantation, the success rate will probably remain low until more effective techniques are developed for preparation of islets from adult pancreases. For the allograft situation, additional advances will be needed in immunosuppression or in techniques to alter islet graft immunogenicity in order to overcome the rejection phenomenon.     

History of islet transplantation

Patients with a diagnosis of type 1 diabetes mellitus endure stringent life-long medical therapy through the use of insulin to prevent end organ complications and maintain normoglycemia. However, some patients still suffer from hypoglycemic unawareness, even under intensive therapy. Within the past decade, noble efforts have been attempted to provide normoglycemia through cadaveric islet of Langerhans transplantation in order to reach a physiologic response. This effort, which has evolved for more than a century, actually predates the discovery of insulin.     

胰腺和胰岛移植的现状和展望

成功的胰岛细胞替代（胰腺器官移植或分离胰岛移植）是治疗1型糖尿病的根本途径。目前胰腺移植主要作为肾移植的附属手术,应用于糖尿病合并尿毒症患者。胰岛细胞移植比胰腺移植更简单、安全。胰岛保存、分离技术和免疫抑制剂的发展将胰岛移植从基础研究推向临床应用。Edmonton方案在胰岛移植临床应用中具有里程碑意义。成体胰岛干细胞研究、胰岛异种移植等新技术的发展,将解决胰岛供体来源不足问题,为胰岛移植带来新的曙光。     

Clinical islet cell transplantation

Summary Diabetes mellitus is perhaps the most devastating chronic disease of all time. A brief history of the evolution of treatment modalities is provided, culminating in the rationale for the physiologic replacement of a functioning β-cell mass by transplantation. Vascularized pancreas transplantation is discussed briefly as an introduction to the transplantation of the isolated islet. A detailed review of the current state of human islet transplantation for the cure of diabetes is then described. Finally, areas for future development are highlighted.     

Assessment of islet function following islet and pancreas transplantation

Pancreas and islet transplant recipients are monitored using various metabolic and imaging methods. The inaccessibility of the transplanted whole pancreas and of the isolated islets poses specific problems (eg, all assessment techniques are indirect). Although successful pancreas transplantation typically restores normal glucose homeostasis, islet transplantation into the liver does not completely normalize islet hormone secretion and glucose metabolism. Development of better testing strategies, such as direct islet imaging, will significantly advance the field.     

Clinical islet transplantation in Japan

Introduction

The results of clinical islet transplantation in Japan are, here in, reported and discussed its efficacy and problems.

Methods

Since the first islet transplantation was performed in 2004, 65 islet isolations and 34 islet transplantations to 18 type 1 diabetic patients have been performed in Japan.

Results

Following islet transplantation, patients experienced decreased insulin requirements and lower hemoglobin A1C levels, and positive serum C-peptide levels. All patients achieved stabilized blood glucose levels and the disappearance of hypoglycemic unawareness. Although three patients achieved insulin independency for a limited period, persistent islet graft function was difficult to maintain. Overall islet graft survival was 86.5% at 6 months, 78.7% at 1 year, and 62.9% at 2 years after the first islet transplantation. In our institution, we carried out 23 islet isolations and six islet transplantations to four patients. Although insulin independency was not achieved, all patients showed a disappearance of hypoglycemic unawareness.

Conclusions

Using data from the Japanese Trial of Islet Transplantation, the effectiveness of islet transplantation was shown even when using the pancreata from non-heart-beating donors. Although there are a number of problems to be solved and further improvement is needed, we can state that the introduction of clinical islet transplantation offers hope for type 1 diabetic patients.     

Pancreas and islet cell transplantation

Currently, for the patient with type 1 diabetes, a definitive treatment without resorting to the use of exogenous insulin can be achieved only with pancreas or islet cell transplantation. These means of restoring beta-cell mass can completely maintain essentially normal long-term glucose homeostasis, although the need for powerful immunosuppressive regimens limits their application to only a subgroup of adult patients. Apart from the shortage of donors that has limited all kinds of transplantation, however, the widespread use of beta-cell replacement has been precluded until recently by the drawbacks associated with both organ and islet cell transplantation. Although the study of recurrence of diabetes has generated attention, the fundamental obstacle to pancreas and islet transplantation has been, and remains, the alloimmune response. With a better elucidation of the mechanisms of alloengraftment achieved during the last 3 years, the stage has been set for further advances.     

Current challenges in islet transplantation

Allogeneic islet transplantation is becoming a treatment option for patients with unstable type 1 diabetes mellitus (T1DM). Around 80% of the islet recipients achieve insulin independence after one or two islet infusions under “Edmonton-like” immunosuppressive protocol, but only 10% will remain insulin independent over the long term. Islet transplantation leads to glucose stabilization, and severe hypoglycemia is prevented even in patients back on insulin injections. Thus, islet transplantation has achieved the proposed targets in patients with unstable T1DM: normalizing blood glucose and hemoglobin A_1c, preventing severe hypoglycemic episodes, and improving quality of life. The current aims of islet transplantation programs are to maintain the success achieved and to overcome remaining obstacles and limitations.     

Optimising islet engraftment is critical for successful clinical islet transplantation

Clinical islet transplantation is currently being explored as a treatment for persons with type 1 diabetes and hypoglycaemia unawareness. Although ‘proof-of-principle’ has been established in recent clinical studies, the procedure suffers from low efficacy. At the time of transplantation, the isolated islets are allowed to embolise the liver after injection in the portal vein, a procedure that is unique in the area of transplantation. A novel view on the engraftment of intraportally transplanted islets is presented that could explain the low efficacy of the procedure.     

Current status of islet cell transplantation

Despite substantial advances in islet isolation methods and immunosuppressive protocol, pancreatic islet cell transplantation remains an experimental procedure currently limited to the most severe cases of type 1 diabetes mellitus. The objectives of this treatment are to prevent severe hypoglycemic episodes in patients with hypoglycemia unawareness and to achieve a more physiological metabolic control. Insulin independence and long term-graft function with improvement of quality of life have been obtained in several international islet transplant centers. However, experimental trials of islet transplantation clearly highlighted several obstacles that remain to be overcome before the procedure could be proposed to a much larger patient population. This review provides a brief historical perspective of islet transplantation, islet isolation techniques, the transplant procedure, immunosuppressive therapy, and outlines current challenges and future directions in clinical islet transplantation.