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Peri-transplant hypoglycemia (PTxH) following islet infusion may be an indication of islet damage and a poor prognostic sign for graft function. This can be related to islet processing, islets infused and adjuncts such as exenatide (Exn). All islet infusions since 2001 were evaluated for PTxH using fingerstick glucose (FSG) records and IV fluid administration. Correlation with peak C-peptide (CP) levels during the first 24 hours, c-peptide/glucose ratio (CPGR) at one month, presence of absence of centrifugation (Cent+ or Cent-) and Exn administration were assessed. A total of 61 islet infusions were evaluated, 18 (30%) utilized islets that had not undergone centrifugation during resuspension (Cent-). Subjects could be divided into 3 groups, Gp 1-no PTxH (n=36), Gp 2-FSG <70 mg/dl, >1.5 hours post infusion (n= 18) & Gp 3- FSG <70 mg/dl, <1.5 hours post infusion (n=7). All subjects in Gp 3 required treatment with D50, 6/7 also received Exn within the hour prior to infusion. 7 subjects received Exn, 6 were in Gp 3.Peri-tx Peak CP levels were significantly higher in Gp 3 compared with Gps 1 & 2 (7.5±4.2, 4.4±1.6 and 4.5±1.3 ng/ml in Gps 1, 2 & 3 respectively p=0.004). Peri-tx Peak CP levels were also significantly higher in Cent - preparations (4.4±1.53 versus 5.7±3.0, p=0.045) even if Exn subjects were removed (4.4±1.53 vs 6.6±4.24, p=0.018). Of the 18 Cent- preparations there was almost equal distribution between the 3 clinical groups (Gp 1 n=6, Gp 2 n=5, Cap 3 n=7). There was no significant difference in CPGR at 1 month between Caps 1, 2 and 3 (1.3±0.65, 1.4±0.72, 1.59±0.8 p=0.463), levels are likely slightly higher in Gp 3 due to ongoing Exn usage. Centrifugation had no impact on CP levels at 1 month ( 1.4±0.76 versus 1.3±0.55, p=0.82); without Exn subjects (1.4±0.76 versus 1.2±0.32, p=0.61).There was no correlation between peak peri-tx CP and CPGR at 1 month (r=0.088, p=0.54). There was no significant difference in the number of islet equivalents infused in any of the groups. Exn administration is strongly associated with significant PTxH and also significantly higher levels of CP. Avoiding centrifugation during islet resuspension also increases peri-tx CP levels, however does not appear to affect long term islet function. PTxH can be severe and close monitoring for 1-4 hours post transplant is recommended. [ABSTRACT FROM AUTHOR]

Successful islet transplantation (IT) leads to disappearance of severe hypoglycemia and maintenance of near-normal glycemic and metabolic control. This contributes to improved quality of life, and patients may consciously or unconsciously modify nutritional behavior to prolong the beneficial effect of IT. Other factors (immunosuppression, insulin) may contribute to changes in nutritional status. We analyzed in a 6 years retrospective and prospective study, changes in dietary habits, nutritional behavior and status in patients (n=52, F/M=31/21, mean age=47) with type 1 diabetes listed for IT. Thirty of 52 patients received one or more IT. Immunosuppression included daclizumab or alemtuzumab and a combination of sirolimus and tacrolimus or MMF. Body weight (BW), body mass index (BMI), waist circumference and fat weight were reduced significantly 3.62 kg, 1.39 kg/m², 3.96 cm and 3.3 kg respectively, p<0.01. The most dramatic weight loss was observed in the first 5 to 7 months post-IT and then stabilized. Carbohydrates (CHO) and protein daily consumption was significantly reduced (23.7 and 13.2g respectively, p≥0.04) without falling below recommended values. Caloric intake and % CHO, fat and protein, total, saturated and unsaturated fat, trans fatty acid, omega 3 and omega 6, cholesterol and fiber intake were not significantly different. This may be due to underestimation of fat intake. We found a significant reduction in the consumption of vitamins B2, B6, Folate, Pantothenic acid, P, Zn, Ca and Mg, when compared to pretransplant. Significant reductions in Hb, Albumin, LDL and HDL Cholesterol were observed after transplantation while triglycerides increased. A1c was 1.3% less in the post-transplant period (p<0.0001); A1c reduction was not associated with lower CHO intake in individual patients. No changes in anthropometric measurements and food intake were observed after the patients restarted exogenous insulin post transplant. In conclusion, we recommend close monitoring of patients' nutritional status by trained professionals pre- and post-IT, and intervention if necessary. [ABSTRACT FROM AUTHOR]

Immunosuppressive management in islet transplantation is mainly based on drug levels, metabolic parameters and clinical course. None of them is completely reliable in preventing rejection, infections or toxicity related side-effects. Immuknow™ by Cylex® is a simple FDA-approved test, used to change immunosuppression in solid organ recipients. It detects the immune cell function of immunosuppressed recipients, by measuring ATP levels of stimulated CD4+ lymphocytes, defining three zones of immune response, strong (>525 ng/mL), moderate (226-524) and low (<225), significantly correlated to different clinical outcomes: rejection, stable graft or infections, respectively. To define the utility of using Immuknow™ assay in islet transplantation, we analyzed 24 recipients with functioning islet allograft from different immunosuppressive protocols and regimens, at several time-points after transplant. Results were expressed as median and 25th-75th percentile range. Nineteen patients with stable islet grafts had an ATP value of 208ng/mL (170-258), 6 patients with evidence of graft dysfunction had 319ng/mL (240356), and 10 patients with evidence of infections or toxicity related side-effects had 65ng/mL (35-90) (see figure), the different clinical events occasionally occurring in the same patient. Bivariate analysis showed significant correlations between ATP values and leukocytes count (r=0.42, p<0.001), both CD4+ and CD8+ lymphocytes (r=0.47, p<0.001), and fasting plasma glucose (r=0.26, p<0.048). This observational study has defined the immune response values in islet transplantation. The ATP levels of graft stability were lower than in solid organ transplant recipients, 208ng/mL respect to 258ng/mL. Immuknow™ Cylex® assay can be of utility in the management of islet recipients, thus minimizing the risk of rejection, infections or toxicity related side-effects. [ABSTRACT FROM AUTHOR]

We evaluated the prevalence and levels of GAD and IA-2 autoantibodies (ab) and possible effects of age at diagnosis, disease duration and gender in 157 C-peptide-negative patients with type 1 diabetes (T1D) at the time of screening for islet transplantation. Mean age was 40.1 ± 9.6 years, 71 were males and 86 females. Mean age at diagnosis was 23.6±7.8 years and the mean duration of diabetes was 25.5±10.4 years. Thirty percent (47/157) and 36.3% (57/157) of the patients had GADab and IA-2ab, respectively. Moreover, 104/157(66.2%) patients had either GADab or IA2ab. By contrast, simultaneous expression of both ab was detected in 18/157(11.4%) patients. The figure shows ab levels for ab-positive patients, where levels are expressed as fold over the assays cutoffs. GADab levels ranged between 1.02-8.86 and the mean was 3.1±SD 1.7. IA-2ab levels ranged between 1.06-67.6 and the mean was 11.3±SD 14.5. Using age 15 as cut-off, neither age of diagnosis or gender influenced ab prevalence expression at the time of screening. There was a positive correlation between GADab levels and age at diagnosis (r=0.167, p=0.03), but not with disease duration. There was no correlation of age at diagnosis with IA-2 levels, but these were inversely correlated with disease duration (r=-0.189, p=0.01). We conclude that T1D patients often present with at least one ab but rarely express both GADab and IA-2ab at the time of screening for islet transplantation. Age of onset and disease duration may not affect their prevalence but may correlate with ab levels. [ABSTRACT FROM AUTHOR]

Our objective was to evaluate the effect of islet transplant(IT) on metabolic control using continuous glucose monitoring(CGM). Glycemic control was assessed in 26 patients with Type 1 Diabetes(T1D). Thirteen underwent IT(Mean age:42±l0y; diabetes duration(DD): 15±9y) and 13 were controls(Mean age:50±7y; DD:18±9y). Time spent in hyperglycemia (>140mg/dl), hypoglycemia(<54mg/dl), and normoglycemia (54-140mg/dl) was measured over 72-h from CGM in the controls(n=13) and at varying times in the IT group: 3(n=6), 6(n=11), 9(n=9), 12(n=8), 15(n=8), and 18(n=5) months(m). We measured HbA1c, 90 min glucose from a mixed meal test, C-peptide/glucose ratio(CPGR) and insulin use. Analysis was done by unpaired t-test; data expressed as mean ± SD. Time in hypoglycemia for the controls was 9±8.8%, for the IT group 0.17±0.41%, 2±3.7%, 2.2±2.3%, 1.4±1.6%, 1.1±1.3%, and 2.4±3.9% at 3,6,9,12,15, and 18m. Decrease between controls and IT was found to be statistically significant for all time points(p<0.05). Time in normoglycemia in the controls was 48.8±11%. In the IT group, this was 70±12%, 72.5±24%, 76.5±20%, 78.7±19%, 62.3±19%, and 80.8±10.5% at 3,6,9,12,15, and 18m respectively. Increased time in normoglycemia between the 2 groups was statistically significant(p<0.01) at all times except 15m post-IT(p=0.085). Percent time in hyperglycemia was 42.44±11% for the controls. In the IT group this was 29.8±12%, 25.3±25%, 21.2±18%, 20±19%, 36.6±19%, 16.8±11% at 3,6,9,12,15, and 18m respectively. Decrease in hyperglycemia was significant at time points 12(p=0.01) and 18m(p=0.003). There was a decrease at other times, which did not reach significance. We found statistical significant differences between HbA1c, 90min glucose, CPGR and insulin use(p< 0.01) at all times between the groups. In conclusion, CGM showed the benefit of IT in T1D, in regards to decreased time spent in hypoglycemia and increased time in normoglycemia. IT is a suitable option for patients who have severe hypoglycemia and unstable glycemic control despite optimal insulin therapy. [ABSTRACT FROM AUTHOR]

The role of anti-donor HLA sensitization testing in islet rejection still remains unanswered. In order to evaluate the development and significance of alloantibodies in clinical islet transplantation we performed a retrospective analysis of allosensitization on a cohort of 66 patients with T1D transplanted between 1985 and 2006 at our center. Alloantibodies were detected by complement-dependent cytotoxicity (CDC) at different post transplant period for the islet recipient transplanted before 2000 and by CDC, ELISA and flowcytometry on 30 available sera of 42 patients transplanted after 2000 and treated with 'Edmonton-like' immunosuppression protocol. All the islet recipients (islet after kidney, IAK or islet transplantation alone ITA) had negative Panel Reactive Antibody (PRA) before islet transplant, with the exception of one patient who received a kidney transplant before the islet infusion (PRA class I=31%, class II=30%). When sera was retested by Flow and ELISA we were able to identify 2 additional subjects who displayed positive PRAs pre-transplant. After transplantation (278±392days) 32 out of 66 patients (48%) showed PRA>20% by CDC at any time. When analyzing alloantibody production in 16 patients treated with 'Edmonton-like' immunosuppression protocol who stopped immunosuppression we found that 100% of them with available serum samples for analysis by Flow and Elisa (n=11) showed increased PRA (>20%) by 6 months from drug withdrawal for both class I and class II. PRA data by CDC were available for 13 patients but only 4 of 13 analyzed patients had detectable sensitization to HLA (PRA > 20%). Conversely, 16 out of 19 patients who are still on immunosuppression maintain graft function (namely, detectable C-peptide) and display negative PRA by Flow while 23 out of 23 display negative PRA by CDC. In summary, our data suggests that following discontinuation of immunosuppression 100% of islet recipients become highly sensitizated (mean class I=76±24%, class II=61±29%), while sensitization is rare in patients continuing immunosuppression. [ABSTRACT FROM AUTHOR]

Calcineurin inhibitors such as tacrolimus have well-recognized efficacy in organ transplantation but side effects of nephrotoxicity, neurotoxicity, and beta-cell toxicity that can be particularly detrimental in islet transplantation. Neuro- and nephrotoxicity have been demonstrated in multiple islet transplant recipients despite the relatively low serum maintenance levels typically used (3-5 ng/ml). We describe a single patient in whom symptoms and signs of neurotoxicity necessitated substitution of tacrolimus with mycophenolate mofetil (MMF), which resulted in complete symptom resolution over the subsequent 9 months. Concomitantly noted were an almost immediate improvement in glycemic control and an improved response to stimulation testing, suggesting remission of tacrolimus-induced beta-cell toxicity and insulin resistance. At 18 months post-"switch," 30 months posttransplant, the patient remains insulin independent with good glycemic control. The goal to remove calcineurin inhibitors from regimens of islet transplantation is a worthy one.