Indications for islet or pancreatic transplantation: Statement of the TREPID working group on behalf of the Société francophone du diabète (SFD), Société francaise d'endocrinologie (SFE), Société francophone de transplantation (SFT) and Société française de néphrologie - dialyse - transplantation (SFNDT).

While either pancreas or pancreatic islet transplantation can restore endogenous insulin secretion in patients with diabetes, no beta-cell replacement strategies are recommended in the literature. For this reason, the aim of this national expert panel statement is to provide information on the different kinds of beta-cell replacement, their benefit-risk ratios and indications for each type of transplantation, according to type of diabetes, its control and association with end-stage renal disease. Allotransplantation requires immunosuppression, a risk that should be weighed against the risks of poor glycaemic control, diabetic lability and severe hypoglycaemia, especially in cases of unawareness. Pancreas transplantation is associated with improvement in diabetic micro- and macro-angiopathy, but has the associated morbidity of major surgery. Islet transplantation is a minimally invasive radiological or mini-surgical procedure involving infusion of purified islets via the hepatic portal vein, but needs to be repeated two or three times to achieve insulin independence and long-term functionality. Simultaneous pancreas-kidney and pancreas after kidney transplantations should be proposed for kidney recipients with type 1 diabetes with no surgical, especially cardiovascular, contraindications. In cases of high surgical risk, islet after or simultaneously with kidney transplantation may be proposed. Pancreas, or more often islet, transplantation alone is appropriate for non-uraemic patients with labile diabetes. Various factors influencing the therapeutic strategy are also detailed in this report.

Inhibition of the MAP3 kinase Tpl2 protects rodent and human ß-cells from apoptosis and dysfunction induced by cytokines and enhances anti-inflammatory actions of exendin-4.

Proinflammatory cytokines exert cytotoxic effects on ß-cells, and are involved in the pathogenesis of type I and type II diabetes and in the drastic loss of ß-cells following islet transplantation. Cytokines induce apoptosis and alter the function of differentiated ß-cells. Although the MAP3 kinase tumor progression locus 2 (Tpl2) is known to integrate signals from inflammatory stimuli in macrophages, fibroblasts and adipocytes, its role in ß-cells is unknown. We demonstrate that Tpl2 is expressed in INS-1E ß-cells, mouse and human islets, is activated and upregulated by cytokines and mediates ERK1/2, JNK and p38 activation. Tpl2 inhibition protects ß-cells, mouse and human islets from cytokine-induced apoptosis and preserves glucose-induced insulin secretion in mouse and human islets exposed to cytokines. Moreover, Tpl2 inhibition does not affect survival or positive effects of glucose (i.e., ERK1/2 phosphorylation and basal insulin secretion). The protection against cytokine-induced ß-cell apoptosis is strengthened when Tpl2 inhibition is combined with the glucagon-like peptide-1 (GLP-1) analog exendin-4 in INS-1E cells. Furthermore, when combined with exendin-4, Tpl2 inhibition prevents cytokine-induced death and dysfunction of human islets. This study proposes that Tpl2 inhibitors, used either alone or combined with a GLP-1 analog, represent potential novel and effective therapeutic strategies to protect diabetic ß-cells.

Continuous glucose monitoring after kidney transplantation in non-diabetic patients: early hyperglycaemia is frequent and may herald post-transplantation diabetes mellitus and graft failure.

OBJECTIVES: New onset of diabetes after transplantation (NODAT) is a known complication of renal transplantation, but early glycaemic status after transplantation has not been described prospectively. This study aimed to assess blood glucose (BG) levels immediately following kidney transplantation in non-diabetic subjects and to explore their relationship to later graft outcomes and NODAT occurrence. PATIENTS AND METHODS: Over a 9-month period, 43 consecutive non-diabetic patients who received a kidney transplant were prospectively investigated. During the first 4 days after transplantation, fasting BG was measured and the 24-h BG profile assessed by continuous glucose monitoring (CGM). Capillary BG was measured on hospital admittance and at least four times a day for CGM calibration thereafter. All adverse events were recorded, and fasting BG and HbA1c were assessed at 3, 6 and 12 months and at the last visit to our centre. RESULTS: Immediately following renal transplantation, capillary BG was 12.2 ± 3.8 mmol/L. On day 1 (D1), fasting BG was 9.9 ± 4.3 mmol/L and decreased to 6.0 ± 1.5 mmol/L on D3. The CGM-reported mean 24-h BG (mmol/L) was 10.2±2.4 on D1, 7.7 ± 1.3 on D2 and 7.5 ± 1.1 on D3. From D1 to D4, 43% of patients spent>12h/day with BG levels>7.7 mmol/L. While morbidity during the 3 months following transplantation appeared unrelated to BG, the first post-transplantation capillary BG measurement and fasting BG on D1 tended to be higher in patients who developed diabetes 3 months later. Tacrolimus treatment was associated with a higher incidence of dysglycaemia at 3 and 6 months. After a mean follow-up of 72 months, NODAT was frequently seen (18.6%), and was associated with tacrolimus medication (P<0.01) and a higher rate of renal transplantation failure (RR: 3.6, P<0.02). CONCLUSION: Hyperglycaemia appears to be a nearly constant characteristic immediately following transplantation in non-diabetic kidney recipients. Higher BG values could identify patients at risk for later post-transplant diabetes and graft failure.

Towards an artificial pancreas at home.

AIM: To review the recent clinical research related to the development of an artificial pancreas and the current perspectives for its home use. METHODS: All clinical investigations assessing closed-loop insulin delivery systems in diabetic patients in the literature were collected and analyzed to identify any significant advances as well as bottlenecks. RESULTS: The development of an artificial pancreas for ambulatory use offering an optimal substitute for insulin secretion has shown promising evolution over the past decade. The accumulated improvements achieved on the performance of insulin pumps using subcutaneous and intraperitoneal routes, continuous glucose monitoring and algorithms driving insulin infusion according to glucose measurement have led to numerous clinical trials recently, albeit only in a hospital setting so far. The key obstacles to achieving permanent normal glucose control are related to the delay of insulin action when infused subcutaneously or, at a lesser extent, into the peritoneal cavity, and blood glucose estimation made by subcutaneous interstitial measurement. These time lags impair the reactivity of the system, and suggest a need to develop complex algorithms aiming at their compensation. So far, manual interventions are needed at times of food intake to prevent hyper- or hypoglycaemic excursions when insulin changes rapidly. CONCLUSION: The most recent models using subcutaneous insulin infusion and glucose measurements linked by predictive control algorithms offer sufficient effectiveness and safety to consider their forthcoming use at home, during the night as a first step.

Quality of life after islet transplantation: data from the GRAGIL 1 and 2 trials.

BACKGROUND: Rigorous assessment of health-related quality of life (HRQL) is mandatory to establish the benefits of islet transplantation. METHODS: The 36-Item Short Form Health Survey (SF-36) and the Diabetes Quality of Life (DQOL) scales were completed by patients included in an Islet Transplantation Alone (ITA) trial (n = 10) and an Islet After Kidney (IAK) trial (n = 10). RESULTS: The two populations differed by HRQL scores at baseline, with poorer scores in ITA patients. SF-36 scores for physical limitations, bodily pain, general health perception, social functioning, and health transition improved significantly in ITA patients 6 and 12 months post transplantation. The DQOL global score was significantly improved at 6 months and remained so at 12 months, because of a significant improvement in the dimensions of satisfaction and impact of diabetes. No improvement was observed in the IAK patients. CONCLUSION: HRQL assessment may help in the selection of candidates with brittle diabetes for islet transplantation.

Insulin secretion from human beta cells is heterogeneous and dependent on cell-to-cell contacts.

AIMS/HYPOTHESIS: We assessed the heterogeneity of insulin secretion from human isolated beta cells and its regulation by cell-to-cell contacts. METHODS: Insulin secretion from single and paired cells was assessed by a reverse haemolytic plaque assay. The percentage of plaque-forming cells, the mean plaque area and the total plaque development were evaluated after 1 h of stimulation with different secretagogues. RESULTS: Not all beta cells were surrounded by a haemolytic plaque under all conditions tested. A small fraction of the beta cell population (20%) secreted more than 90% and 70% of total insulin at 2.2 and 22.2 mmol/l glucose, respectively. Plaque-forming cells, mean plaque area and total plaque development were increased at 12.2 and 22.2 compared with 2.2 mmol/l glucose. Insulin secretion of single beta cells was similar at 12.2 and 22.2 mmol/l glucose. Insulin secretion of beta cell pairs was increased compared with that of single beta cells and was higher at 22.2 than at 12.2 mmol/l glucose. Insulin secretion of beta cells in contact with alpha cells was also increased compared with single beta cells, but was similar at 22.2 compared with 12.2 mmol/l glucose. Delta and other non-beta cells did not increase insulin secretion of contacting beta cells compared with that of single beta cells. Differences in insulin secretion between 22.2 and 12.2 mmol/l glucose were observed in murine but not in human islets. CONCLUSIONS/INTERPRETATION: Human beta cells are highly heterogeneous in terms of insulin secretion so that a small fraction of beta cells contributes to the majority of insulin secreted. Homologous and heterologous intercellular contacts have a significant impact on insulin secretion and this could be related to the particular architecture of human islets.

Assessment of 18F-FDG-leukocyte imaging to monitor rejection after pancreatic islet transplantation.

AIM: We sought to investigate the feasibility of 18F-FDG-leukocyte imaging to detect islet rejection. METHODS: Two thousand Sprague-Dawley (SD, syngeneic group) or Lewis (allogeneic group) islet equivalents were intraportally injected into SD rat recipients. Four and 7 days after transplantation, 10(8) 18F-FDG-labeled splenocytes were injected into the jugular vein. Splenocytes were harvested from naïve or sensitized (12 days after intraportal transplantation of 2000 Lewis IEQ) SD rats. Positron emission tomography (PET) imaging was started 5 minutes after splenocyte infusion and performed hourly for 4 hours. RESULTS: One hour after splenocyte injection, FDG was mainly detected in the heart and lungs. It was then further distributed to other organs, and from the second hour, the highest tracer concentration was located in the abdomen. Liver FDG uptake was similar between syngeneic, allogeneic, and sensitized allogeneic groups at 4 and 7 days after islet transplantation. DISCUSSION: No islet rejection was detected by 18F-FDG-leukocyte imaging. The amount of transplanted tissue was only few millilitres and the additional related inflammation in case of rejection is small and difficult to detect. The liver showed a relatively high spontaneous tracer uptake; the related background prevented detection of a potential increase in tracer uptake in cases of islet rejection.

Detection of insulin mRNA in the peripheral blood after human islet transplantion predicts deterioration of metabolic control.

Recent updates of the Edmonton trial have shown that insulin independence is progressively lost in approximately 90% of islet transplant recipients over the first 5 years. Early prediction of islet graft injury could prompt the implementation of strategies attempting to salvage the transplanted islets. We hypothesize that islet damage is associated with the release and detection of insulin mRNA in the circulating blood. Whole blood samples were prospectively taken from 19 patients with type 1 diabetes receiving 31 islet transplants, immediately prior to transplantation and at regular time-points thereafter. After RNA extraction, levels of insulin mRNA were determined by quantitative reverse tran-scriptase-polymerase chain reaction. All patients exhibited a primary peak of insulin mRNA immediately after transplantation, without correlation of duration and amplitude with graft size or outcome. Twenty-five subsequent peaks were observed during the follow-up of 17 transplantations. Fourteen secondary peaks (56%) were closely followed by events related to islet graft function. Duration and amplitude of peaks were higher when they heralded occurrence of an adverse event. Peaks of insulin mRNA can be detected and are often associated with alterations of islet graft function. These data suggest that insulin mRNA detection in the peripheral blood is a promising method for the prediction of islet graft damage.

Sequential kidney/islet transplantation: efficacy and safety assessment of a steroid-free immunosuppression protocol.

The aim of this study was to assess the efficiency and safety of the Edmonton immunosuppression protocol in recipients of islet-after-kidney (IAK) grafts. Fifteen islet infusions were administered to 8 patients with type 1 diabetes and a functioning kidney graft. Immunosuppression was switched on the day of transplantation to a regimen associating sirolimus-tacrolimus-daclizumab. Insulin-independence was achieved in all patients for at least 3 months, with an actual rate of 71% at 1 year after transplantation (5 of 7 patients). After 24-month mean follow-up, five have ongoing insulin independence, 11-34 months after transplantation, with normal HbA1c, fructosamine and mean amplitude of glycemic excursions (MAGE) values. Results of arginine-stimulation tests improved over time, mostly after the second islet infusion. Severe adverse events included bleeding after percutaneous portal access (n=2), severe pneumonia attributed to sirolimus toxicity (n=1), kidney graft loss after immunosuppression discontinuation (n=1), reversible humoral kidney rejection (n=1) and fever of unknown origin (n=1). These data indicate that the Edmonton approach can be successfully applied to the IAK setting. This procedure is associated with significant side effects and only patients with stable function of the kidney graft should be considered. The net harm versus benefit has not yet been established and will require further studies with larger numbers of enrolled subjects.

A comparison of cold storage solutions for pancreas preservation prior to islet isolation.

BACKGROUND: Several solutions are used to preserve the pancreas prior to islet isolation. This study sought to assess whether the type of solution had an impact on the isolation outcome. METHODS: We reviewed data from 125 islet isolation procedures performed from January 2002 to January 2005. Pancreata were preserved in University of Wisconsin (UW) (n = 101), Celsior (CS) (n = 19), or IGL-1 (n = 5) solutions. Islet isolation results and transplantation rates were compared between groups. RESULTS: UW, CS, and IGL-1 groups were similar according to donor's age, weight, and body mass index. Weight of undigested pancreas was 20 +/- 13.1, 21.4 +/- 15.7, and 17.4 +/- 8.7 g for UW, CS, and IGL-1, respectively (P > .2). Final total number of IEQ was 267,000 +/- 132,000, 277,000 +/- 155,000, and 311,000 +/- 163,000, respectively (P > .4). Success rate (defined as >250,000 IEQ) was 55.5%, 52.9%, and 60% for UW, Celsior, and IGL-1 (P > .9); the transplantation rate was 42.2% for UW, 36.8% for Celsior, and 80% for IGL-1 preservation (P > .2). CONCLUSIONS: In this preliminary study, UW, Celsior, and IGL-1 solutions demonstrated similar islet isolation results. The new IGL-1 solution appears promising.