Cellular and physiological mechanisms of new-onset diabetes mellitus after solid organ transplantation

New-onset diabetes after transplantation is recognized as one of the metabolic consequences which may increase the risk of morbidity and mortality after solid organ transplantation. The pathophysiology of new-onset diabetes after transplantation has not been clearly defined and may resemble that of Type 2 diabetes, characterized by predominantly insulin resistance or defective insulin secretion, or both. This review aims to summarize the current state of knowledge regarding the prevalence, consequences, pathogenesis, and management of new-onset diabetes after transplantation, with a major focus on the possible mechanisms involved in the pathogenesis of the disorder. The aetiology of new-onset diabetes after transplantation is multifactorial, with diabetogenic immunosuppressive drugs playing a major role. Multiple cellular and physiologic mechanisms are involved in the process. Selection of an appropriate maintenance immunosuppressive regimen should involve balancing the risk of patient and graft survival vs. the potential for new-onset diabetes after transplantation.     

免疫耐受在胰岛移植中的研究进展

胰岛移植已经被公认为治疗胰岛素依赖型糖尿病（IMDD）的有效手段,而现如今胰岛移植的最大障碍是移植排斥反应。目前控制胰岛移植的免疫抑制治疗因其对胰岛细胞的毒性作用及长期应用带来的全身并发症而无法在临床推广,诱导移植术后受体的免疫耐受是防止排斥反应的最理想方法。本文综述了诱导免疫耐受的途径及胰岛移植的最新实验进展。随着研究的深入和免疫学的发展,相信在未来的胰岛移植治疗糖尿病领域,移植排斥现象将能得到高效可靠的解决。     

Current progress and perspectives in cell therapy for diabetes mellitus

Recent advances of cell transplantation and tissue engineering are remarkable. And also the diabetic treatment using pancreatic beta cells have performed great advances. Even clinical islet transplantation has been considered a common curative treatment for diabetes mellitus in the place of an experimental treatment. Still more the lack of donor's organ as a worst problem of transplantation will be overcome by using the beta cells produced in vitro culture. Therefore diabetes mellitus will be closed to cure in the near future.     

免疫耐受在胰岛移植中的研究进展

胰岛移植已经被公认为治疗胰岛素依赖型糖尿病(IMDD)的有效手段,而现如今胰岛移植的最大障碍是移植排斥反应。目前控制胰岛移植的免疫抑制治疗因其对胰岛细胞的毒性作用及长期应用带来的全身并发症而无法在临床推广,诱导移植术后受体的免疫耐受是防止排斥反应的最理想方法。本文综述了诱导免疫耐受的途径及胰岛移植的最新实验进展。随着研究的深入和免疫学的发展,相信在未来的胰岛移植治疗糖尿病领域,移植排斥现象将能得到高效可靠的解决。     

Diabetes Mellitus after Hematopoietic Stem Cell Transplantation

ObjectiveTo review the current literature on posttransplant diabetes mellitus after hematopoietic stem cell transplantation, including its epidemiologic features, transplant-related risk factors, and treatment.MethodsA literature search was conducted in PubMed for articles on diabetes mellitus after hematopoietic stem cell transplantation and effects of immunosuppressants on glucose metabolism.ResultsWithin 2 years after hematopoietic stem cell transplantation, up to 30% of patients may have diabetes. Although some of these cases resolve, the rates of diabetes and metabolic syndrome remain elevated in comparison with those in the nontransplant patient population during long-term follow-up. Traditional risk factors for diabetes as well as features related to the transplantation process, including immunosuppressive medications, are associated with posttransplant diabetes. Cardiovascular risk also appears to be increased in this population. Limited data are available on hypoglycemic agents for posttransplant diabetes; thus, treatment decisions must be based on safety, efficacy, and tolerability, with consideration of each patient’s transplant-related medications and comorbidities.ConclusionTreatment of diabetes mellitus in patients who have undergone hematopoietic stem cell transplantation necessitates attention to the posttransplant medication regimen and clinical course. Although no guidelines specific to treatment of posttransplant diabetes in this patient population currently exist, treatment to goals similar to those for nontransplant patients with diabetes should be considered in an attempt to help reduce long-term morbidity and mortality. (Endocr Pract. 2010;16:699-706)     

胰高血糖素样肽1与干细胞定向分化

糖尿病已经成为21世纪严重威胁人类健康的疾病之一。胰岛移植被认为是治疗Ⅰ型和部分Ⅱ型糖尿病的最有效方法。然而,供体组织来源的匮乏限制了其应用。随着细胞移植和组织工程的日益发展,干细胞研究为新型胰岛的来源开辟了新的途径。干细胞定向诱导分化的关键是筛选合适的诱导剂以及优化诱导微环境,使干细胞培养微环境尽可能接近体内正常细胞发育分化的微环境,从而有利于干细胞适宜生长及定向分化。最近研究证实,胰高血糖素样肽1（Glucagon- Like PeptideⅠ,GLP-1）在干细胞向胰岛样细胞诱导分化中具有显著作用。因此,为了更好地应用GLP-1在干细胞定向分化中的潜能、促进应用干细胞治疗糖尿病新疗法研究的进程及干细胞定向分化技术逐渐成熟,本文就胰高血糖素样肽-1及它诱导干细胞定向分化胰岛样细胞的研究进展作一阐述。     

La thérapie cellulaire du diabète de type 1. Situation actuelle et perspective

Nowadays human pancreatic islet transplantation is a therapeutic approach in kidney transplanted patients with type 1 diabetes having severe macrovascular disease. Because of its low morbidity compared to pancreas transplantation, islet transplantation can be also proposed to patients with brittle type 1 diabetes and severe hypoglycemic events despite intensive insulin therapy. Evaluation of glucose instability is crucial for the optimal selection of candidates and to assess the benefit/risk ratio. The main objective of islet transplantation is not to reverse diabetes but to restore a satisfactory glucose control aiming to improve the clinical management and the quality of life. Further clinical trials with new immunosuppressive drugs are needed in order to improve the efficiency of islet transplantation and to apply this treatment to a large number of patients.     

胚胎干细胞移植治疗糖尿病的研究进展

糖尿病是一种严重的免疫缺陷性疾病,目前的治疗方法很难从根本上治愈。近年来的研究表明,通过诱导胚胎干细胞定向分化为胰岛β细胞,并进行移植治疗糖尿病,是一种有希望的根治方案。本文就利用胚胎干细胞移植治疗糖尿病的最新进展作一综述。     

Mesenchymal stem cells to treat type 1 diabetes

What is clear is we are in the era of the stem cell and its potential in ameliorating human disease. Our perspective is generated from an in vivo model in a large animal that offers significant advantages (complete transplantation tolerance, large size and long life span). This review is an effort to meld our preclinical observations with others for the reader and to outline potential avenues to improve the present outlook for patients with diabetes. This effort exams the history or background of stem cell research in the laboratory and the clinic, types of stem cells, pluripotency or lack thereof based on a variety of pre-clinical investigations attempting endocrine pancreas recovery using stem cell transplantation. The focus is on the use of hematopoietic and mesenchymal stem cells. This review will also examine recent clinical experience following stem cell transplantation in patients with type 1 diabetes.     

Role and impact of the extracellular matrix on integrin‐mediated pancreatic β‐cell functions

Understanding the organisation and role of the extracellular matrix (ECM) in islets of Langerhans is critical for maintaining pancreatic β‐cells, and to recognise and revert the physiopathology of diabetes. Indeed, integrin‐mediated adhesion signalling in response to the pancreatic ECM plays crucial roles in β‐cell survival and insulin secretion, two major functions, which are affected in diabetes. Here, we would like to present an update on the major components of the pancreatic ECM, their role during integrin‐mediated cell‐matrix adhesions and how they are affected during diabetes. To treat diabetes, a promising approach consists in replacing β‐cells by transplantation. However, efficiency is low, because β‐cells suffer of anoikis, due to enzymatic digestion of the pancreatic ECM, which affects the survival of insulin‐secreting β‐cells. The strategy of adding ECM components during transplantation, to reproduce the pancreatic microenvironment, is a challenging task, as many of the regulatory mechanisms that control ECM deposition and turnover are not sufficiently understood. A better comprehension of the impact of the ECM on the adhesion and integrin‐dependent signalling in β‐cells is primordial to improve the healthy state of islets to prevent the onset of diabetes as well as for enhancing the efficiency of the islet transplantation therapy.     

Tolerance and pancreatic islet transplantation

Islet transplantation holds renewed promise as a cure for type I diabetes mellitus. Results of recent clinical trials have shown remarkable success, and have reignited universal optimism for this procedure. In spite of this success, the need for life-long immunosuppression of the recipient still limits islet transplantation to patients with poorly controlled diabetes or to those requiring kidney transplantation. It is obvious that the achievement of immunological tolerance would broaden the indication for islet transplantation to a much larger cohort of patients with type I diabetes mellitus, most likely preventing long-term complications and contributing to a much improved quality of life. Increased understanding of the basic mechanisms of tolerance induction has resulted in the implementation of numerous experimental approaches to achieve long-term survival of islet grafts in the absence of chronic immunosuppression. In this brief review we will attempt to summarize the current status of research and knowledge.     

Islet transplantation in type I diabetes mellitus

For most patients with type I diabetes, insulin therapy and glucose monitoring are sufficient to maintain glycemic control. However, hypoglycemia is a potentially lethal side effect of insulin treatment in patients who are glycemically labile or have hypoglycemia-associated autonomic failure [1]. For those patients, an alternative therapy is beta cell replacement via pancreas or islet transplantation. Pancreas transplants using cadaveric donor organs reduce insulin dependence but carry risks involved in major surgery and chronic immunosuppression. Islet transplantation, in which islets are isolated from donor pancreases and intravenously infused, require no surgery and can utilize islets isolated from pancreases unsuitable for whole organ transplantation. However, islet transplantation also requires immunosuppression, and standard steroid regimens may be toxic to beta cells [2]. The 2000 Edmonton Trial demonstrated the first long-term successful islet transplantation by using a glucocorticoid-free immunosuppressive regimen (sirolimus and tacrolimus). The Clinical Islet Transplantation (CIT) Consortium seeks to improve upon the Edmonton Protocol by using anti-thymocyte globulin (ATG) and TNFα antagonist (etanercept). The trials currently in progress, in addition to research efforts to find new sources of islet cells, reflect enormous potential for islet transplantation in treatment of type I diabetes.     

Inosine protects against the development of diabetes in multiple-low-dose streptozotocin and nonobese diabetic mouse models of type 1 diabetes

Inosine, a naturally occurring purine, was long considered to be an inactive metabolite of adenosine. However, recently inosine has been shown to be an immunomodulator and anti-inflammatory agent. The aim of this study was to determine whether inosine influences anti-inflammatory effects and affects the development of type 1 diabetes in murine models. Type 1 diabetes was induced either chemically by streptozotocin or genetically using the nonobese diabetic mouse (NOD) model. Mice were treated with inosine (100 or 200 mg kg(-1)d(-1)d) and diabetes incidence was monitored. The effect of inosine on pancreas immune cell infiltration, oxidative stress, and cytokine profile also was determined. For the transplantation model islets were placed under the renal capsule of NOD mice and inosine (200 mg kg(-1)d d(-1)d) treatment started the day of islet transplantation. Graft rejection was diagnosed by return of hyperglycemia accompanied by glucosuria and ketonuria. Inosine reduced the incidence of diabetes in both streptozotocin-induced diabetes and spontaneous diabetes in NOD mice. Inosine decreased pancreatic leukocyte infiltration and oxidative stress in addition to switching the cytokine profile from a Th1 to a Th2 profile. Inosine prolonged pancreatic islet graft survival, increased the number of surviving beta cells, and reduced the number of infiltrating leukocytes. Inosine protects against both the development of diabetes and against the rejection of transplanted islets. The purine exerts anti-inflammatory effects in the pancreas, which is its likely mode of action. The use of inosine should be considered as a potential preventative therapy in humans susceptible to developing Type 1 diabetes and as a possible antirejection therapy for islet transplant recipients.     

Atypical Diabetes Mellitus Associated with Bone Marrow Transplantation

ObjectiveTo describe 3 cases of atypical diabetes mellitus following bone marrow transplantation.MethodsWe describe the clinical presentation and relevant laboratory findings of 3 patients who presented with new-onset diabetes mellitus after bone marrow transplantation and discuss the possible mechanisms.ResultsA 52-year-old white man with chronic myelogenous leukemia, a 51-year-old white woman with acute myelogenous leukemia, and a 38-year-old Hispanic woman with acute myelogenous leukemia presented with acute onset of diabetes mellitus after bone marrow transplantation. Although blood glucose levels were initially very high, the patients required only small insulin dosages for glycemic control. Both the acute onset and requirement of relatively small insulin dosages were characteristic of type 1 diabetes mellitus. Onset of diabetes appeared to be unrelated to immunosuppressive drug therapy because it happened several months after starting these drugs. C-peptide was detectable, and glutamic acid decarboxylase antibodies were absent. Diabetes mellitus remitted spontaneously after a few months while the immunosuppressive drugs were continued.ConclusionAlthough the underlying mechanisms are unknown, cytokine changes after bone marrow transplantation may have led to temporary b-cell dysfunction in these patients. (Endocr Pract. 2010;16:93-96)     

Gene therapy for diabetes mellitus

There are diverse strategies for gene therapy of diabetes mellitus. Prevention of beta-cell autoimmunity is a specific gene therapy for prevention of type 1 (insulin-dependent) diabetes in a preclinical stage, whereas improvement in insulin sensitivity of peripheral tissues is a specific gene therapy for type 2 (non-insulin-dependent) diabetes. Suppression of beta-cell apoptosis, recovery from insulin deficiency, and relief of diabetic complications are common therapeutic approaches to both types of diabetes. Several approaches to insulin replacement by gene therapy are currently employed: 1) stimulation of beta-cell growth, 2) induction of beta-cell differentiation and regeneration, 3) genetic engineering of non-beta cells to produce insulin, and 4) transplantation of engineered islets or beta cells. In type 1 diabetes, the therapeutic effect of beta-cell proliferation and regeneration is limited as long as the autoimmune destruction of beta cells continues. Therefore, the utilization of engineered non-beta cells free from autoimmunity and islet transplantation with immunological barriers are considered potential therapies for type 1 diabetes. Proliferation of the patients' own beta cells and differentiation of the patients' own non-beta cells to beta cells are desirable strategies for gene therapy of type 2 diabetes because immunological problems can be circumvented. At present, however, these strategies are technically difficult, and transplantation of engineered beta cells or islets with immunological barriers is also a potential gene therapy for type 2 diabetes.     

Beneficial Effect of Insulin Treatment on Islet Transplantation Outcomes in Akita Mice

Islet transplantation is a promising potential therapy for patients with type 1 diabetes. The outcome of islet transplantation depends on the transplantation of a sufficient amount of β-cell mass. However, the initial loss of islets after transplantation is problematic. We hypothesized the hyperglycemic status of the recipient may negatively affect graft survival. Therefore, in the present study, we evaluated the effect of insulin treatment on islet transplantation involving a suboptimal amount of islets in Akita mice, which is a diabetes model mouse with an Insulin 2 gene missense mutation. Fifty islets were transplanted under the left kidney capsule of the recipient mouse with or without insulin treatment. For insulin treatment, sustained-release insulin implants were implanted subcutaneously into recipient mice 2 weeks before transplantation and maintained for 4 weeks. Islet transplantation without insulin treatment did not reverse hyperglycemia. In contrast, the group that received transplants in combination with insulin treatment exhibited improved fasting blood glucose levels until 18 weeks after transplantation, even after insulin treatment was discontinued. The group that underwent islet transplantation in combination with insulin treatment had better glucose tolerance than the group that did not undergo insulin treatment. Insulin treatment improved graft survival from the acute phase (i.e., 1 day after transplantation) to the chronic phase (i.e., 18 weeks after transplantation). Islet apoptosis increased with increasing glucose concentration in the medium or blood in both the in vitro culture and in vivo transplantation experiments. Expression profile analysis of grafts indicated that genes related to immune response, chemotaxis, and inflammatory response were specifically upregulated when islets were transplanted into mice with hyperglycemia compared to those with normoglycemia. Thus, the results demonstrate that insulin treatment protects islets from the initial rapid loss that is usually observed after transplantation and positively affects the outcome of islet transplantation in Akita mice.     

Beta cell apoptosis in diabetes

Apoptosis of beta cells is a feature of both type 1 and type 2 diabetes as well as loss of islets after transplantation. In type 1 diabetes, beta cells are destroyed by immunological mechanisms. In type 2 diabetes abnormal levels of metabolic factors contribute to beta cell failure and subsequent apoptosis. Loss of beta cells after islet transplantation is due to many factors including the stress associated with islet isolation, primary graft non-function and allogeneic graft rejection. Irrespective of the exact mediators, highly conserved intracellular pathways of apoptosis are triggered. This review will outline the molecular mediators of beta cell apoptosis and the intracellular pathways activated.     

实验动物胰岛细胞的分离纯化

胰岛移植作为治疗1型糖尿病的有效方法,临床应用前景较好。但是,由于在胰岛移植手术中,有功能的胰岛细胞数量较少,而严重影响其治疗效果。因此,如何提高胰岛分离纯化效果,获取尽可能多的高质量的胰岛,成为胰岛移植手术成败的关键。本文仅就在采用实验动物分离和纯化胰岛方面的实验经验作以简要介绍。     

NIH-supported national islet transplantation registry

An estimated 300,000 to 500,000 cases of type 1 diabetes exist today in the United States. Despite strict monitoring and attempts at control, people with type 1 diabetes still face the prospect of diminished health and earlier death than the general population. Islet transplantation offers an alternative to insulin usage and a potential treatment for type 1 diabetes mellitus. There are more than 30 islet transplant centers in the world focusing their efforts on the challenges and methods of this procedure. As the field of islet transplantation matures and the number of islet transplants performed increases, detailed analyses on factors that predict patient and graft survival are needed. This increased amount of data will allow for a better understanding of the safety and efficacy of islet transplantation. In response to the need for more complete information in the field, the National Institute of Diabetes and Digestive and Kidney Diseases is sponsoring the North American Collaborative Islet Transplant Registry (CITR). The mission of CITR is to expedite progress and promote safety in islet/β-cell transplantation through the collection, analysis, and communication of comprehensive and current data on all islet/β-cell transplants performed in North America. Compiling and analyzing data from all transplant centers in North America will accelerate the identification of both critical risk factors and key determinants of success, and thereby guide transplant centers in developing and refining islet/β-cell transplant protocols, leading to an advancement in the field of islet transplantation. Participation in CITR is voluntary, and more than 22 transplant centers have been invited to join. Seven centers are actively participating in CITR, with an additional 11 centers in the process of joining. Both an executive committee and a scientific advisory committee guide CITR. All islet transplants performed in North America since January 1, 1996, are captured by the CITR database. Through an electronic, Internet-based data capture system, quality control procedures, and minimization of duplicate efforts at the transplant center, the most relevant and succinct information are entered. From these data a comprehensive report will be published annually. In addition, special analyses will be performed and published periodically.