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Long-term success in beta-cell replacement remains limited by the toxic effects of calcineurin inhibitors (CNI) on beta-cells and renal function. We report a multi-modal approach including islet and pancreas-after-islet (PAI) transplant utilizing calcineurin-sparing immunosuppression. Ten consecutive non-uremic patients with Type 1 diabetes underwent islet transplant with immunosuppression based on belatacept (BELA; n = 5) or efalizumab (EFA; n = 5). Following islet failure, patients were considered for repeat islet infusion and/or PAI transplant. 70% of patients (four EFA, three BELA) maintained insulin independence at 10years post-islet transplant, including four patients receiving a single islet infusion and three patients undergoing PAI transplant. 60% remain insulin independent at mean follow-up of 13.3 ± 1.1years, including one patient 9years after discontinuing all immunosuppression for adverse events, suggesting operational tolerance. All patients who underwent repeat islet transplant experienced graft failure. Overall, patients demonstrated preserved renal function, with a mild decrease in GFR from 76.5 ± 23.1mL/min to 50.2 ± 27.1mL/min (p = 0.192). Patients undergoing PAI showed the greatest degree of renal impairment following initiation of CNI (56% ± 18.7% decrease in GFR). In our series, repeat islet transplant is ineffective at maintaining long-term insulin independence. PAI results in durable insulin independence but is associated with impaired renal function secondary to CNI dependence.

Most life-threatening diabetes-related complications involve the kidneys, eyes, cardiovascular system, and autonomic nervous system. Clinical islet transplantation (CITx) may be a therapeutic option for some patients. In this study, we analyzed the progression of diabetic complications after CITx and in patients waiting for islet transplantation.From 2008 to 2015, 67 patients were listed for pancreatic or islet transplantation. We compared beta scores, islet scores, and secondary complications between patients who underwent islet allotransplantation (CITx group, n = 6) and the patients awaiting islet transplantation (wait group, n = 19) at baseline and during the 1-year follow-up.In the CITx group, good islet function was observed in 80% of patients 1 month post-transplantation and 40% of patients 1 year post-transplantation; however, no patient achieved insulin independence. One patient who underwent simultaneous islet-kidney transplantation died on day 8 because of severe bleeding in the retroperitoneal space. In 1 case, islet primary nonfunction was observed. Mean islet score in the CITx group 1 year post-transplantation was significantly higher than the pretransplant score and wait group scores at enrollment and 1 year later (P .01). Increased albuminuria was observed in 3 of 11 (27%) patients in the wait group and 0 patients in the CITx group (P = .08). One patient (9%) in the wait group developed chronic renal failure requiring hemodialysis. Ophthalmologic procedures were required by 47% of patients in the wait group and 0 patients in the CITx group in the first year after transplantation (P .01).Successful islet transplantation slows the progression of diabetic complications.

Pancreatic-islet transplantation is a safe and noninvasive therapy for type 1 diabetes. However, the currently applied site for transplantation, ie, the liver, is not the optimal site for islet survival. Because the human body has shortcomings in providing an optimal site, artificial transplantation sites have been proposed. Such an artificial site could consist of a polymeric scaffold that mimics the pancreatic microenvironment and supports islet function. Recently, remarkable progress has been made in the technology of engineering scaffolds. The polymer-islet interactions, the site of implantation, and scaffold prevascularization are critical factors for success or failure of the scaffolds. This article critically reviews these factors while also discussing translation of experimental studies to human application as well as the steps required to create a clinically applicable prevascularized, retrievable scaffold for implantation of insulin-producing cells for treatment of type 1 diabetes mellitus. Important advances have been made in the design and testing of polymeric scaffolds for pancreatic islet transplantation, but some challenges remain to be solved before human application.

Restoration of insulin-independence and normoglycemia has been the overarching goal in diabetes research and therapy. While whole organ and islet transplantation have become gold standard procedures in achieving glucose control in diabetic patients, the profound lack of suitable donor tissues severely hampers the broad application of these therapies. Here, we describe current efforts aimed at generating a sustainable source of functional human stem cell-derived insulin-producing islet cells for cell transplantation and present state-of-the-art efforts to protect such cells via immune modulation and encapsulation strategies.

The transplantation of pancreatic islets, following the Edmonton Protocol, is a promising treatment for type I diabetics. However, the need for multiple donors to achieve insulin independence reflects the large loss of islets that occurs when islets are infused into the portal vein. Finding a less hostile transplantation site that is both minimally invasive and able to support a large transplant volume is necessary to advance this approach. Although the s.c. site satisfies both these criteria, the site is poorly vascularized, precluding its utility. To address this problem, we demonstrate that modular tissue engineering results in an s.c. vascularized bed that enables the transplantation of pancreatic islets. In streptozotocin-induced diabetic SCID/beige mice, the injection of 750 rat islet equivalents embedded in endothelialized collagen modules was sufficient to restore and maintain normoglycemia for 21 days; the same number of free islets was unable to affect glucose levels. Furthermore, using CLARITY, we showed that embedded islets became revascularized and integrated with the host’s vasculature, a feature not seen in other s.c. studies. Collagen-embedded islets drove a small (albeit not significant) shift toward a proangiogenic CD206 + MHCII − (M2-like) macrophage response, which was a feature of module-associated vascularization. While these results open the potential for using s.c. islet delivery as a treatment option for type I diabetes, the more immediate benefit may be for the exploration of revascularized islet biology.

JDRF is the leading global organization dedicated to type 1 diabetes (T1D) research, an autoimmune disease affecting millions worldwide and with increased incidence and prevalence each year. The foundation collaborates with strategic partners who share the mission of improving the lives of people with T1D by accelerating progress on the most promising opportunities for curing, better treating, and preventing the disease. One of the therapeutic goals at JDRF is to restore full glycemic control in T1D by replacing the loss of beta-cell function with an unlimited source of highly functional insulin-producing cells. To achieve this goal, the main priority is to support discovery, preclinical development, and provide clinical proof of concept for a beta-cell replacement product. Development and validation of renewable beta-cell sources, strategies to protect such cells from immune-mediated responses, and a transplant environment that supports long-term graft function is expected to overcome the limitation of donor pancreata and the need for systemic immunosuppression that restrict the benefits of islet transplantation to people living with unstable T1D. At JDRF, strategic roadmaps are developed based on current gaps and opportunities in the field and guides directing research funding in the most efficient manner, as well as better positioning our funded investigators and resources to succeed. The combination of research-focused programs with strengths in regulatory, health policy, and advocacy culminate into JDRF being a leader in the field and in a position to deliver clinically impactful and disease-modifying therapies for T1D, such as beta-cell replacement products. We review the strategy within this document.

Islet transplantation is an available option to treat brittle type 1 diabetes and to prevent pancreatogenic diabetes. Despite the remarkable improvements performed in the field, the successful rate of insulin independence at 5 years posttransplant is not fully satisfactory. One of the key players contributing to this poor outcome is inflammation. Indeed it has been recognized that the inflammation associated with the islet transplantation is one of the main cause of early damage to islets and graft loss. In this chapter, we have elucidated some of the relevant mechanisms that induce inflammation in islet transplantation from the donor to the recipient, passing through all steps of the islet isolation process (cold ischemia, dissociation, and culture conditions). Here, we provide a literature overview of the acquired knowledge and the latest findings, paying particular attention to the most promising anti-inflammatory strategies for intrahepatic islet transplantation.

Stresses encountered during human islet isolation lead to unavoidable β-cell death after transplantation. This reduces the chance of insulin independence in chronic pancreatitis patients undergoing total pancreatectomy and islet autotransplantation. We tested whether harvesting islets in carbon monoxide-saturated solutions is safe and can enhance islet survival and insulin independence after total pancreatectomy and islet autotransplantation. Chronic pancreatitis patients who consented to the study were randomized into carbon monoxide (islets harvested in a carbon monoxide-saturated medium) or control (islets harvested in a normal medium) groups. Islet yield, viability, oxygen consumption rate, β-cell death (measured by unmethylated insulin DNA), and serum cytokine levels were measured during the peri-transplantation period. Adverse events, metabolic phenotypes, and islet function were measured prior and at 6 months post-transplantation. No adverse events directly related to the infusion of carbon monoxide islets were observed. Carbon monoxide islets showed significantly higher viability before transplantation. Subjects receiving carbon monoxide islets had less β-cell death, decreased CCL23, and increased CXCL12 levels at 1 or 3 days post transplantation compared with controls. Three in 10 (30%) of the carbon monoxide subjects and none of the control subjects were insulin independent. This pilot trial showed for the first time that harvesting human islets in carbon monoxide-saturated solutions is safe for total pancreatectomy and islet autotransplantation patients.

This study aimed to evaluate whether the BETA-2 score is a reliable early predictor of graft decline and loss of insulin independence after islet allotransplantation. Islet transplant procedures were stratified into 3 groups according to clinical outcome: long-term insulin independence without islet graft decline (group 1, N = 9), initial insulin independence with subsequent islet graft decline and loss of insulin independence (group 2, N = 13), and no insulin independence (group 3, N = 13). BETA-2 was calculated on day 75 and multiple times afterwards for up to 145 months posttransplantation. A BETA-2 score cut-off of 17.4 on day 75 posttransplantation was discerned between group 1 and groups 2 and 3 (area under the receiver operating characteristic 0.769, P = .005) with a sensitivity and negative predictive value of 100%. Additionally, BETA-2 ≥ 17.4 at any timepoint during follow-up reflected islet function required for long-term insulin independence. While BETA-2 did not decline below 17.4 for each of the 9 cases from group 1, the score decreased below 17.4 for all transplants from group 2 with subsequent loss of insulin independence. The reduction of BETA-2 below 17.4 predicted 9 (1.5-21) months in advance subsequent islet graft decline and loss of insulin independence (P = .03). This finding has important implications for posttransplant monitoring and patient care.

Islet cell transplantation is a promising functional cure for type 1 diabetes; however, maintaining long-term islet graft function and insulin independence is difficult to achieve. In this short report we present a patient with situs inversus, who at the time of islet transplantation had a 26-year history of type 1 diabetes, complicated by hypoglycemic unawareness and severe hypoglycemic events. After a single allogeneic islet transplant of a low islet mass, and despite developing de novo anti-insulin and anti-GAD65 autoantibodies, the patient has remarkably maintained insulin independence with tight glycemic control and normal metabolic profiles for 10 years, after receiving prolonged non-T-cell depleting immunosuppression.

Milestones in the history of diabetes therapy include the discovery of insulin and successful methods of beta cell replacement including whole pancreas and islet cell transplantation options. While pancreas transplantation remains the gold standard for patients who have difficulty controlling their symptoms with exogenous insulin, islet allotransplantation is now able to provide similar results with some advantages that make it an attractive potential alternative. The Edmonton Protocol, which incorporated a large dose of islets from multiple donors with steroid-free immunosuppression helped to establish the modern era of islet transplantation almost 20 years ago. While islet allotransplantation is recognized around the world as a powerful clinical therapy for type 1 diabetes it is not yet recognized by the Federal Drug Administration of the United States. Large-scale clinical trials administered by the Clinical Islet Transplantation Consortium have recently demonstrated that the well-regulated manufacture of a human islet product transplanted into patients with difficult to control type 1 diabetes and with a history of severe hyperglycemic episodes can safely and efficaciously maintain glycemic balance and eliminate the most severe complications associated with diabetes. The results of these clinical trials have established a strong basis for licensure of clinical islet allotransplantation in the US. Recognition by the Federal Drug Administration would likely lead to third party reimbursement for islet allotransplantation as a therapeutic option in the United States and would make the treatment available to many more patients. The high costs of rampant diabetes justify the expense of the treatment, which is in-line with the costs of clinical pancreas transplantation. While much enthusiasm and hope is raised toward the development and optimization of stem cell therapy, the islet transplantation community should push toward licensure, if that means broader access of this procedure to patients who may benefit from it. Even as we prepare to take the first steps in that direction, we must acknowledge the new challenges that a shift from the experimental to clinical will bring. Clinical islet allotransplantation in the United States would be a game-changing event in the treatment of type 1 diabetes and also generate enthusiasm for continued research.

Islet transplantation is currently the only minimally invasive therapy available for patients with type 1 diabetes that can lead to insulin independence, however, it is limited to only a small number of patients Although clinical procedures have improved in the isolation and culture of islets, a large number of islets are still lost in the pretransplant period, limiting the success of this treatment Moreover, current practice includes islets being prepared at specialized centers, which are sometimes remote to the transplant location Thus, a critical point of intervention to maintain the quality and quantity of isolated islets is during transportation between isolation centers and the transplanting hospitals, during which 20-40% of functional islets can be lost The current study investigated the use of an oxygen-permeable PDMS microwell device for long-distance transportation of isolated islets. We demonstrate that the microwell device protected islets from aggregation during transport, maintaining viability and average islet size during shipping. Refereed/Peer-reviewed

Background Human islet allotransplantation for the treatment of type 1 diabetes is in phase III clinical trials in the U.S. and is the standard of care in several other countries. Current islet product release criteria include viability based on cell membrane integrity stains, glucose-stimulated insulin release, and islet equivalent (IE) dose based on counts. However, only a fraction of patients transplanted with islets that meet or exceed these release criteria become insulin independent following 1 transplant. Measurements of islet oxygen consumption rate (OCR) have been reported as highly predictive of transplant outcome in many models. Method In this article we report on the assessment of clinical islet allograft preparations using OCR dose (or viable IE dose) and current product release assays in a series of 13 first transplant recipients. The predictive capability of each assay was examined and successful graft function was defined as 100% insulin independence within 45 days post-transplant. Results OCR dose was most predictive of CTO. IE dose was also highly predictive, while glucoses stimulated insulin release and membrane integrity stains were not. Conclusion OCR dose can predict CTO with high specificity and sensitivity and is a useful tool for evaluating islet preparations prior to clinical human islet allotransplantation.

Islet transplantation (IT) is a promising therapy for the treatment of diabetes. The large number of islets required to achieve insulin independence limit its cost-effectiveness and the number of patients who can be treated. It is believed that >50% of islets are lost in the immediate post-IT period. Poor oxygenation in the early post-IT period is recognized as a possible reason for islet loss and dysfunction but has not been extensively studied. Several key variables affect oxygenation in this setting, including (1) local oxygen partial pressure ( pO2), (2) islet oxygen consumption, (3) islet size (diameter, D), and (4) presence or absence of thrombosis on the islet surface. We discuss implications of oxygen-limiting conditions on intraportal islet viability and function. Of the 4 key variables, the islet size appears to be the most important determinant of the anoxic and nonfunctional islet volume fractions. Similarly, the effect of thrombus formation on the islet surface may be substantial. At the University of Minnesota, average size distribution data from clinical alloislet preparations (n = 10) indicate that >150-µm D islets account for only ~30% of the total islet number, but >85% of the total islet volume. This suggests that improved oxygen supply to the islets may have a profound impact on islet survivability and function since most of the β-cell volume is within large islets which are most susceptible to oxygen-limiting conditions. The assumption that the liver is a suitable islet transplant site from the standpoint of oxygenation should be reconsidered.

Summary The β-cell replacement by islet transplantation is an attractive approach for normalizing blood glucose without hypoglycaemia in patient with type 1 diabetes mellitus (T1D). A pioneer study by the Edmonton group more than a decade ago showed that alloislet transplantation may result in insulin independence for at least 1 year after transplantation. This breakthrough excited researchers, physicians and patients, who felt that the ultimate goal of cure for T1D was at hand. Longer follow-up of patients who underwent islet transplantation showed less favourable results, with only approximately 10% of the patients remaining insulin-free 5 years after transplantation. In the last few years, progress has been made, and the success rate of islet transplantation has steadily increased. Important hurdles, however, related to limited tissue supply and need for life-long immunosuppressive drugs have yet to be overcome. Herein, we review recent achievements in islet transplantation and the challenges that still need to be addressed before this procedure can become a standard therapy for T1D. Copyright © 2013 John Wiley & Sons, Ltd.

PURPOSE OF REVIEW The dramatic results of the Edmonton Protocol in 2000 triggered tremendous excitement over the application of pancreatic islet transplantation as a viable approach to achieving consistent insulin independence in type 1 diabetic patients. However, this optimism in the field was tempered by follow-up studies showing frequent attrition of graft function commonly requiring a return to exogenous insulin therapy within 1-3 years after transplant. The purpose of this review is to put these initial studies in perspective and to highlight progress and challenges in this important field. RECENT FINDINGS Recent clinical and experimental findings demonstrate a progressive improvement in the function and durability of islet allografts. Induction therapies targeting T lymphocytes and costimulatory pathways have been highly effective at promoting islet transplant function. It is also apparent that islet injury associated with metabolic distress provides a nonimmune barrier to islet transplant outcomes. SUMMARY Newer therapeutic interventions show great promise for attenuating the adaptive immune response to islet allografts. Also, clarifying the mechanisms of metabolic-related tissue distress may provide additional potential targets for improving islet graft outcomes.

In this review, we discuss the application of microfluidic devices in studying the physiology and pathophysiology of human islets and beta-cells, especially its application for human islet transplantation. Human islet transplantation is a promising therapy for Type I diabetes; however, the islet transplant outcomes for achieving complete insulin independence are far from perfect and face many challenges. This review focuses on the microfluidic devices developed in our laboratory, which can address these challenges in the field of human islet transplantation, and briefly review the design and fabrication principles of these microfluidic devices and their main application.

Alloislet transplantation for the treatment of type 1 diabetes enjoyed highly favorable status in the first half of the last decade but declined in favor during the second half. In this Perspective, I will briefly review the literature published in this area from 2000 to 2010 for the purposes of extracting lessons we have learned, considering whether the procedure should be deemed a partial success or a partial failure, and offering several strategies to improve alloislet transplantation outcomes in the future. In the end, I hope to strike a positive note about where this procedure is going, and how it will be applied to establish insulin independence in patients with type 1 diabetes.

The ability to culture porcine islets for extended times allows for both their functional assessment and the assurance of their microbiological safety prior to transplantation. We have previously shown that agarose-encapsulated porcine islets can be cultured for at least 24 weeks. In the current study, porcine islet agarose macrobeads cultured for up to 67 weeks were assessed for their ability to restore normoglycemia, respond to an intraperitoneal glucose challenge, maintain spontaneously diabetic BB rats free of insulin therapy for more than 6 months, and for their biocompatibility. Porcine islets were encapsulated in agarose macrobeads and subjected to weekly static perifusion assays for the assessment of insulin production. After in vitro culture for either 9, 40, or 67 weeks, 56–60 macrobeads were transplanted to each spontaneously diabetic BB rat. Transplanted rats were monitored daily for blood glucose levels. Glucose tolerance tests and assessments for porcine C-peptide were conducted at various intervals throughout the study. Normoglycemia (100–200 mg/dl) was initially restored in all islet transplanted rats. Moderate hyperglycemia (200–400 mg/dl) developed at around 30 days posttransplantation and continued throughout the study period of 201–202 days. Importantly, all rats that received encapsulated porcine islets continued to gain weight and were free of exogenous insulin therapy for the entire study. Porcine C-peptide (0.2–0.9 ng/ml) was detected in the serum of islet recipients throughout the study period. No differences were detected between recipient animals receiving islet macrobeads of various ages. These results demonstrate that the encapsulation of porcine islets in agarose macrobeads allows for extended culture periods and is an appropriate strategy for functional and microbiological assessment prior to clinical use.

More than 500 patients with type 1 diabetes mellitus have now received islet transplants at over 50 institutions worldwide in the past 5 years. Rates of insulin independence at 1 year with current protocols are impressive. However, inexorable decay of islet function over time indicates that there are many opportunities for improvement. Improved control of glycosylated hemoglobin and reduced risk of recurrent hypoglycemia are seen as important benefits of islet transplantation, irrespective of the status regarding insulin independence. For the use of islet transplantation to expand it is essential that the donor-to-recipient ratio be reliably reduced to 1 : 1. Enormous opportunities lie ahead for the development of successful living donor islet transplantation, single donor protocols, improved engraftment, islet proliferation in vitro and in the recipient, alternative islet sources, and novel tolerizing drugs. With these emerging opportunities, islet transplantation may expand to include more patients with type 1 diabetes, including children, and will not be restricted to the most unstable forms of the disease, as it is today.

Insulin independence after conversion from tacrolimus to cyclosporine in islet transplantation

Although islet transplantation is emerging as a critical solution for type I diabetes, it faces several problems like long-term independence of insulin, donor supply, immune rejection, and cell viability. Around two-thirds of the transplanted islets die in the first few days of the posttransplant and during the time in which remaining islets become functional, hyperglycemia eventually returns as islets are lost. The infused islets may coagulate and may lead to instant blood-mediated inflammatory reaction that causes extensive islet damage during transplantation. The researchers are now focusing on developing three-dimensional scaffolds that promote islet survival and growth and to achieve prolonged insulin independence for patients suffering from type I diabetes. This chapter focuses on the recent developments in 3D scaffolding to support pancreatic islet transplantation.

Islet transplantation is considered an advanced therapy in the treatment of type-1 diabetes, with a progressive improvement of clinical results as seen in the Collaborative Islet Transplant Registry (CITR) report. It is an accepted method for the stabilization of frequent hypoglycemia, or severe glycemic lability, in patients with hypoglycemic unawareness, poor diabetic control, or a resistance to intensive insulin-based therapies. Worldwide data confirm a positive trend in this field, with the integrated management of pivotal factors: adequate islet mass, immunosuppressive protocols, additional anti-inflammatory therapy, and pre-transplant allo-immunity assessment. Insulin independence has been observed in several clinical trials with different rate, ranging 100-65% of patients; the maintenance of this condition during the follow-up progressively decreased, actually arranged on 44% 3 years after the last infusion, according to data reported from the CITR. Successful duration is progressively increasing, with ≥13 years being the longest reported insulin-free condition on record. The immediate results of functioning islet transplantation are an improvement in hypoglycemic awareness and a reduction in the glycated hemoglobin level. Furthermore, many studies have shown its influence on the chronic complications of diabetes, such as peripheral neuropathy, retinopathy, and macroangiopathy. Pre-transplant nephropathy remains an exclusion criterion as immunosuppressive therapy can exacerbate kidney-function deterioration. The problems linked to immunosuppression following islet transplantation for the treatment of type-1 diabetes need to be considered in order to achieve the correct risk/benefit ratio for each patient.

Islet allotransplantation can provide prolonged insulin independence in selected individuals with type 1 diabetes. Whether islet transplantation also restores hypoglycemic counterregulation is unclear. To determine if hypoglycemic counterregulation is restored by islet transplantation, we studied hormone responses and hypoglycemic symptom recognition in seven insulin-independent islet transplant recipients using a 3-h stepped hypoglycemic clamp, and compared their responses to those of nontransplanted type 1 diabetic subjects and nondiabetic control subjects. Glucagon responses of islet transplant recipients to hypoglycemia were significantly less than that observed in control subjects (incremental glucagon [mean ± SE]: −12 ± 12 vs. 64 ± 22 pg/ml, respectively; P < 0.05), and not significantly different from that of nontransplanted type 1 diabetic subjects (−17 ± 10 pg/ml). Epinephrine responses and symptom recognition were also not restored by islet transplantation (incremental epinephrine [mean ± SE]: 195 ± 128 [islet transplant recipients] vs. 238 ± 73 [type 1 diabetic subjects] vs. 633 ± 139 pg/ml [nondiabetic control subjects], P < 0.05 vs. control; peak symptom scores: 3.3 ± 0.9 [islet transplant recipients] vs. 3.1 ± 1.1 [type 1 diabetic subjects] vs. 6.7 ± 0.8 [nondiabetic control subjects]). Thus the results indicate that despite providing prolonged insulin independence and near-normal glycemic control in these patients with long-standing type 1 diabetes, hypoglycemic hormonal counterregulation and symptom recognition were not restored by intrahepatic islet transplantation.

Islet transplantation as a procedure to induce insulin independence is still a long way from benefitting the population of more than I million type I diabetic patients in the United States. In addition to the problems involved with immune suppression, the most significant obstacle is a scarcity of human organs for transplantation. In 1999, only 5882 donated pancreases were available, of which only 50% could be expected to produce islet yields suitable for clinical purposes. In this article, we review various sources with the potential to provide tissue for transplantation. These sources include islet and nonislet cells derived from both human and nonhuman sources, with an emphasis on human cells.

Pancreatic islet transplantation is a minimally invasive procedure that can restore normoglycemia and insulin independence in Type 1 diabetics without the surgical complications associated with vascularized pancreas transplantation. The advances made in this field over the past decade have dramatically improved patient outcomes, and the procedure is now transitioning from an experimental treatment to a clinical reality. Nonetheless, a number of important issues continue to hamper the success of islet transplantation and must be addressed before there is widespread clinical acceptance. These include the relative inefficiency of the islet isolation process, the progressive loss of islet function over time and the need for multiple donors to achieve insulin independence. Here, we discuss the current status of islet transplantation and examine its future as a treatment for Type 1 diabetes.

BACKGROUND Islet transplantation is a recognized treatment option for select patients with type I diabetes mellitus. However, islet infusions from multiple donors are often required to achieve insulin independence. Ideally, insulin independence would be achieved routinely with only a single donor. Identification of factors associated with insulin independence after single-donor islet transplantation may help to select recipient-donor combinations with the highest probability of success. METHODS Subjects undergoing islet transplantation at a single center (Edmonton, Canada) between March 1999 and August 2013 were included. Recipient, donor, and transplant characteristics were collected and compared between recipients who became insulin independent after one islet transplantation and those who did not. RESULTS Thirty-one patients achieved insulin independence after a single-donor islet transplantation, and 149 did not. Long-term insulin-free survival was not different between the groups. Factors significantly associated with single-donor success included recipient age, insulin requirement at baseline, donor weight, donor body mass index, islet transplant mass, and peritransplant heparin and insulin administration. On multivariate analysis, pretransplantation daily insulin requirements, the use of peritransplantation heparin and insulin infusions, and islet transplant mass remained significant. CONCLUSION We have identified clinically relevant differences defining the achievement of insulin independence after single-donor transplantation. Based on these differences, a preoperative insulin requirement of less than 0.6 U/kg per day and receiving more than 5,646 islet equivalents (IEQ)/kg have a sensitivity of 84% and 71% and specificity of 50% and 50%, respectively, for insulin independence after single-donor islet transplantation. With ideal patient selection, this finding could potentially increase single-donor transplantation success and may be especially relevant for presensitized subjects or those who may subsequently require renal replacement.

Islet xenotransplantation is a prospective treatment to bridge the gap between available human cells and needs of patients with diabetes. Pig is the ideal candidate to obtain such available islet cells. However, potential clinical application of pig islet transplantation still faces obstacles such as inadequate yield of high-quality functional islets and xenorejection of the transplants. Adequate amounts of available islets can be obtained based on selection of a suitable pathogen-free source herd and the development of isolation and purification methods. Several studies demonstrated feasibility of successful pre-clinical pig islet xenotransplantation and provided insights and possible mechanisms of xenogeneic immune recognition and rejection. Particularly promising is the achievement of long-term insulin independence in diabetic models by means of distinct islet products and novel immunotherapeutic strategies. Nonetheless, further efforts are needed to obtain much more data on safety and efficacy to translate these findings into clinical practice

A type 1-diabetes results from autoimmune destruction of the insulin producing ß-cells in the pancreas. Today there is no cure to the disorder, and the patients require life-long insulin medication to survive. Treatment with exogenous insulin cannot mimic the second-by second regulation of blood glucose levels achieved by the ß-cells, and the current regimen presents a difficult navigation between the Scylla of life-threatening hypoglycemia and the Charybdis of hyperglycemic tissue glycosylation and late-complications.

Evaluation of engraftment is important to assess the success of islet transplantation. Recently we developed secretory unit of islet transplant objects (SUITO) index for simple evaluation of engraftment. Assuming that normal subjects aged40 years have 100% pancreatic beta-cell function, SUITO index was calculated by the formula: 1500 x fasting C-peptide immunoreactivity [ng/dL]/(fasting blood glucose [mg/dL] - 63). In this study, we compared the efficacy of islet transplantation from cadaveric and living donors using the SUITO index.We performed eight islet transplantations with non-heart-beating donors (NHBDs) into five patients. Two patients received fresh islets once, one patient received fresh islets twice, one patient received cultured islets once, and one patient received cultured islets twice plus fresh islets once. In addition, one patient received fresh islets from a living donor. We calculated the SUITO index from postoperative days 3 to 30 for each case.Mean SUITO index after one fresh islet transplant was 11.7 +/- 1.0, after two fresh islet transplants was 28.5 +/- 3.4, after one cultured islet transplant was 2.1 +/- 0.4, after two cultured islet transplant was 12.1 +/- 1.9, and after two cultured islet transplant plus one fresh islet transplant was 26.7 +/- 1.7. The mean SUITO index after single living donor islet transplant was 40.7 +/- 2.6, which was significantly higher compared with all other groups. Insulin independence was obtained when the SUITO index was26, which might reflect that 26% beta-cell mass was required for insulin independence.SUITO index is useful to evaluate islet engraftment and to predict the possibility of insulin independence.

Background Current success in islet transplantation will lead to a donor shortage. Living donor islet transplantation could be an alternative approach to expand the potential donor pool. In this study we describe the first successful living donor islet transplantation for unstable diabetes, performed at Kyoto University Hospital on January 19, 2005. Methods The donor was a healthy 56-year-old woman and mother of the recipient. The recipient was a 27-year-old woman with insulin-dependent diabetes since the age of 15 years. She experienced frequent hypoglycemic unawareness episodes. Her blood glucose concentration was difficult to control and C-peptide level was negative after glucagon stimulation. She needed an average 28 of units of insulin per day. The donor underwent a distal pancreatectomy and islets were isolated from the resected pancreas graft. The total islet yield was 408,114 islet equivalents and isolated islets were immediately transplanted into the recipient’s liver. Results After transplant, the blood glucose level of the recipient was tightly controlled without hypoglycemic episodes. She was discharged on day 37 with a normal oral glucose tolerance test (OGTT). The recipient remained insulin-independent for >3 months, since day 22 posttransplant. The donor’s postoperative clinical course was uneventful. She was discharged on postoperative day 18 and returned to her job within 1 month. Conclusions We report the first successful living donor islet transplantation for the treatment of unstable diabetes. We believe that living donor islet transplantation may become an option in the treatment of insulin-dependent diabetes.

A few groups have endured the challenges of time, anecdotal success stories, logistic and funding impediments, to bring the field of clinical islet transplantation where it stands today. The recent improvement in clinical results has paralleled a renewed interest in islet transplantation and an increasing number of centers have entered the field. Selected institutions have now clearly demonstrated that insulin independence can be a reproducible and achievable goal. Other centers struggle with mixed results, while occasional early failures of islet transplants are still observed. This center effect underlines not just a learning curve, but also the complexity of the approach, which requires multidisciplinary expertise and attention to critical variables that need to be closely monitored to assure adequate clinical outcomes. The future success and large scale applicability of islet transplantation will rely on the synergistic research progress in critical areas that contribute to the sequential and integrated approach required for success in clinical islet transplantation.

Percutaneous pancreatic islet cell transplantation is a promising cellular-based therapy for type 1 diabetes mellitus (DM). This procedure involves portal venous injection of islet cells and affords 1-year insulin independence in up to 70 % of recipients. While transplant surgeons represent the historical drivers of islet therapy, requirement for image-guidance and transcatheter techniques has fostered collaboration with interventional radiologists (IRs), who play a significant role in clinical performance of islet transplantation. The following case reviews the procedural elements of islet cell transplantation with stepwise illustration of the interventional radiologic technique. The logistics involved in establishing and developing an islet cell transplantation program and the technical aspects of pancreatic organ harvest and islet cell isolation and preparation are beyond the scope of this chapter and will not be presented.

Islet transplantation is a minimally invasive β-cell replacement strategy. Islet transplantation is a reimbursed treatment in Norway. Here, we summarize the cost and clinical outcome of 31 islet transplantations performed at Oslo University Hospital (OUS) from January 2010 to June 2015. Patients were retrospectively divided into three groups. Thirteen patients received either one or two islet transplantation alone (ITA), while five patients received islet transplantation after previous solid organ transplantation. For the group receiving 2 ITA, Kaplan-Meier estimates show an insulin independence of 20% more than 4 years after their last transplantation. An estimated 70% maintain at least partial graft function, defined as fasting C-peptide >0.1 nmol L−1, and 47% maintain a HbA1c below 6.5% or 2 percent points lower than before ITA. For all groups combined, we estimate that 44% of the patients have a 50% reduction in insulin requirement 4 years after the initial islet transplantation. The average cost for an islet transplantation procedure was 347 297±60 588 NOK, or 35 424±6182 EUR, of which isolation expenses represent 34%. We hereby add to the common pool of growing experience with islet transplantation and also describe the cost of the treatment at our center.

Background Current islet transplantation approaches have various defects. This study was to investigate the feasibility and safety of an indwelling catheter in the right gastric vein for intra-hepatic islet transplantation. Methods Twenty patients had islet transplants through the indwelling catheter in the right gastric vein. The catheters were placed into the portal vein trunk using open surgery. While monitored with Doppler ultrasound, the islet suspensions were infused after the catheter location was confirmed in the trunk of the portal vein. The catheter was kept indwelling and secured to the skin for optional subsequent infusions and flushed with heparinized saline once per day to avoid peri-catheter thrombosis. After one month, the catheter was removed. Adverse effects and transplant efficacy parameters were observed. Results Insulin independence was finally achieved in 17 patients; 11 patients received a second infusion. The mean surgical duration was 55 ∓ 7 minutes and the hemorrhage volume was approximately 40 ∓ 11 mL. No significant change in portal pressure was observed (before infusion 2.9 ∓ 1.5 cm H2O, after infusion 2.6 ∓ 1.7 cm H2O, p>0.05). However, peak systolic velocity (PRV) of the hepatic artery after infusion was markedly higher than that before infusion (35.1 ∓ 10.7 cm/s vs. 68.5 ∓ 46.2 cm/s, pConclusions It is feasible, convenient, and safe to use an indwelling catheter in the right gastric vein for islet transplantation.

The publication of the promising results of the Edmonton protocol in 2000 generated optimism for islet transplantation as a potential cure for Type 1 Diabetes Mellitus. Unfortunately, follow-up data revealed that less than 10% of patients achieved long-term insulin independence. More recent data from other large trials like the Collaborative Islet Transplant Registry show incremental improvement with 44% of islet transplant recipients maintaining insulin independence at three years of follow-up. Multiple underlying issues have been identified that contribute to islet graft failure, and newer research has attempted to address these problems. Stem cells have been utilized not only as a functional replacement forβcells, but also as companion or supportive cells to address a variety of different obstacles that prevent ideal graft viability and function. In this paper, we outline the manners in which stem cells have been applied to address barriers to the achievement of long-term insulin independence following islet transplantation.

Since the advent of islet transplantation, there has been a significant emphasis on the importance of islet purity despite an inevitable associated loss of islet mass during the purification process. One of the key elements of the 'Edmonton Protocol' for islet transplantation published in 2000 was an emphasis on the need for sequential transplants of highly purified islets (averaging 24% beta cell purity) and the close correlation between the numbers of islets transplanted and the success of the procedure. However, the emphasis on islet purity may warrant further consideration as auto transplantation of non-purified islets currently provides the most successful insulin independence rates within the field of islet transplantation. While the role of auto and allo immunity could contribute to the differences in the success rates it is clear that within the clinical setting, significant acinar and ductal contamination is well tolerated. However, one could go further and hypothesize that extra-insular tissue including acinar tissue, ductal tissue, peri-pancreatic lymph nodes and vascular tissue actually confer an advantage to islet survival/function and may even contribute to the insulin secreting capacity of the graft post transplant. As such this review will assess the influence of extra-insular pancreatic tissue on the results of islet transplantation based on published evidence and will also explore the possibility that non-islet pancreatic cells are capable of differentiating into a beta cell phenotype in vivo contributing to an ongoing regeneration of endocrine mass during the period following transplantation.

Islet transplantation has been established as a promising treatment for patients suffering from life-threatening hypoglycemic episodes (Shapiro et al., 2000, Shapiro et al., 2006). Apart from the achievement of insulin independence, islet transplantation has been shown to improve metabolic control (Meyer et al., 1998), renal and cardiovascular function (Fiorina et al., 2003a, Fiorina et al., 2003b) and to ameliorate the progression of diabetic complications such as retinopathy (Thompson et al., 2008, Warnock et al., 2008). With regard to long-term posttransplant outcome islet transplantation alone has now reached equivalent function rates when compared to pancreas transplantation alone (Bellin et al., 2008, Vantyghem et al., 2009, Maffi et al., 2011). However, the broad application of this treatment on diabetic patients is limited with respect to the number of suitable islet preparations required to induce long-term insulin independence in recipients of islet allografts (Guignard et al., 2004, Kempf et al., 2005).

Although experimental islet isolation and transplantation has continued for over 25 years, the results of human islet transplantation in patients with type 1 diabetes were disappointing until June 2000 when the University of Alberta, Edmonton, Canada reported 100% insulin independence in a cohort of seven patients. The study introduced several innovations now under evaluation worldwide. In the United Kingdom, an Islet Transplant Consortium has been established to co-ordinate clinical trials in several centres. The Canadian results have renewed hope of establishing islet transplantation as a treatment for diabetes while highlighting the need to identify plentiful sources of insulin secreting tissue and alternatives to current immunosuppressive therapies.

As embryonic development of the pancreas progresses, a wide range of congenital anomalies and variations can occur. We report on the incidental observation of partial agenesis of the dorsal pancreas coexistent with cricumportal pancreas in a donor for islet transplantation. We successfully recovered a high yield of islets from such a pancreas, and the islet recipient achieved insulin independence after transplant. This case report discusses the suitability of the anomalous pancreas as a donor organ for islet transplant and the possible embryologic association between the two entities.

Unlike other potential targets of future stem cell approaches, there is already a current cell therapy for the treatment of type I diabetes. Indeed, islet transplantation has proven successful in inducing insulin independence for at least 1 year after the procedure. Progress in this discipline during the past 20 years has paved the way for stem cell-based therapies. Here we review the current state of the art of islet transplantation and examine the challenges that need to be addressed before a transition is made to stem cell-derived insulin-producing cells, with particular emphasis on the immunological aspects (rejection and autoimmunity) of type I diabetes.

With the first demonstration of insulin independence following intraportal islet transplantation into a patient with type 1 diabetes, a new era of clinical islet transplantation will begin. This report provides our initial experience of clinical islet transplantation with a total of nine consecutive portal vein islet transplants in seven diabetic recipients. The first three transplants were done in nonrenal failure diabetics (NRFI) using 6319 +/- 2173 islets/kg body weight with islets processed from single pancreas and cultured for 7 days at 24 degrees C. Prednisone, azathioprine, and cyclosporine were initiated prior to transplant. While all three recipients demonstrated C-peptide function posttransplant, all three rejected their grafts at 2 weeks. Five days of OKT3 treatment failed to recover more than 10% of their rejecting islet grafts. The studies were then shifted to established kidney transplant recipients (EKI) maintaining their basal immunosuppression while adding 7 days of Minnesota antilymphoblast globulin (MALG) to the recipient using islets from single donor pancreas that had been cultured for 7 days at 24 degrees C. There were an average of 6161 +/- 911 islets transplanted intraportally into three EKI recipients. All three had C-peptide response from the transplant, but none achieved insulin independence. While the first patient rejected his graft at 2 weeks, two recipients demonstrated long-term islet function up to 10 months posttransplant. Sustacal challenge testing demonstrated C-peptide responsiveness, but in a delayed pattern suggesting insufficient islet mass had been transplanted. The next three kidney transplant recipients received islets from more than one donor pancreas averaging 13,916 +/- 556 islets/kg body weight. The first of these was the first to achieve insulin independence from 10 to day 25 posttransplant when she appeared to have a rejection episode. The second and third recipients were retransplanted with islets from multiple donors having achieved partial islet function from single pancreas donor. The first patient on triple immunosuppression is demonstrating long-term partial function at 184 days but is not insulin independent. The third patient on prednisone and azathioprine received one half his islets after 7-day culture and the other half after 7-day culture combined with cryopreservation. He is continuing to demonstrate insulin independence for 154 days post-transplant with a glycated hemoglobin value of 5.6%. Sustacal challenge data demonstrate a total stimulated C-peptide response of 155 rhomol/ml at 4 months post-transplant compared with 148 +/- 12 rhomol/ml for normal controls (NC) and 425 rhomol/ml for nondiabetic, established kidney transplant recipients on triple immunosuppression.(ABSTRACT TRUNCATED AT 400 WORDS)