Bioenergetics of Islet Preparations in a Pilot Clinical Trial of Peri-Transplant Hydroxychloroquine for Autologous Islet Transplantation.

The inflammatory response is an obstacle to success in both allogeneic and autologous islet transplantation. In autologous islet transplantation (AIT), however, the recipient is also the donor, permitting pretreatment of donor/recipient for a controlled duration prior to transplantation. We sought to exploit this feature of (AIT) by pretreating donor/recipients with chronic pancreatitis undergoing total pancreatectomy and autologous islet transplantation (TPAIT) to test the hypothesis that peri-transplant treatment with the FDA-approved anti-inflammatory hydroxychloroquine (HCQ) improves graft function. In this randomized placebo-controlled pilot clinical study, patients (n = 6) were treated with oral HCQ for 30 days prior to and 90 days after TPAIT. In vivo islet function was assessed via Mixed Meal Tolerance Testing before HCQ treatment, 6- and 12-months after surgery. In vitro islet bioenergetics were assessed at the time of transplantation via extracellular flux analysis of islet preparation samples from the clinical trial cohort and six additional patients (n = 12). Our study shows that HCQ did not alter clinical endpoints, but HCQ-treated patients showed greater spare respiratory capacity (SRC) compared to samples from control patients (P=0.028). Glycolytic metabolism of islet preparations directly correlated with stimulated C-peptide secretion both before and after TPAIT (P=0.01, R2=0.489 and P=0.03, R2=0.674, respectively), and predicted in vivo islet function better than mitochondrial metabolism of islet preps or islet equivalents infused. Overnight culture of islet preparations altered bioenergetic function, significantly decreasing SRC and maximal respiration (P<0.001). In conclusion, while HCQ did not alter clinical outcomes, it was associated with significantly increased SRC in islet preparations. Bioenergetic analyses of islet preparations suggests that culture should be avoided and that glycolysis may be a more sensitive indicator of in vivo islet function than current metrics, including islet oxygen consumption and islet equivalents infused.

Perioperative Nutritional Aspects in Total Pancreatectomy: A Comprehensive Review of the Literature.

Total pancreatectomy (TP) is a highly invasive procedure often performed in patients affected by anorexia, malabsorption, cachexia, and malnutrition, which are risk factors for bad surgical outcome and even may cause enhanced toxicity to chemo-radiotherapy. The role of nutritional therapies and the association between nutritional aspects and the outcome of patients who have undergone TP is described in some studies. The aim of this comprehensive review is to summarize the available recent evidence about the influence of nutritional factors in TP. Preoperative nutritional and metabolic assessment, but also intra-operative and post-operative nutritional therapies and their consequences, are analyzed in order to identify the aspects that can influence the outcome of patients undergoing TP. The results of this review show that preoperative nutritional status, sarcopenia, BMI and serum albumin are prognostic factors both in TP for pancreatic cancer to support chemotherapy, prevent recurrence and prolong survival, and in TP with islet auto-transplantation for chronic pancreatitis to improve postoperative glycemic control and obtain better outcomes. When it is possible, enteral nutrition is always preferable to parenteral nutrition, with the aim to prevent or reduce cachexia. Nowadays, the nutritional consequences of TP, including diabetes control, are improved and become more manageable.

Diazoxide Preconditioning of Nonhuman Primate Pancreas Improves Islet Isolation Outcomes by Mitochondrial Protection.

OBJECTIVES: Previously, we showed that diazoxide (DZ), an effective ischemic preconditioning agent, protected rodent pancreas against ischemia-reperfusion injury. Here, we further investigate whether DZ supplementation to University of Wisconsin (UW) solution during pancreas procurement and islet isolation has similar cytoprotection in a preclinical nonhuman primate model. METHODS: Cynomolgus monkey pancreata were flushed with UW or UW + 150 µM DZ during procurement and preserved for 8 hours before islet isolation. RESULTS: First, a significantly higher islet yield was observed in UW + DZ than in UW (57,887 vs 23,574 IEq/pancreas and 5396 vs 1646 IEq/g). Second, the DZ treated islets had significantly lower apoptotic cells per islet (1.64% vs 9.85%). Third, DZ significantly inhibited ROS surge during reperfusion with a dose-response manner. Fourth, DZ improved in vitro function of isolated islets determined by mitochondrial potentials and calcium influx in responses to glucose and KCI. Fifth, the DZ treated islets had much higher cure rate and better glycemia control in diabetic mice transplant model. CONCLUSIONS: This study showed a strong mitochondrial protection of DZ on nonhuman primate islets against ischemia-reperfusion injury that provides strong evidence for its clinical application in islet and pancreas transplantation.

Necrostatin-1 supplementation enhances young porcine islet maturation and in vitro function.

BACKGROUND: Necroptosis has been demonstrated to be a primary mechanism of islet cell death. This study evaluated whether the supplementation of necrostatin-1 (Nec-1), a potent inhibitor of necroptosis, to islet culture media could improve the recovery, maturation, and function of pre-weaned porcine islets (PPIs). METHODS: PPIs were isolated from pre-weaned Yorkshire piglets (8-15 days old) and either cultured in control islet culture media (n = 6) or supplemented with Nec-1 (100 µM, n = 5). On days 3 and 7 of culture, islets were assessed for recovery, insulin content, viability, cellular composition, GLUT2 expression in beta cells, differentiation of pancreatic endocrine progenitor cells, function, and oxygen consumption rate. RESULTS: Nec-1 supplementation induced a 2-fold increase in the insulin content of PPIs on day 7 of culture. When compared to untreated islets, Nec-1 treatment doubled the beta- and alpha-cell composition and accelerated the development of delta cells. Additionally, beta cells of Nec-1-treated islets had a significant upregulation in GLUT2 expression. The enhanced development of major endocrine cells and GLUT2 expression after Nec-1 treatment subsequently led to a significant increase in the amount of insulin secreted in response to in vitro glucose challenge. Islet recovery, viability, and oxygen consumption rate were unaffected by Nec-1. CONCLUSION: This study underlines the importance of necroptosis in islet cell death after isolation and demonstrates the novel effects of Nec-1 to increase islet insulin content, enhance pancreatic endocrine cell development, facilitate GLUT2 upregulation in beta cells, and augment insulin secretion. Nec-1 supplementation to culture media significantly improves islet quality prior to xenotransplantation.

JAK3 inhibitor-based immunosuppression in allogeneic islet transplantation in cynomolgus monkeys.

Islet transplantation is efficacious to prevent severe hypoglycemia and glycemic liability of selected patients of type 1 diabetes. However, since calcineurin inhibitor (CNI) causes ß-cell and nephrotoxicity, alternative drug(s) with similar potency and safety profile to CNI will be highly desirable. Here we tested whether JAK3 inhibitor, tofacitinib could be used instead of tacrolimus in CIT07 immunosuppression regimen in cynomolgus nonhuman primate (NHP) model. Five independent streptozotocin (STZ)-induced diabetic monkeys were transplanted with MHC-mismatched allogeneic islets and three animals were further re-transplanted upon insufficient glycemic control or early islet graft rejection. After islet transplantation, blood glucose levels were quickly stabilized and maximal islet graft survival as measured by serum C-peptide concentration was >330, 98, >134, 31, or 22 days, respectively, after transplantation (median survival day; 98 days). Cellular and humoral immune responses were efficiently suppressed by JAK3 inhibitor-based immunosuppression during the follow-up periods. Although intermittent increases of the genome copy number of cynomolgus cytomegalovirus (CMV) were detected by quantitative real-time PCR analyses, serious infections or posttransplant lymphoproliferative disease (PTLD) was not found in all animals. Taken together, we have shown that JAK3 inhibitor could be used in replacement of tacrolimus in a highly translatable NHP islet transplantation model and these results suggest that JAK3 inhibitor will be potentially incorporated in human allogeneic islet transplantation.

Physiologic Doses of Bilirubin Contribute to Tolerance of Islet Transplants by Suppressing the Innate Immune Response.

Bilirubin has been recognized as a powerful cytoprotectant when used at physiologic doses and was recently shown to have immunomodulatory effects in islet allograft transplantation, conveying donor-specific tolerance in a murine model. We hypothesized that bilirubin, an antioxidant, acts to suppress the innate immune response to islet allografts through two mechanisms: 1) by suppressing graft release of damage-associated molecular patterns (DAMPs) and inflammatory cytokines, and 2) by producing a tolerogenic phenotype in antigen-presenting cells. Bilirubin was administered intraperitoneally before pancreatic procurement or was added to culture media after islet isolation in AJ mice. Islets were exposed to transplant-associated nutrient deprivation and hypoxia. Bilirubin significantly decreased islet cell death after isolation and hypoxic stress. Bilirubin supplementation of islet media also decreased the release of DAMPs (HMGB1), inflammatory cytokines (IL-1ß and IL-6), and chemokines (MCP-1). Cytoprotection was mediated by the antioxidant effects of bilirubin. Treatment of macrophages with bilirubin induced a regulatory phenotype, with increased expression of PD-L1. Coculture of these macrophages with splenocytes led to expansion of Foxp3+ Tregs. In conclusion, exogenous bilirubin supplementation showed cytoprotective and antioxidant effects in a relevant model of islet isolation and hypoxic stress. Suppression of DAMP release, alterations in cytokine profiles, and tolerogenic effects on macrophages suggest that the use of this natural antioxidant may provide a method of preconditioning to improve outcomes after allograft transplantation.

The synergistic effect of ω3 and Vit D3 on glycemia and TNF-α in islet transplantation.

The current treatment of type 1 diabetes consists of insulin administration. Transplantation of islets of Langerhans is considered very favorable because the full effect of insulin treatment cannot be obtained in severe cases. Although agents such as omega-3 (ω3) and vitamin D3 (Vit D3) are known to contribute to the success of islet allo-transplantation (ITX), in this study we aimed to experimentally determine their effects on glycemia and TNF-α production. Wistar albino rats, which were used as recipients, were given ω3, Vit D3, and islets by gavage, and intraperitoneal- and intraportal injections, respectively. Daclizumab (DAC) was used for immunosuppression. Glycemia levels decreased in rats treated with ω3 and vit D3. TNF-α increased in all groups due to application of STZ. After ITX (day +1), the weakest increase was observed in the ω3 + Vit D3 group. In the ITX+DAC group, compared with that of ITX only, DAC was shown to decrease levels of TNF- α following ITX, only in control group, however, similar levels of TNF-α were observed in other groups. The values in the treated groups were already lower than those of the controls in the ITX group and also remained almost equal in the ITX+DAC group. We suggest that the use of ω3 and Vit D3 together will improve the pro-inflammatory aspect encountered during and after ITXs, and contribute to the reduction of the dose of immunosuppressants in these procedures.

Pancreatic L-Glutamine Administration Protects Pig Islets From Cold Ischemic Injury and Increases Resistance Toward Inflammatory Mediators.

The isolation and transplantation of porcine islets represent a future option for the treatment of type 1 diabetic patients. Stringent product release criteria and limited availability of transgenic and specific pathogen-free pigs will essentially require processing of explanted pig pancreata in specialized, possibly remote isolation facilities, whereby pancreata are exposed to cold ischemia due to prolonged tissue transit time. In the present study we investigated whether pancreas oxygenation can be efficiently combined with an antioxidant strategy utilizing intraductal L-glutamine administration. Pig pancreata were intraductally perfused after retrieval and after cold storage in oxygen-precharged perfluorohexyloctane utilizing University of Wisconsin solution supplemented with (n = 16) or without (n = 14) 5 mmol/L L-glutamine. After isolation purified islets were subjected to extensive quality assessment. Islet recovery postpurification was significantly higher in glutamine-treated pancreata (77.0 ± 3.3% vs. 60.3 ± 6.0%, p < 0.05). Glutamine administration increased intraislet content of reduced glutathione (117.8 ± 16.5 vs. 15.9 ± 2.8 ng/ng protein, p < 0.001) associated with increased islet recovery after culture (65.8 ± 12.1% vs. 40.3 ± 11.7%, p < 0.05), enhanced glucose stimulation index (1.82 ± 0.16 vs. 1.38 ± 0.10, p < 0.05), and improved posttransplant function in diabetic nude mice (p < 0.05). Furthermore, intraductally administered glutamine increased pig islet resistance toward reactive oxygen species, nitric oxide, and high-dose proinflammatory cytokines. The present study demonstrates that quality and function of pig islets exposed to warm and cold ischemia can significantly be improved using intraductal l-glutamine administration. As the efficiency of the intraductal route may be inferior compared to intravascular administration further studies should aim on assessment of l-glutamine as supplement for pancreas perfusion during organ procurement.

Pharmacological strategies for protection of extrahepatic islet transplantation.

The safety and effectiveness of islet transplantation has been proven through world-wide trials. However, acute and chronic islet loss has hindered the ultimate objective of becoming a widely used treatment option for type 1 diabetes. A large islet loss is attributed, in part, to the liver being a less-than-optimal site for transplantation. Over half of the transplanted islets are destroyed shortly after transplantation due to direct exposure to blood and non-specific inflammation. Successfully engrafted islets are continuously exposed to the liver micro-environment, a unique immune system, low oxygen tension, toxins and high glucose, which is toxic to islets, leading to premature islet dysfunction/death. Investigations have continued to search for alternate sites to transplant islets that provide a better environment for prolonged function and survival. This article gathers courses and conditions that lead to islet loss, from organ procurement through islet transplantation, with special emphasis on hypoxia, oxidative stress, and antigen non-specific inflammation, and reviews strategies using pharmacological agents that have shown effectiveness in protecting islets, including a new treatment approach utilizing siRNA. Pharmacological agents that support islet survival and promote ß-cell proliferation are also included. Treatment of donor pancreata and/or islets with these agents should increase the effectiveness of islets transplanted into extrahepatic sites. Furthermore, the development of methods designed to release these agents over an extended period, will further increase their efficacy. This requires the combined efforts of both islet transplant biologists and bioengineers.

Dietary zinc supplementation to the donor improves insulin secretion after islet transplantation in chemically induced diabetic rats.

OBJECTIVES: Zinc (Zn) is related to insulin synthesis, storage, and secretion. This study demonstrates the effects of Zn supplementation in donor rats on the outcomes of islet transplantation. METHODS: Donor rats received 3 different regimens of dietary Zn supplementation for 2 weeks before undergoing pancreas donation: a standard diet containing Zn at 50 ppm (control), 1 ppm (low-Zn group) or 1000 ppm (high-Zn group), respectively. Diabetic recipient rats underwent islet transplantation, and the blood glucose levels and insulin secretion were monitored for 7 days after transplantation. RESULTS: The serum and pancreatic Zn levels at the time of donation were significantly lower in the low-Zn group (48.8 ± 25.5 µg/dL and 11.3 ± 1.9 µg/g) and higher in the high-Zn group (147.3 ± 17.6 µg/dL and 18.7 ± 2.2 µg/g) when compared with those observed in the controls (118.7 ± 7.9 µg/dL and 14.6 ± 2.0 µg/g) (P < 0.05). The blood glucose levels became re-elevated 2 days after transplantation in rats receiving islet grafts from the controls and the low-Zn groups. In contrast, in the rats that received islets from the high-Zn groups, these were maintained within a reference range (P < 0.01). CONCLUSIONS: These data indicate that a Zn-rich diet for donor rats improves the function of islet grafts in chemically induced diabetic rats.

Treating diabetes with islet transplantation: lessons from the past decade in Lille.

Type 1 diabetes (T1D) is due to the loss of both beta-cell insulin secretion and glucose sensing, leading to glucose variability and a lack of predictability, a daily issue for patients. Guidelines for the treatment of T1D have become stricter as results from the Diabetes Control and Complications Trial (DCCT) demonstrated the close relationship between microangiopathy and HbA1c levels. In this regard, glucometers, ambulatory continuous glucose monitoring, and subcutaneous and intraperitoneal pumps have been major developments in the management of glucose imbalance. Besides this technological approach, islet transplantation (IT) has emerged as an acceptable safe procedure with results that continue to improve. Research in the last decade of the 20th century focused on the feasibility of islet isolation and transplantation and, since 2000, the success and reproducibility of the Edmonton protocol have been proven, and the mid-term (5-year) benefit-risk ratio evaluated. Currently, a 5-year 50% rate of insulin independence can be expected, with stabilization of microangiopathy and macroangiopathy, but the possible side-effects of immunosuppressants, limited availability of islets and still limited duration of insulin independence restrict the procedure to cases of brittle diabetes in patients who are not overweight or have no associated insulin resistance. However, various prognostic factors have been identified that may extend islet graft survival and reduce the number of islet injections required; these include graft quality, autoimmunity, immunosuppressant regimen and non-specific inflammatory reactions. Finally, alternative injection sites and unlimited sources of islets are likely to make IT a routine procedure in the future.

Transdisciplinary approach to restore pancreatic islet function.

The focus of our research is on islet immunobiology. We are exploring novel strategies that could be of assistance in the treatment and prevention of type 1 diabetes, as well as in the restoration of metabolic control via transplantation of insulin producing cells (i.e., islet cells). The multiple facets of diabetes and ß-cell replacement encompass different complementary disciplines, such as immunology, cell biology, pharmacology, and bioengineering, among others. Through their interaction and integration, a transdisciplinary dimension is needed in order to address and overcome all aspects of the complex puzzle toward a successful clinical translation of a biological cure for diabetes.

Anodic aluminium oxide membranes for immunoisolation with sufficient oxygen supply for pancreatic islets.

Immunoisolation membranes have been developed for various cell encapsulations for therapeutic purposes. However effective encapsulation systems have been hindered by low oxygen (O2) permeability or imperfect immunoisolation caused by either low porosity or non-uniform pore geometry. Here, we report an encapsulation method that uses an anodic aluminum oxide membrane formed by polyethylene oxide self-assembly to obtain nanochannels with both high selectivity in excluding immune molecules and high permeability of nutrients such as glucose, insulin, and O2. The extracorporeal encapsulation system composed of these membranes allows O2 flux to meet the O2 demand of pancreatic islets of Langerhans and provides excellent in vitro viability and functionality of islets.

The impact of oxidative stress on islet transplantation and monitoring the graft survival by non-invasive imaging.

Islet transplantation is an attractive strategy to treat severe diabetic conditions in patients suffering from autoimmune derived diabetes, and it has currently been considered a forefront research arena in diabetes. Major aim of islet transplantation is to achieve successful insulin independent disease free survival. The key challenges in transplanted islets are the generation of reactive oxygen species (ROS) and associated oxidative stress, pro-inflammatory cytokine - (TNFα) mediated apoptotic induction, attack by immune cells, and achieving revascularization with minimal hypoxic microenvironment. Free radicals and their derivatives are constantly produced in living systems, but at relatively low level, and in a balanced state. Oxidative stress, which occurs as a result of an imbalance between the intracellular free radicals production and the cellular antioxidant defense mechanisms in the transplanted islets, can lead to cell death. The balance between oxidants and antioxidants in a cell can be easily disturbed by increase in ROS production or reduction in the level of cellular antioxidant defensive substances, which can cause many metabolic complications, including pancreatic ß-cell damage. Antioxidants function as blockers of radical processes by eliminating harmful ROS produced during normal cellular metabolism. A complex antioxidant defense mechanism has been developed by nature in cells to protect the cellular homeostasis. This system mainly includes antioxidant enzymes, vitamins and minerals. As transplanted islet survival is crucial for achieving successful therapy, most of these antioxidants can be used as a supplement to scavenge the local ROS thereby improving the survival of transplanted islets. Currently, very few techniques have been routinely used to qualitatively and quantitatively assess the survival and function of islet grafts, especially to confirm the success of treatment, which includes metabolic parameters such as blood glucose, insulin and C-peptide levels. These biochemical measurements provide markers at only the late stages of islet rejection. Use of molecular imaging techniques has the potential for real-time non-invasive monitoring of the functional status and viability of transplanted islet grafts in living animals. This review mainly focuses on the current status of islet transplantations, potential preventive strategies used to reduce oxidative stress-mediated toxicity in islet grafts, and use of molecular imaging as a tool to quantitatively evaluate the functional status of the transplanted islets in living animals.

Significant improvement in islet yield and survival with modified ET-Kyoto solution: ET-Kyoto/Neutrophil elastase inhibitor.

Although islet transplantation can achieve insulin independence in patients with type 1 diabetes, sufficient number of islets derived from two or more donors is usually required to achieve normoglycemia. Activated neutrophils and neutrophil elastase (NE), which is released from these neutrophils, can directly cause injury in islet grafts. We hypothesized that inhibition of NE improves islet isolation and islet allograft survival. We tested our hypothesis by examining the effects of modified ET-Kyoto solution supplemented with sivelestat, a NE inhibitor (S-Kyoto solution), on islet yield and viability in islet isolation and the effect of intraperitoneally injected sivelestat on islet graft survival in a mouse allotransplant model. NE and proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 increased markedly at the end of warm digestion during islet isolation and exhibited direct cytotoxic activity against the islets causing their apoptosis. The use of S-Kyoto solution significantly improved islet yield and viability. Furthermore, treatment with sivelestat resulted in significant prolongation of islet allograft survival in recipient mice. Furthermore, serum levels of IL-6 and TNF-α at 1 and 2 weeks posttransplantation were significantly higher in islet recipients than before transplantation. Our results indicated that NE released from activated neutrophils negatively affects islet survival and that its suppression both in vitro and in vivo improved islet yield and prolonged islet graft survival. The results suggest that inhibition of NE activity could be potentially useful in islet transplantation for patients with type 1 diabetes mellitus.

Induction of beta-cell resistance to hypoxia and technologies for oxygen delivery to transplanted pancreatic islets.

Hypoxia is believed to be a crucial factor involved in cell adaptation to environmental stress. Islet transplantation, especially with immunoisolated islets, interrupts vascular connections, resulting in the substantially decreased delivery of oxygen and nutrients to islet cells. Insulin-producing pancreatic beta cells are known to be highly susceptible to oxygen deficiency. Such susceptibility to hypoxia is believed to be one of the main causes of beta-cell death in the post-transplantation period. Different strategies have been developed for the protection of beta cells against hypoxic injury and for oxygen delivery to transplanted islets. The enhancement of beta-cell defense properties against hypoxia has been achieved using various techniques such as gene transfection, drug supplementation, co-culturing with stem cells and cell selection. Technologies for oxygen delivery to transplanted islets include local neovascularization of subcutaneous sites, electrochemical and photosynthetic oxygen generation, oxygen refuelling of bio-artificial pancreas and whole body oxygenation by using hyperbaric therapy. Progress in the field of oxygen technologies for islet transplantation requires a multidisciplinary approach to explore and optimize the interaction between components of the biological system and different technological processes. This review article focuses mainly on the recently developed strategies for oxygenation and protection from hypoxic injury - to achieve stable and long-term normoglycaemia in diabetic patients with transplanted pancreatic islets.

Role of substrates in diabetes therapy: stem cell differentiation and islet transplantation.

Type 1 diabetes affects more than a million people in the United States and many more across the world. While pharmaceutical interventions and insulin supplementation are the most commonplace treatment of diabetes, these are not essentially cures and can potentially lead to long-term complications. Transplantation of insulin-producing Islets of Langerhans from donor pancreas has been established as a promising alternative to diabetes therapy. While successful islet transplantation has the potential of providing a cure, the primary hurdles to be overcome for it to be clinically viable are the scarcity of donor islets and immune rejection of transplanted islets. Recent advances in stem cell culture and differentiation techniques have established stem cells as a likely source of transplantable islets. Different stem cell sources have been induced toward pancreatic differentiation using specific chemical perturbations along with use of specific substrates. An approach to overcoming the second hurdle of immune rejection of transplantable islets is to encapsulate the islets in specific biomaterials. In this review, we discuss the extensive use of various substrates for pancreatic differentiation of different stem cell sources, along with different biomaterial designs used for islet transplantation.

[End-stage nephropathy in type 1-diabetes mellitus - kidney transplantation alone or combined with islet or pancreas transplantation?]. / Der nierenkranke Patient mit Typ 1-Diabetes mellitus - Nierentransplantation allein oder mit Insel- oder Pankreastransplantation?

Due to the recent changes in reimbursement politics in islet and pancreas transplantation in Switzerland, the question, which patients with type 1-diabetes mellitus get which form of beta-cell replacement, is of utmost importance for referring physicians. As of July 1, 2010 all forms of islet- or pancreas-transplantations are reimbursed by the Swiss health care system. The limited availability of donor organs and the necessity of transplantation of the islets of several pancreata in order to achieve insulin independence has led to a change in paradigms in Switzerland, where insulin independence by multiple islet transplantations is not the key goal in islet transplantation any longer. The primary goal is achieving a good blood glucose control and avoidance of severe hypoglycaemic episodes. This goal can be achieved in 80 - 90 % of all patients. Only if this goal cannot be achieved by a single islet transplantation, a second or third islet transplantation is performed. By adapting this strategy more patients can benefit from this new therapy. Unlike the North American centers, the Swiss centers in Zurich and Geneva concentrated their efforts on islet after kidney and simultaneous islet kidney transplantation. Due to the organ donor shortage in Switzerland, 50 % of kidney transplants are nowadays living-organ donations, therefore this option has to be included in the decision tree of a beta cell replacement. The choice between islet and pancreas transplantation depends on the existence of diabetes complications (because the perioperative risk is considerably higher in pancreas transplantation) and the potential benefit of a pancreas- or islet transplantation. The first question in the decision tree is, therefore, whether the patient with type 1-diabetes and severe renal failure is a potential candidate for simultaneous pancreas-islet transplantation. If the perioperative risk is considered to be too high, or if revascularisation procedures cannot be done before transplantation, the patient qualifies only for islet transplantation. If a living organ donation for the kidney is possible and the patient not yet on dialysis then the patient can be listed for simultaneous islet-kidney or pancreas-kidney-transplantation. If dialysis is imminent or already performed, a living-donor kidney should be transplanted with the option of a later islet- or pancreas after kidney transplantation. If the patient with type 1-diabetes mellitus is able to maintain a reasonable glycemic level, he would be a good candidate for islet transplantation. If the patient is willing to take the additional risk of complications associated with a pancreas transplant, was never able to maintain a good glycated haemoglobin, has an acceptable perioperative risk, and wishes to become insulin-independent, a simultaneous pancreas-kidney transplant would be recommended. If the kidney has already been transplanted previously, a pancreas- after kidney transplantation would be the procedure of choice. An islet or pancreas transplantation alone is reserved for the patient with type 1-diabetes with a good renal function and frequent life-threatening hypoglycemias, which have to be balanced against the risks of a life-long immunosuppression. In this review article the advantages, disadvantages, and current indications for both beta-cell replacement options in Switzerland are discussed in the light of the available evidence with the help of a new flow chart.

Effect of zinc on early graft failure following intraportal islet transplantation in rat recipients.

BACKGROUND: Zinc (Zn) is related to insulin synthesis, storage and secretion. Zn status in patients with Type 1 diabetes is significantly lower than in healthy controls. Intraportal islet transplantation (IPIT) is a radical treatment for diabetes, the success of which depends largely on the survival of the transplanted islets. This study demonstrates the impact of a Zn-rich environment on transplanted islet survival. MATERIAL/METHODS: Diabetic Wistar rats were transplanted with syngeneic islets. Rats in the high-Zn-diet group were fed a standard pelleted diet containing ZnSO4 at 1000 ppm, whereas those in the control group were fed an ordinary diet alone (ZnSO4 at 50 ppm) for two weeks prior to islet transplantation. We examined Zn level of plasma, the blood glucose levels, and histological findings, etc., after intraportal islet transplantation. RESULTS: The high-Zn-diet group showed excellent blood glucose control compared with the control group on observation days 3, (237.1±120.6 mg/dl vs. 164.2±69.1 mg/dl; p<0.05) and 14, (273.7±160.9 mg/dl vs. 179.2±114.3 mg/dl; p<0.05). Early graft failure was found to be suppressed in the high-Zn-diet group on day 3 after transplantation (6.7% vs. 33.3%: p<0.05). As for the percentage of granulated islets, the high-Zn-diet group was improved (65.1% vs. 41.8%: p<0.05). CONCLUSIONS: These results indicated that a zinc-rich environment is advantageous for the recipient in intraportal islet transplantation. Zn is harmless in humans; thus, we consider that Zn supplementation could be a simple way to improve clinical results of intraportal islet transplantation.

Alterations of the female reproductive system in islet recipient receiving immunosuppression.

Pancreatic islet allotransplantation is an option for patients with unstable type 1 diabetes mellitus (T1DM). Major improvements in islet isolation techniques and the implementation of steroid-free immunosuppressive regimens can maintain insulin independence in the majority of T1DM for at least 1 year after transplantation. Recent studies have emphasized the impact of sirolimus on female reproductive tract. In this communication we report on the alterations of the female reproductive tract in 18 chronically immunosuppressed patients with T1DM following allogenic islet transplantation. Previous research has shown development of ovarian cysts in islet transplant patients receiving sirolimus. We extensively reevaluated this and other possible side effects on the female reproductive system. These side effects have been underestimated, although they are significant, requiring surgical or intensive medical treatment. Pre- and posttransplant gynecological evaluation should be performed to address the development of complications secondary to sirolimus in order to intervene sooner with alternative therapies.