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Context The Igls criteria were developed to provide a consensus definition for outcomes of β-cell replacement therapy in the treatment of diabetes during a January 2017 workshop sponsored by the International Pancreas & Islet Transplant Association (IPITA) and the European Pancreas & Islet Transplant Association. In July 2019, a symposium at the 17th IPITA World Congress was held to examine the Igls criteria after 2 years in clinical practice, including validation against continuous glucose monitoring (CGM)-derived glucose targets, and to propose future refinements that would allow for comparison of outcomes with artificial pancreas system approaches. Evidence acquisition Utilization of the criteria in various clinical and research settings was illustrated by population as well as individual outcome data of 4 islet and/or pancreas transplant centers. Validation against CGM metrics was conducted in 55 islet transplant recipients followed-up to 10 years from a fifth center. Evidence synthesis The Igls criteria provided meaningful clinical assessment on an individual patient and treatment group level, allowing for comparison both within and between different β-cell replacement modalities. Important limitations include the need to account for changes in insulin requirements and C-peptide levels relative to baseline. In islet transplant recipients, CGM glucose time in range improved with each category of increasing β-cell graft function. Conclusions Future Igls 2.0 criteria should consider absolute rather than relative levels of insulin use and C-peptide as qualifiers with treatment success based on glucose assessment using CGM metrics on par with assessment of glycated hemoglobin and severe hypoglycemia events.

One century after the discovery of insulin, the French Health regulations have just authorized the reimbursement for islet transplantation. Intraportal islet allotransplantation from a pancreatic donor is indicated in patients with type 1 diabetes (T1D) complicated with lability or hypoglycemia unawareness, or in case of a functioning kidney graft; islet auto-transplantation may be indicated after pancreatic surgery.Compared with insulin even administered in closed-loop pumps, the specificity of islet allotransplantation is the restoration of C-peptide secretion. Long-term insulin-independence is observed when the engrafted islet mass is sufficient, at the cost of immunosuppression. Fewer low-glucose events and less glucose variability, are observed even with minimal functional islet graft, after islet transplantation as at onset of T1D, when a residual C-peptide secretion is maintained, an objective currently approached with less aggressive immuno-modulating therapies than in the past. Therefore, restoration or preservation of endogen insulin secretion is an important goal, allowing to maintain a long-term glucose balance with more than 70% of time in range 3.9-10mmol/L and less than 3% of time3.9mmol/L, thus reducing the occurrence of diabetic complications. In the clinical setting, - the preservation of C-peptide at early stage of T1D, - the use of technological ressources (multi-injections, sensors, insulin pump, closed-loop systems) at later stages, - and islet transplantation when hypoglycemia awareness becomes impaired are complementary for a personalized care all along the life of T1D patients.

Total pancreatectomy with autologous islet cell transplant (TPAIT) is a treatment option for patients suffering from chronic or recurrent acute pancreatitis, providing benefits of pain relief, enhanced quality of life, and prevention of brittle type 3c diabetes [1]. While surgical procedure requires extensive dissection and elevates risk of bleeding [2, 3], this operation also carries potential risk of portal venous thrombosis(0.9 to 3.4%) when impure or partially purified autologous islet preparations are infused into the portomesenteric circulation[4,5]. To mitigate the risk of thrombosis and to assist with islet engraftment by reducing Instant Blood-Mediated Inflammatory Reaction (IBMIR), anticoagulants are often utilized intra- and post-operatively [6]. Through literature review and personal communications , it is clear that different centers vary in their anticoagulation practices without any consensus guideline on the type, amount, or duration of anticoagulation, nor on the type and targets for postoperative monitoring [7]. The aim of this study is to gather information about the various anticoagulation strategies utilized by programs internationally.

Background and Aims In patients with type 1 diabetes and end-stage renal disease, kidney transplantation improves both quality of life and survival. When simultaneous kidney-pancreas transplantation appears too invasive, or after failure of the pancreatic graft, an islet after kidney transplantation (IAK) may be considered to restore a stable endocrine function. The aim of our work was to assess the impact of islet transplantation on kidney transplantation outcomes versus insulin alone. Method In this retrospective parallel-arm cohort study in Lille, we included all type 1 diabetes patients who received a kidney graft from 2000 to 2017, followed by an islet transplantation after kidney (IAK) or not (kidney alone, KA). The primary study endpoint was the change of renal function (estimated glomerular filtration rate, eGFR). Secondary endpoints were glycemic control-related markers, such as HBA1c. Results During the period of study, 14 patients were included in the KA group versus 15 in the IAK group (including 5 after failure of a simultaneous pancreatic graft) were enrolled. At baseline, kidney donor sex, BMI, cause of death, cold ischemia time and recipient sex, waiting time on dialysis, type of dialysis, and number of previous kidney transplantation, were similar between the two groups. Yet, there were significant differences between KA and IAK, considering donor age (resp. 56.0±15.0 vs 35.2±13.7 years, p Conclusion In patients with type 1 diabetes and a functioning kidney graft, IAK was associated with a better glucose control and a slower decrease of eGFR than standard insulin therapy. Our results suggest that IAK should be proposed to type 1 diabetes patients with a functional kidney graft.

Islet allotransplantation has been shown to be effective in restoring endogenous insulin secretion. Many initial reports showed, however, a sharp decline of islet graft function with time. In the late 1990s we hypothesized that islet transplantation success could be significantly prolonged by increasing islet primary graft function, through the deliberate repetition of islet infusions. We report here the favorable long-term outcome of this strategy in patients with type 1 diabetes and severe hypoglycemia unawareness or after a kidney graft with the Edmonton immunosuppressive regimen. Our results suggest that optimizing initial graft function is essential for the long-term success of beta cell replacement.

Objective. This retrospective study in 87 clinical islet transplants sought to determine if the quantitative in vivo islet potency assay (QIVIPA) based on human c-peptide measurement in normoglycemic immunodeficient mice transplanted with 1% of clinical islet transplant (n = 165) could predict islet function in man after transplantation (tx). Since each recipient receives a mean of 2.7 grafts in our center, the ultimate goal of this work was to prospectively determine the functional islet mass required in 1–3 transplants in the QIVIPA mice to achieve optimal long-term islet function (beta score ≥ 7) in man. Methods. Islet preparations that met in vitro release criteria (200,000 IEQ, viability ≥ 80%, sterility) were transplanted in severe type 1 diabetic patients (n = 87). 2% of the preparation was used for in vitro quality controls, and 2% for in vivo controls: tx under the kidney capsule of two normoglycemic nude or RAG2 mice where fasting c-peptide and glycemia were measured over 30 days. Human islet function was defined by immediate graft function (hCP increase 7 days after tx), primary graft function (PGF = beta score 1 month after the last tx) and beta score at 1 year. Results. The QIVIPA model is robust and reproducible with two mice transplanted per human islet preparation (P Conclusion. Evidence from this retrospective study on 87 clinical islet transplants in 165 mice suggests that in vivo quantitative islet potency assays like QIVIPA in normoglycemic immunodeficient are a key indicator of the quality of manufactured clinical graft preparations as they predict islet function in man, both early function at 7 days post tx, PGF (beta score 1 month after the last tx), and 1-year beta score even when multiple grafts are transplanted per recipient.

The names of the working groups that collaborated in the study reported in this article were inadvertently omitted from the byline. The corrected byline should … 2019;42

OBJECTIVE The long-term outcome of allogenic islet transplantation is unknown. The aim of this study was to evaluate the 10-year outcome of islet transplantation in patients with type 1 diabetes and hypoglycemia unawareness and/or a functioning kidney graft. RESEARCH DESIGN AND METHODS We enrolled in this prospective parallel-arm cohort study 28 subjects with type 1 diabetes who received islet transplantation either alone (ITA) or after a kidney graft (IAK). Islet transplantation consisted of two or three intraportal infusions of allogenic islets administered within (median [interquartile range]) 68 days (43–92). Immunosuppression was induced with interleukin-2 receptor antibodies and maintained with sirolimus and tacrolimus. The primary outcome was insulin independence with A1C ≤6.5% (48 mmol/mol). Secondary outcomes were patient and graft survival, severe hypoglycemic events (SHEs), metabolic control, and renal function. RESULTS The primary outcome was met by (Kaplan-Meier estimates [95% CI]) 39% (22–57) and 28% (13–45) of patients 5 and 10 years after islet transplantation, respectively. Graft function persisted in 82% (62–92) and 78% (57–89) of case subjects after 5 and 10 years, respectively, and was associated with improved glucose control, reduced need for exogenous insulin, and a marked decrease of SHEs. ITA and IAK had similar outcomes. Primary graft function, evaluated 1 month after the last islet infusion, was significantly associated with the duration of graft function and insulin independence. CONCLUSIONS Islet transplantation with the Edmonton protocol can provide 10-year markedly improved metabolic control without SHEs in three-quarters of patients with type 1 diabetes, kidney transplanted or not.

Total pancreatectomy with intraportal islet autotransplantation (TPIAT) rather than partial pancreatectomy could represent a major shift in the management of patients with resectable pancreatic ductal adenocarcinoma (PDAC) when risks of postoperative pancreatic fistula are well identified. This approach provides a theoretical risk of tumor cell dissemination when islet cells are transplanted into the portal vein. Our objective was to explore the safety of TPIAT in PDAC in a mouse preclinical model of subcutaneous xenotransplantation of human cells isolated from pancreatic specimen during partial pancreatectomy performed for PDAC.Patients requiring pancreatectomy for PDAC were prospectively included. Immunocompromised mice were transplanted with pancreatic cells isolated from the nonmalignant part of the surgical specimen (experimental group). Results were compared with pancreatic tumor implants (control group). Pancreatic grafts were explanted at 6 weeks for histological analyses.Nine patients were included, and 31 mice were transplanted. In the experimental group, explants were microscopically devoid of tumor cell, and no metastasis was observed. In the control group, all explants were composed of tumor.We report in a preclinical model the absence of local and distant spreading of malignant cells after pancreatic islets xenograft isolated from PDAC patients. These data supports the oncological safety of TPIAT as valuable alternative to partial pancreatectomy for PDAC patients with a high risk of postoperative pancreatic fistula.

Epidemiological studies identify tobacco as an independent risk factor for T2D, however, the mechanisms involved remains unclear. Clinical studies incriminate an increase of insulin resistance but a direct effect on pancreatic islet mass is suggested by some animal studies. The aim of this study was to document the association between tobacco smoking and pancreatic islet mass in humans.Total islet mass (TIM) was measured in 484 pancreata from organ donors processed with standardized islet isolation technique for clinical islet transplantation. Number and size of islets were assessed following enzymatic digestion. Functional islet mass was estimated in a cohort of 845 obese subjects, by measuring c-peptide to glucose ratio at 30 min (CP/G-30) following an oral glucose load. Pancreatic islet mass proxies were correlated with donor smoking status and tobacco consumption (generalized linear model).TIM was negatively associated with smoking status in organ donors (estimate:-0.131;P=0.017), independently of other known predictors: BMI (-0.019; P=0.001), age (-0.009; P=0.0001). CP/G-30 was also reduced in vivo in subjects with smoking history. TIM (Figure A-B) and CP/G-30 (Figure C-D) were negatively correlated with the level of tobacco consumption.Pancreatic islet mass was reduced in subjects with smoking history, with a dose-response relationship with tobacco consumption. Our results support the direct implication of smoking in T2D. Disclosure M. Chetboun: None. J.A. Kerr-Conte: None. V. Gmyr: None. D. Thuillier: None. R. Ezzouaoui: None. T. Hubert: None. V. Raverdy: None. A. Bongiovanni: None. M. Daoudi: None. M. Vantyghem: Board Member; Self; Aegerion Pharmaceuticals. Other Relationship; Self; Elsevier. Research Support; Self; Ipsen Biopharmaceuticals, Inc., Novartis Pharmaceuticals Corporation. F. Pattou: None.

In allogenic islet transplantation (IT), high purity of islet preparations and low contamination by non-islet cells are generally favored. The aim of the present study was to analyze the relation between the purity of transplanted preparations, and graft function during 5 years post-IT. Twenty-four type 1 diabetic patients, followed-up 5 years after IT, were enrolled. Metabolic parameters and daily insulin requirements were compared between patients who received islet preparations with a mean purity < 50% (LOW purity) or ≥50% (HIGH purity). We also analyzed blood levels of carbohydrate 19-9 (CA 19-9) - a biomarker of pancreatic ductal cells - and glucagon, before and after IT. At 5 years, mean HbA1c levels (p=0.01) and daily insulin requirements (p=0.03) were lower in the LOW purity group. Insulin independence was more frequent in the LOW purity group (p

Human islet transplantation is a viable treatment option for type 1 diabetes mellitus (T1DM). However, pancreatic islet inflammation after transplantation induced by innate immune responses is likely to hinder graft function. This is mediated by incompatibility between islets and the blood interface, known as instant blood-mediated inflammatory reaction (IBMIR). Herein we hypothesized that portal venous administration of islet cells with human recombinant antithrombin (ATryn®), a serine protease inhibitor (serpin), which plays a central role in the physiological regulation of coagulation and exerts indirect anti-inflammatory activities, may offset coagulation abnormalities such as disseminated intravascular coagulation (DIC) and IBMIR. The current prospective, randomized experiment was conducted using an established preclinical pig model. Three groups were constituted for digested pancreatic tissue transplantation (0.15 ml/kg): control, NaCl 0.9% ( n = 7); gold standard, heparin (25 UI/kg) ( n = 7); and human recombinant ATryn® (500 UI/kg) ( n = 7). Blood samples were collected over time (T0 to 24 h), and biochemical, coagulation, and inflammatory parameters were evaluated. In both the control and heparin groups, one animal died after a portal thrombosis, while no deaths occurred in the ATryn®-treated group. As expected, islet transplantation was associated with an increase in plasma IL-6 or TNF-α levels in all three groups. However, DIC was only observed in the control group, an effect that was suppressed after ATryn® administration. ATryn® administration increased antithrombin activity by 800%, which remained at 200% for the remaining period of the study, without any hemorrhagic complications. These studies suggest that coadministration of ATryn® and pancreatic islets via intraportal transplantation may be a valuable therapeutic approach for DIC without risk for islets and subjects.