Outcome Of Clinical Islet Transplantation Research Articles

Could Transplantation into the Thyroid Gland Benefit Pancreatic Islet Grafting in Unstable Type 1 Diabetes (T1DM), Complicated Type 2 Diabetes (T2DM), and Patients with Total Pancreatectomy?

Insular allograft for unstable type 1 diabetes and autograft in pancreatectomy patients are nowadays considered established procedures with precise indications and predictable outcomes. The clinical outcome of islet transplantation is similar to that of pancreas transplantation, avoiding the complications associated with organ transplantation. We hypothesised that transplantation of islets of Langerhans within an endocrine organ could better promote their engraftment and function. This could help to resolve or ameliorate known pathological conditions such as unstable type 1 diabetes and complicated type 2 diabetes. Pancreatic islet transplantation is currently performed almost exclusively in the liver. The liver provides a sufficiently favourable environment, although not entirely. The hepatic parenchyma has a lower oxygen tension than the pancreatic parenchyma and the vascular structure of the liver is not typical of an exclusively endocrine organ. Moreover, islet transplantation into the liver is not without complications, including hematoma or portal vein thrombosis. The thyroid gland is the endocrine gland proposed as a 'container'. In fact, it has all the characteristics of 'physio-compatibility' which can address the objectives assumed. It is indeed an ideal site because it is an easily accessible anatomical site that allows islets to be implanted using ultrasound-guided transcutaneous inoculation technique. Moreover, it has physiological and anatomical endocrine affinities with pancreatic islets and, if necessary, it can be removed, using hormone supplementation or replacement therapy. The thyroid gland may be proposed as an ideal site for islet implantation due to its anatomical and physiocompatibility characteristics.

Association between primary graft function and 5-year outcomes of islet allogeneic transplantation in type 1 diabetes: a retrospective, multicentre, observational cohort study in 1210 patients from the Collaborative Islet Transplant Registry

Allogeneic islet transplantation is a validated therapy in type 1 diabetes; however, there is decline of transplanted islet graft function over time and the mechanisms underlying this decline are unclear. We evaluated the distinct association between primary graft function (PGF) and 5-year islet transplantation outcomes. In this retrospective, multicentre, observational cohort study, we enrolled all patients from the Collaborative Islet Transplant Registry who received islet transplantation alone (ITA recipients) or islet-after-kidney transplantation (IAK recipients) between Jan 19, 1999, and July 17, 2020, with a calculable PGF (exposure of interest), measured 28 days after last islet infusion with a validated composite index of islet graft function (BETA-2 score). The primary outcome was cumulative incidence of unsuccessful islet transplantation, defined as an HbA1c of 7·0% (53 mmol/mol) or higher, or severe hypoglycaemia (ie, requiring third-party intervention to correct), or a fasting C-peptide concentration of less than 0·2 ng/mL. Secondary outcomes were graft exhaustion (fasting C-peptide <0·3 ng/mL); inadequate glucose control (HbA1c ≥7·0% [53 mmol/mol] or severe hypoglycaemia); and requirement for exogenous insulin therapy (≥14 consecutive days). Associations between PGF and islet transplantation outcomes were explored with a competing risk analysis adjusted for all covariates suspected or known to affect outcomes. A predictive model based on PGF was built and internally validated by using bootstraps resampling method. In 39 centres worldwide, we enrolled 1210 patients with a calculable PGF (of those without missing data, mean age 47 years [SD 10], 712 [59·5%] were female, and 865 (97·9%) were White), who received a median of 10·8 thousand islet-equivalents per kg of bodyweight (IQR 7·4-13·5). 986 (82·4%) were ITA recipients and 211 (17·6%) were IAK recipients. Of 1210 patients, 452 (37·4%) received a single islet infusion and 758 (62·6%) received multiple islet infusions. Mean PGF was 14·3 (SD 8·8). The 5-year cumulative incidence of unsuccessful islet transplantation was 70·7% (95% CI 67·2-73·9), and was inversely and linearly related to PGF, with an adjusted subhazard ratio (sHR) of 0·77 (95% CI 0·72-0·82) per 5-unit increase of BETA-2 score (p<0·0001). Secondary endpoints were similarly related to PGF. The model-adjusted median C-statistic values of PGF for predicting 5-year cumulative incidences of unsuccessful islet transplantation, graft exhaustion, inadequate glucose control, and exogenous insulin therapy were 0·70 (range 0·69-0·71), 0·76 (0·74-0·77), 0·65 (0·64-0·66), and 0·72 (0·71-0·73), respectively. This global multicentre study reports a linear and independent association between PGF and 5-year clinical outcomes of islet transplantation. The main study limitations are its retrospective design and the absence of analysis of complications. Public Health Service Research, National Institutes of Health, Juvenile Diabetes Research Foundation International, Agence National de la Recherche, Fondation de l'Avenir, and Fonds de Dotation Line Renaud-Loulou Gasté.

207.3: Predictive Value of C-peptide Measures for Clinical Outcomes of Islet Transplantation in Type 1 Diabetes: A Report From the Collaborative Islet Transplant Registry (CITR)

CITR Investigators Introduction: Long-standing type 1 diabetes (T1D) can lead to impaired awareness of hypoglycemia and high-risk for severe hypoglycemic episodes (SHE). Islet transplantation (ITx) can restore endogenous insulin production, ameliorate glucose control, and abolish SHE. In the DCCT, a stimulated C-peptide >0.2 nmol/L was associated with lower HbA1c, reduced insulin requirements, and decreased prevalence of SHE. We set forth to determine what measures of C-peptide and levels are associated with achievement of ITx positive outcomes in T1D. Methods: Collaborative Islet Transplant Registry (CITR) Islet-Alone recipients with pre-transplant C-peptide <0.1 nmol/L and mean follow up of 4.6±1.1 years were included in the analyses (n=677). Post-transplant metabolic measures obtained from arginine stimulation test, IVGTT, OGTT, glucagon stimulation test and mixed meal stimulation test (MMTT) were evaluated. Predictive value of these measures for 7 primary outcomes of clinical ITx (i.e., absence of SHEs (ASHE); HbA1c<7.0%; HbA1c <7.0% & ASHE; HbA1c≤6.5; HbA1c≤6.5% & ASHE; insulin independence; and ASHE, HbA1c≤6.5%, and insulin independence) was assessed by area under the curve of receiver-operator characteristics curves (ROC-AUC). Measures with the highest ROC-AUC were then selected for determination of optimal cut points by ITx outcome. Results: Fasting C-peptide, MMTT stimulated C-peptide, fasting C-peptide to Glucose (Cpep/Glu) ratio, and MMTT stimulated Cpep/Glu ratio showed the highest ROC-AUCs among all measures evaluated (Table 1). Fasting C-peptide was highly predictive for ASHE (ROC-AUC = 0.9228; optimal cut point = 0.07 nmol/L), and the composite outcome of ASHE, HbA1c≤6.5%, and insulin independence (ROC-AUC = 0.8456; optimal cut point = 0.33 nmol/L) (Table 2). However, MMTT stimulated Cpep/Glu ratio outperformed both fasting and stimulated C-peptide for all outcomes except ASHE alone. Optimal cut point for the ideal composite outcome of ASHE, HbA1c≤6.5%, and insulin independence was 0.12 nmol/mmol for the MMTT stimulated Cpep/Glu ratio, and 0.97 nmol/L for MMTT stimulated C-peptide (Table 2). Discussion/Conclusion: Fasting C-peptide reliably predicts rates of ITx primary endpoints and is similar to other C-peptide measures at predicting ASHE. Although marginal endogenous fasting C-peptide is sufficient to eliminate SHEs, higher levels are required to achieve optimal ITx outcomes. The MMTT stimulated Cpep/Glu ratio provides better predictiveness for composite ITX outcomes, including insulin independence. In the absence of a MMTT, a fasting C-peptide ≥0.33 nmol/L is a reassuring measure of optimal metabolic control in ITx T1D recipients.The CITR has been funded continuously by grants from the National Institute of Diabetes and Digestive and Kidney Diseases since 2001 (Grants 1UCHDK098086-01, 1UC4DK114839-01) to collect data on the efficacy and safety of clinical islet transplantation from US and collaborating international institutions. The Juvenile Diabetes Research Foundation provided supplemental funding for reimbursement of efforts to report data from the European and Australian sites from 2006–2015. No other sponsors have provided support to the CITR. MRR is supported in part by Public Health Service Research Grant R01 DK 091331-8. We thank all the study participants and staff.

Particulate-Based Single-Dose Local Immunosuppressive Regimen for Inducing Tolerogenic Dendritic Cells in Xenogeneic Islet Transplantation.

Recent studies emphasize on developing immune tolerance by an interim administration of various immunosuppressive drugs. In this study, a robust protocol is reported for local immunomodulation using a single-dose of FK506 microspheres and clodronate liposomes (mFK+CLO) in a xenogeneic model of islet transplantation. Surprisingly, the single-dose treatment with mFK+CLO induce tolerance to the islet xenograft. The recipient mice display tolerogenic dendritic cells (tDCs) with decreased antigen presenting ability and T cell activation capacity. Furthermore, a reduced percentage of CD4+ and CD8+ T cells and an impaired differentiation of naïve CD4+ T cells into interferon-γ producing Th1 and interleukin-17 producing Th17 cells are observed. In addition, the immunosuppressive protocol leads to the generation of Foxp3+ regulatory T cells (Tregs) which are required for the long-term graft survival. The enhanced generation of tDCs and Tregs by the single treatment of mFK+CLO cause xenograft tolerance, suggesting a possible clinical strategy which may pave the way towards improving therapeutic outcomes of clinical islet transplantation.

Improving Clinical Islet Transplantation Outcomes.

Transplantation of islets purified from donor pancreata is one of only a few clinical strategies that can reverse type 1 diabetes (T1D) and restore glycemic control (1–3). Significant progress has been made by improving transplantation strategies in areas including immune suppressive regimes, islet quality, transplanted β-cell mass and purity, and donor selection (4–6). However, while improved metabolic control and reduced glycemic side effects such as hypoglycemia persist long term in the majority of T1D patients, insulin independence beyond 1 year is only achieved in a minority of cases (2). Early loss of islet mass upon portal vein infusion is believed to have a major negative impact (7). Recurrence of insulitis, the hallmark of T1D immunopathogenesis leading to autoimmune mediated β-cell destruction, and islet allograft rejection pose additional therapeutic hurdles (8,9). Recently, neutrophils were suggested as part of the innate immune system contributing to development of T1D (10). Chemokines produced by distressed islet tissue attract leukocytes to the site of implantation (Fig. 1). The chemokine CXCL8, produced by recruited and resident macrophages, attracts neutrophils carrying its receptors CXCR1/2 to the lesion. In this issue of Diabetes Care , Piemonti and colleagues (11) now report the results of a phase 3 clinical trial assessing whether interference in homing of leukocytes to the implanted islet graft using reparixin, a small molecule that interferes with CXCR1/2 signaling, may improve transplantation outcome. The rationale for this strategy is outstanding. Early studies in mice and humans were very encouraging. Treatment with reparixin prevented and reversed autoimmune diabetes in NOD mice and improved graft survival …

Mesenchymal stromal cell secretory factors induce sustained improvements in islet function pre- and post-transplantation

Background aimsMesenchymal stromal cells (MSCs) enhance islet function both in vitro and in vivo, at least in part by secreting ligands that activate islet G-protein coupled receptors (GPCRs). We assessed whether pre-treatment with a defined “cocktail” of MSC-secreted GPCR ligands enhances islet functional survival in vitro and improves the outcomes of islet transplantation in an experimental model of diabetes. MethodsIsolated islets were cultured for 48 h with ANXA1, SDF-1 or C3a, alone or in combination. Glucose-stimulated insulin secretion (GSIS) and cytokine-induced apoptosis were measured immediately after the 48 h culture period and at 24 h or 72 h following removal of the ligands from the culture media. Islets were syngeneically transplanted underneath the kidney capsule of streptozotocin-induced diabetic C57BL/6 mice and blood glucose levels monitored for 28 days. ResultsPre-culturing islets with a cocktail of ANXA1/SDF-1/C3a potentiated GSIS and protected islet cells from cytokine-induced apoptosis in vitro. These effects were maintained for up to 72 h after the removal of the factors from the culture medium, suggesting a sustained protection of islet graft functional survival during the immediate post-transplantation period. Islets pre-treated with the cocktail of MSC secretory factors were more effective in reducing blood glucose in diabetic mice, consistent with their improved functional survival in vivo. DiscussionPre-culturing islets with a cocktail of MSC secretory products offers a well-defined, cell-free approach to improve clinical islet transplantation outcomes while avoiding many of the safety, regulatory and logistical hurdles of incorporating MSCs into transplantation protocols.

Clinical Islet Transplantation Outcomes Are Comparable in Obese Type 1 Diabetes Recipients

Many clinical islet transplant programs have body mass index (BMI) and/or weight based thresholds for eligibility. Large subjects may require higher islet mass to reliably achieve insulin independence. However, for long term graft function and protection from hypoglycemia, data supporting a BMI based exclusion is lacking. Methods: Subjects undergoing islet transplantation at a single center, between 1999 and 2017 were included. Graft survival as measured by C-peptide positivity from last CIT was compared between recipients with BMI&amp;lt;30 kg/m2 (n=237, 24.8±2.8 kg/m2) and BMI &amp;gt;30 kg/m2 (n=24, mean±SD 31.9±2.1 kg/m2) pre-transplant. Results: Apart from BMI and weight (BMI&amp;lt;30 vs. BMI&amp;gt;30, 70.9±11.3 kg vs. 82.8±9.5 kg; P&amp;lt;0.05) there were no difference between groups in terms of baseline recipient characteristics, including in daily insulin dose (0.58±0.16 U/kg vs. 0.59±0.18 U/kg; P=0.34). Both groups received similar total number of islet infusions (2.4±0.9 and 2.3±0.6, p=0.6), total islet equivalents (1 053 022±471 532 vs. 1 182 498±366 368, P=0.19) and total islet equivalents per recipient body weight (15 208±6 373 IE/kg vs. 14 120±5 041 IE/kg, P=0.42). Long term C-peptide survival was not different between groups (P=0.18). Conclusion: T1D patients with BMI&amp;gt;30 appear to have similar islet mass requirements and graft survival compared to those with BMI&amp;lt;30. This likely reflects careful selection of smaller (weight &amp;lt;90 kg), insulin sensitive (&amp;lt;0.6 U/kg) subjects with only class I obesity. Given the prevalence of obesity in T1D, future studies should evaluate the roles of obesity, weight and insulin sensitivity to ensure rational and equitable access to transplantation. Disclosure A. Lam: None. K.J. Potter: None. S. Forbes: None. S. Imes: None. A.J. Malcolm: None. A. Haqq: None. A. Shapiro: Consultant; Self; Viacyte, Inc., Protokinetix. P.A. Senior: Consultant; Self; Abbott, AstraZeneca. Research Support; Self; AstraZeneca, Prometic Life Sciences Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc., Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; AstraZeneca, Merck &amp; Co., Inc., Abbott. Research Support; Self; Viacyte, Inc..

A Novel Subcutaneous Site of Islet Transplantation Superior to the Liver

Islet transplantation is an attractive treatment for patients with insulin-dependent diabetes mellitus, and currently, the liver is the favored transplantation site. However, an alternative site is desirable because of the low efficiency of hepatic transplantation, requiring 2 to 3 donors for a single recipient, and because the transplanted islets cannot be accessed or retrieved. We developed a novel procedure of islet transplantation to the inguinal subcutaneous white adipose tissue (ISWAT) of mice and described functional and morphological characteristics of transplanted syngeneic islets. Also, it was determined whether islet allograft rejection in the ISWAT can be prevented by immunosuppressive agents. Furthermore, it was examined whether human islets function when grafted in this particular site of immune-deficient mice. In this site, transplanted islets are engrafted as clusters and function to reverse streptozotocin-induced diabetes in mice. Importantly, transplanted islets can be visualized by computed tomography and are easily retrievable, and allograft rejection is preventable by blockade of costimulatory signals. Of much importance, the efficiency of islet transplantation in this site is superior to the liver, in which hyperglycemia of diabetic recipient mice is ameliorated after transplantation of 200 syngeneic islets (the islet number yielded from 1 mouse pancreas) to the ISWAT but not to the liver. Furthermore, human islets transplanted in this particular site function to reverse diabetes in immune-deficient mice. Thus, the ISWAT is superior to the liver as the site of islet transplantation, which may lead to improved outcome of clinical islet transplantation.

Cost and clinical outcome of islet transplantation in Norway 2010-2015.

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 4years after their last transplantation. An estimated 70% maintain at least partial graft function, defined as fasting C-peptide >0.1nmolL-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 4years after the initial islet transplantation. The average cost for an islet transplantation procedure was 347297±60588NOK, or 35424±6182EUR, 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.

Clinical pancreatic islet transplantation.

Clinical pancreatic islet transplantation can be considered one of the safest and least invasive transplant procedures. Remarkable progress has occurred in both the technical aspects of islet cell processing and the outcomes of clinical islet transplantation. With >1,500 patients treated since 2000, this therapeutic strategy has moved from a curiosity to a realistic treatment option for selected patients with type 1 diabetes mellitus (that is, those with hypoglycaemia unawareness, severe hypoglycaemic episodes and glycaemic lability). This Review outlines the techniques required for human islet isolation, in vitro culture before the transplant and clinical islet transplantation, and discusses indications, optimization of recipient immunosuppression and management of adjunctive immunomodulatory and anti-inflammatory strategies. The potential risks, long-term outcomes and advances in treatment after the transplant are also discussed to further move this treatment towards becoming a more widely available option for patients with type 1 diabetes mellitus and eventually a potential cure.

High-Resolution Intravital Imaging for Monitoring the Transplanted Islets in Mice

Intravital imaging techniques will be a valuable tool to monitor the post-transplantation dynamics of the cells/tissues in regenerative medicine research. Among the conventional live imaging techniques, the cranial window model has various advantages regarding resolution, longevity, and easy manipulability. We describe the use of the cranial window model to visualize the post-transplantation processes of primary pancreatic islets in the living mouse. Macroscopic or microscopic analyses were performed to evaluate the post-transplantation dynamics of primary murine islets, including the revascularization process inside the cranium. Consistent with earlier literature on clinical outcomes of islet transplantation, marked loss of transplanted islets was observed within 7 days. Intravital confocal microscope analysis revealed that functional revascularization seldom occurred in the central regions of the transplants. Our results suggest that the cranial window model offers an ideal platform for understanding cellular dynamics, through the possibility of long-term imaging studies over time scales. This platform is possibly applied not only for transplant studies of pancreatic islets, but also for other endodermal cell/tissue types in vivo.

Co-Transplantation of VEGF-Expressing Human Embryonic Stem Cell Derived Mesenchymal Stem Cells to Enhance Islet Revascularization in Diabetic Nude Mice

Background: Pancreatic islet transplantation has emerged as a promising treatment for type I diabetes. However, its efficacy is severely hampered due to poor islet engraftment and revascularization, which have been resulted to partially loss of transplanted islets. It has been shown that local delivery of vascular endothelial growth factor (VEGF) could accelerate transplanted islet revascularization, although permanent high level of VEGF may lead to undesirable side effects. In this study we investigated the effects of conditional cell-based delivery of VEGF through collagen-fibrin hydrogel on transplanted islet function and revascularization. Material and Methods: RH6 human embryonic stem cell derived mesenchymal stem cells (ES-MSCs) have been generated, characterized and transduced by two lentiviruses containing rtTA and VEGF-A. Tet-on expression of VEGF from these cells was shown by tube formation assay and was confirmed through VEGF ELISA. After co-transplantation of these cells and mouse isolated islets through collagen-fibrin hydrogel in the omental pouch of diabetic nude mice, the blood glucose, body weight, glucose tolerance and serum C-peptide was measured after 28 days. As control groups, islets were transplanted alone and with non-transgenic ES-MSCs. For measurement of revascularization, immunohistoflourscence examination was done and micro vessel density (MVD) and vessel size have been measured. Results: Receiving the same number of islets (300 IEQ) in all transplanted groups, the average blood glucose concentrations of mice transplanted with islets/hESC-MSC:VEGF were significantly lower than mice transplanted with islets or islet/hESC-MSC at different time points. This notable difference in blood sugar of transplant groups, was also reflected in their weight gain. Serum C-peptide level was higher in islet/hESC-MSC:VEGF (349.8±51.2 pM) compared with islet/hESC-MSC group and islet group but it was not markedly different from C-peptide levels in normal mice. In intraperitoneal glucose tolerance test (IP-GTT) to examine glucose responsiveness of the islet graft, mice in islet/hESC-MSC:VEGF group returned to normoglycemic state at the same rate as normal mice, while mice in islet/hESC-MSC and islet groups responded more slowly and did not return to the normoglycemic state. The results showed improved islet functionality and micro-vessel density in the group of mice received islets with VEGF expressing hESC-MSC, compared with control groups. Conclusion: We conclude that conditional expression of VEGF from hESC-MSCs during islet transplantation could enhance islet functionality and revascularization. This result can be used to improve the outcome of clinical islet transplantation. Keywords:Co-transplantation, Embryonic stem, Mesenchymal stem cells.

Alloantibody and Autoantibody Monitoring Predicts Islet Transplantation Outcome in Human Type 1 Diabetes

Long-term clinical outcome of islet transplantation is hampered by the rejection and recurrence of autoimmunity. Accurate monitoring may allow for early detection and treatment of these potentially compromising immune events. Islet transplant outcome was analyzed in 59 consecutive pancreatic islet recipients in whom baseline and de novo posttransplant autoantibodies (GAD antibody, insulinoma-associated protein 2 antigen, zinc transporter type 8 antigen) and donor-specific alloantibodies (DSA) were quantified. Thirty-nine recipients (66%) showed DSA or autoantibody increases (de novo expression or titer increase) after islet transplantation. Recipients who had a posttransplant antibody increase showed similar initial performance but significantly lower graft survival than patients without an increase (islet autoantibodies P < 0.001, DSA P < 0.001). Posttransplant DSA or autoantibody increases were associated with HLA-DR mismatches (P = 0.008), induction with antithymocyte globulin (P = 0.0001), and pretransplant panel reactive alloantibody >15% in either class I or class II (P = 0.024) as independent risk factors and with rapamycin as protective (P = 0.006) against antibody increases. DSA or autoantibody increases after islet transplantation are important prognostic markers, and their identification could potentially lead to improved islet cell transplant outcomes.

Improvement in Outcomes of Clinical Islet Transplantation: 1999–2010

OBJECTIVETo describe trends of primary efficacy and safety outcomes of islet transplantation in type 1 diabetes recipients with severe hypoglycemia from the Collaborative Islet Transplant Registry (CITR) from 1999 to 2010.RESEARCH DESIGN AND METHODSA total of 677 islet transplant-alone or islet-after-kidney recipients with type 1 diabetes in the CITR were analyzed for five primary efficacy outcomes and overall safety to identify any differences by early (1999–2002), mid (2003–2006), or recent (2007–2010) transplant era based on annual follow-up to 5 years.RESULTSInsulin independence at 3 years after transplant improved from 27% in the early era (1999–2002, n = 214) to 37% in the mid (2003–2006, n = 255) and to 44% in the most recent era (2007–2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone). C-peptide ≥0.3 ng/mL, indicative of islet graft function, was retained longer in the most recent era (P < 0.001). Reduction of HbA1c and resolution of severe hypoglycemia exhibited enduring long-term effects. Fasting blood glucose stabilization also showed improvements in the most recent era. There were also modest reductions in the occurrence of adverse events. The islet reinfusion rate was lower: 48% by 1 year in 2007–2010 vs. 60–65% in 1999–2006 (P < 0.01). Recipients that ever achieved insulin-independence experienced longer duration of islet graft function (P < 0.001).CONCLUSIONSThe CITR shows improvement in primary efficacy and safety outcomes of islet transplantation in recipients who received transplants in 2007–2010 compared with those in 1999–2006, with fewer islet infusions and adverse events per recipient.

Immune monitoring of pancreatic islet graft: towards a better understanding, detection and treatment of harmful events

Importance of the field: Long-term clinical outcomes of islet transplantation are hampered by rejection and recurrence of autoimmunity, which lead to a gradual decrease in islet function usually taking place over the first five years after transplantation. An accurate monitoring strategy could allow for the detection and treatment of harmful immune events, potentially resulting in higher rates of insulin-independence.Areas covered in this review: This article provides a critical review of the various assays currently available for the assessment of allo- and autoimmunity both prior to and after islet transplantation. The accuracy in predicting clinical outcome is specifically addressed.What the reader will gain: Most current tests based on the assessment of allo- and auto-immune antibody are of minimal help in clinical practice. Cell-based tests (including the assessment of cytotoxic T lymphocyte precursors, proliferation tests, enzyme-linked immunospot) have the potential to allow earlier and more accurate detection of harmful events.Take home message: A specific and accurate immune monitoring has the potential to significantly improve islet transplant outcomes. The development and use of such tests (favouring cell-based tests) should be promoted.

Excellence of S uito Index for Assessing Clinical Outcome of Islet Transplantation

Background Monitoring functional islet mass after transplantation is critical to follow patients. Previously we demonstrated that the average secretory unit of islet transplant objects (SUITO) index within 1 month was an excellent predictor of insulin-free status or reduction in insulin dose. In this study, we analyzed the usefulness of daily SUITO index to assess clinical outcomes. Methods Five patients underwent islet transplantation, including 3 who received 2 transplantations and 2 who received a single graft. All 5 patients achieved insulin-free status with 3 remaining insulin free at the time of evaluation. We analyzed the daily relative insulin dose and SUITO index. The daily relative insulin dose was calculated as the total daily insulin dose/average pretransplant insulin dose. The SUITO index was calculated as [fasting C-peptide (ng/mL)]/[fasting blood glucose (mg/mL) − 63] × 1,500. The data analyzed based on time after islet transplantation were categorized as within or after 1 month. Results Within 1 month after islet transplantation, there was no correlation between the daily relative insulin dose and the daily SUITO index ( P = .068; R = −0.33). After 1 month, the daily relative insulin dose and the daily SUITO index were strongly correlated ( P < .0001; R = −0.70). When the cutoff value of the SUITO index was decided at 26 for insulin-free status, the positive predictive value was 84.1% and negative predictive value 89.4%. Conclusion SUITO index was an excellent index to assess clinical outcomes beyond 1 month after islet transplantation.

Point: Steady Progress and Current Challenges in Clinical Islet Transplantation

The field of β-cell replacement therapies has evolved substantially over the last decades. The lesson learned from recent islet transplantation trials in patients with unstable type 1 diabetes is that primary goals are the achievement of stable, normalized glycemic control in the absence of severe hypoglycemic episodes with improvement of quality of life and the prevention of progressive, chronic diabetes complications. Insulin independence, although desirable, should not be considered the main objective, particularly in light of the sustained positive effects achieved even with a “marginal” functional islet mass via restoration of C-peptide secretion and reduction of insulin requirements. As present limitations of islet transplantation are progressively overcome, the clinical application will greatly expand from the currently limited indication in controlled clinical research trials to more widely available cellular therapies and regenerative medicine solutions that will eventually be offered as standard treatment to the majority of patients with insulin-requiring diabetes. Vantyghem et al. (1) in the article in this issue of Diabetes Care evaluated the predictive value of primary graft function on long-term clinical outcomes of islet transplantation alone (ITA). Surrogate measures have been proposed to monitor or predict β-cell function, but they are not yet fully validated (2–4). In this report, the use of the β-score in the early posttransplant period allowed to quantify primary graft function that, when “optimal,” was associated with prolonged graft survival and better metabolic control following islet transplantation (1). In agreement with previous reports using the “Edmonton Protocol” (5–10), this trial resulted in a significant improvement of metabolic control and long-term graft function (∼70% having measurable C-peptide at 5 years). Importantly, the investigators also showed prolonged insulin independence in 57% of the patients at 5 years, with the subjects with optimal primary graft …

SUITO Index for Evaluation of Efficacy of Single Donor Islet Transplantation

Evaluation of engrafted islets mass is important for clinical care of patients after islet transplantation. Recently, we developed the secretory unit of islet transplant objects (SUITO) index, which reflected engrafted islet mass. In this study, we evaluated the SUITO index for the prediction of clinical outcome after single islet transplantation. Single islet transplantations were performed into six type 1 diabetic patients. Isolated islets were quantitatively assessed at the time of transplantation. The SUITO index was calculated as follows: fasting C-peptide (ng/dl)/[fasting blood glucose (mg/dl) - 63] x 1500. Islet yield/recipient's body weight and SUITO index were evaluated, along with HbA(1C), relative insulin dose (insulin dose posttransplant/pretransplant), and M-values. HbA(1C) improved in all cases, irrespective of the SUITO index score or islet yield/body weight. The average SUITO index from postoperative days 3 to 30 (R(2) = 0.728, p < 0.04), but not islet yield/body weight (R(2) = 0.259, p = 0.303), correlated with relative insulin dose. The daily SUITO index strongly correlated with the daily relative insulin dose (R(2) = 0.558, p < 0.0001) and weakly correlated with the daily M-values (R(2) = 0.207, p < 0.02). A SUITO index score of less than 10 was associated with increasing insulin dose even after islet transplantation. The SUITO index seems to be a better predictor of success of islet transplantations than islet yield/body weight. SUITO index is recommended to assess clinical outcome of islet transplantation.

A Novel Predictive Method for Assessing the Quality of Isolated Pancreatic Islets Using Scanning Electrochemical Microscopy

Introduction The current methods for evaluating islet potency are not useful in clinical transplantation. Therefore, we need reliable, rapid methods enabling accurate prediction of islet quality. Materials and Methods We evaluated respiratory activity using scanning electrochemical microscopy (SECM), glucose-stimulated respiratory activity, glucose-stimulated insulin release, ADP/ATP assays, insulin/DNA levels, and Trypan blue exclusion tests as predictive methods for the ability of isolated rat islets to cure syngeneic diabetic rats. Results Although glucose-stimulated respiratory activity, basal respiratory activity, ADP/ATP ratio, and glucose-stimulated insulin release were significantly correlated with the outcome of transplantation into diabetic rats, there was no correlation between outcomes, insulin/DNA ratios, and Trypan blue exclusion tests. The glucose-stimulated respiratory activity in islet preparations that could cure diabetic rats was significantly greater than those unable to cure diabetes. Rat islets with >1.5-fold glucose-stimulated respiratory activity consistently cured diabetic rats, whereas those with a value <1.5 hardly cured any rats. Conclusion Measurement of the glucose-stimulated respiratory activity using SECM technique is a novel method that may be useful as a rapid, potent predictor of the outcome of clinical islet transplantation.

Effect of Pituitary Adenylate Cyclase–Activating Polypeptide in Islet Transplantation

Introduction Pituitary adenylate cyclase–activating polypeptide (PACAP) is an islet substance serving as an intra-islet amplifier of glucose-induced insulin secretion similar to exendin-4. It has been reported that systemic administration of PACAP maintained beta-cell mass, delayed the onset of hyperglycemia, and protected beta cells from glucose toxicity. Moreover, PACAP increases glucose-stimulated insulin release in vitro and in vivo. In this study, we investigated the possibility of PACAP use in human islet transplantation. Methods Human islets were cultured in the presence or absence of PACAP (10 −12 mol/L) for 48 hours. We assessed beta-cell viability using FACS, cellular composition analysis by iCys/LSC, and glucose-stimulated insulin secretion. In vivo, islets were transplanted beneath the kidney capsule of Streptozotocin-induced diabetic immunodeficient mice. An intravenous glucose tolerance test (IVGTT) was also performed in the presence or absence of PACAP (Peptide International, Louisville, Ky, United States; 1.3 nmol/kg). Results There were significant improvements in terms of beta-cell viability and cellular composition between islets cultured with or without PACAP, respectively ( P < .05). Moreover, glucose-stimulated insulin secretion significantly improved in islets cultured with PACAP compared with controls, respectively ( P < .05). Treatment of recipient mice with PACAP resulted in beneficial effects on insulin secretion (PACAP vs control, 13.2 vs 1.9 mU/L), in IVGTT. However, no significant difference was observed in glucose levels between the 2 groups. Conclusions Our study indicated that PACAP significantly improved beta-cell viability and survival during culture, and increased insulin secretion in vitro and in vivo. However, blood glucose levels in vivo after an IVGTT did not significantly improve, probably due to increased glucagon secretion from alpha cells. PACAP supplementation to culture medium could be of assistance to improve clinical islet transplantation outcomes.