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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.

Patients with chronic pancreatitis have benefited from total pancreatectomy and autologous islet cell transplantation (TPAIT) since the 1970s. Over the past few decades, improvements have been made in surgical technique and perioperative management that have led to improved success of islet cell function, insulin independence and patient survival. This article focuses on recent updates and advances for the TPAIT procedure that continue to expand and innovate the impact on patients with debilitating disease.

Present-day treatments for people that are insulin dependent require multiple insulin injections, sometimes with an insulin pump, coupled with regular blood glucose monitoring. The availability of modified insulins, each with peaks of activity at varying times, has improved diabetes management. On the other hand, there have been impressive results leading to insulin independence by transplantation of cadaveric islets coupled with immune suppression. This review focuses on the possibility of treating diabetes with cellular transplants, specifically with the use of pluripotent stem cells, to produce a virtually unlimited and uniform supply of human islet-like clusters by directed differentiation. Prospects for improving the in vitro differentiation of human endocrine cells for the study of endocrine function and their possible clinical uses are also discussed.

Islet cell replacement therapies represent an effective way to restore physiologic glycemic control in patients with type 1 diabetes (T1DM) and severe hypoglycemia. Despite being able to provide long-term insulin independence, patients still require lifelong immunosuppression, which has myriad detrimental effects including an increased risk for opportunistic infections and some types of cancer. This vital issue precludes widespread application of these therapies as a true cure for T1DM. Encapsulation of islets into immunoisolating/immunoprotective devices provides the potential of abrogating the requisite for lifelong immunosuppression. The field of cellular encapsulation lies at a complex intersection between the areas of chemistry, physics, bioengineering, cell biology, immunology, and clinical medicine. In diabetes, cellular encapsulation has existed for nearly 50 years, nevertheless, a resurgence of interest in the field has been motivated by promising results in small- and large-animal models. Recent studies have demonstrated that long-term diabetes reversal without immunosuppression is indeed routinely achievable. Future researchers interested in exploring cellular encapsulation strategies will require a clear understanding of the basic theoretical and practical principles, guiding this rapidly expanding field. This article will provide essential considerations concerning the physicochemical properties of the most commonly used biomaterials, relevant aspects of the immune response to bioencapsulation, current encapsulation strategies, potential implantation sites for encapsulated cell therapies and, finally, a comprehensive review on the current state of clinical translation. © 2020 American Physiological Society. Compr Physiol 10:839-878, 2020.

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.

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.

Introduction: The goal of the study was using BETA-2 to define suboptimal islet allograft function, which precedes clinical need of the insulin support and to discriminate it from the optimal function which allows for persistent insulin independence after islet allotransplantation. Material: Thirty five islet transplants were performed in 16 patients with T1DM. BETA-2 trends over the time were assessed in 3 transplant groups depending on the clinical outcome: Group 1 (N=9) persistent insulin independence; Group 2 (N=13) insulin independence loss preceded by the gradual islet graft decline; Group 3 (N=13) no insulin independence. Day 75 was a surrogate day of accomplished islet engraftment. Results: None of the transplants with BETA-2 < 17.4 on Day 75 resulted in persistent insulin independence (ROC AUC=17.4 for BETA-2 Group 1 vs. Group 2+ Group 3 with 100% sensitivity). Moreover, afterwards BETA-2 always oscillated above 17.4 and never dropped below after each transplant from Group 1 with up to 12 years follow-up. In contrast BETA-2 dropped below 17.4 in every case from Group 2, 9 months (3-24) prior to the loss of insulin independence (Kaplan-Meyer, p=0.03). Based on above, we defined that optimal islet function at any time point was represented by BETA-2 >=17.4, whereas suboptimal when BETA-2 was below that. Once BETA-2 dropped below 17.4 at any time point, islet function never recovered, instead gradually deteriorated with subsequent need for insulin support in every patient from group 2. Optimal vs. suboptimal islet graft function could be also discriminated based on individual fasting glucose, c-peptide or A1c values but with lower sensitivity and specificity. BETA-2 values never reached 17.4 at any time point after each transplant from Group 3. Conclusion: BETA-2 with cut off 17.4 allowed to define and discriminate optimal vs. suboptimal islet allograft function before need for insulin support. Disclosure P.J. Bachul: None. J.E. Golebiewska: None. F. Antic: None. M. Para: None. L. Basto: None. K. Golab: None. L. Perea: None. L. Wang: None. M.L. Tibudan: None. C.C. Thomas: None. P. Witkowski: None. Funding State of Illinois; Dompé

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.

On 11 January 1922 insulin injection was used for the first time in the treatment of diabetes. Even today, daily insulin injections are the life-saving treatment for patients with Type 1 diabetes and advanced Type 2 diabetes. However, insulin injections often fail to achieve full glucose control, which in the long-term leads to multiple complications and mortality. Beta-cells, the natural producers and secretors of insulin, remain the gold-standard in regulating blood glucose levels. In this review, we focus on three strategies aiming at counteracting beta-cell loss in order to gain insulin independence: replacement, replication and protection. The three approaches, together termed as the triumvirate of beta-cell regeneration, may constitute the basis for a future cure for diabetes.

Latent autoimmune diabetes in adults (LADA) is characterized by the presence of islet autoantibodies and initial insulin independence, which can lead to misdiagnosis of type 2 diabetes (T2D). As such, understanding the genetic etiology of LADA could aid in more accurate diagnosis. However, there is ongoing debate regarding the exact definition of LADA, so understanding its impact in different populations when contrasted with type 1 diabetes (T1D) and T2D is one potential strategy to gain insight into its etiology. Unfortunately, the lack of consistent and thorough autoantibody screening around the world has hampered well-powered genetic studies of LADA. This review highlights recent genetic and epidemiological studies of LADA in diverse populations as well as the importance of autoantibody screening in facilitating future 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

Whole-organ pancreas transplantation, either alone or combined with a kidney transplant, is the only definitive treatment for many patients with type 1 diabetes that restores normal glucose homoeostasis and insulin independence. Pancreas transplantation delays, or potentially prevents, secondary diabetes complications and is associated with improvement in patient survival when compared with either patients remaining on the waiting list or those receiving kidney transplant alone. Pancreas transplantation is safe and effective, with 1-year patient survival >97 % and graft survival rates of 85 % at 1 year and 76 % at 5 years in recent UK data. This review focuses on some current areas of interest in pancreas transplantation.

Widespread application of β cell replacement to obtain insulin independence in people with type 1 diabetes requires an unlimited source of insulin-producing cells and the ability to block the pathological immune response. Recent reports in Nature Medicine and Nature Biotechnology present a creative bioengineering strategy for achieving these goals.

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.

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 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.