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Introduction: A large proportion of clinical islet transplant recipients fail to initially achieve or sustain meaningful independence from exogenous insulin use. We hypothesized that immediate allograft injury is a key constraint on independence from exogenous insulin use., Methods: Standard human leukocyte antigen genotyping was reviewed to identify nonshared polymorphisms between 21 prospectively recruited islet transplant recipients from a single institution and their respective donors. Human leukocyte antigen polymorphism-specific quantitative polymerase chain reaction was used to quantify donor DNA shed into blood by injured islets from serial sera acquired over the first 10 days postprocedure and examined for correlation with achievement of insulin independence., Results: Nearly fourfold higher serum concentrations of donor DNA were detected in subjects whose grafts failed to generate insulin independence. The median for the average area under the curve in recipients who did and did not achieve insulin independence was 12 (range, 1-61) and 45 (range, 14-255) donor genome equivalents (gEq)-day/mL (p=0.03), respectively., Conclusions: These findings represent the first direct testing of allograft injury in humans undergoing islet cell transplantation. Injury to donor islets very soon after transplantation may represent an important barrier to achieving insulin independence other than adaptive immune responses targeting allografts at later times. In addition, soluble donor DNA merits further development as a quantifiable biomarker to evaluate new interventions aimed at mitigating immediate islet injury.

Background: Successful islet transplantation can result in insulin independence in many patients with type 1 diabetes mellitus, but it often requires more than one islet infusion. The ability to achieve insulin independence with a single donor is an important goal in clinical islet transplantation due to the limited organ supply., Methods: We examined factors that may be associated with insulin independence after islet transplantation with islets from a single donor, using univariate and multivariate analysis., Results: Thirteen of 85 (15.3%) achieved insulin independence after single-donor islet transplantation. Using multivariate analysis, only the use of insulin and heparin infusions peritransplant was a significant factor associated with insulin independence, with an adjusted odds ratio of 8.6 (95% confidence interval 2.0-37.0). Patients who had received insulin and heparin infusions peritransplant had greater indices of islet engraftment and a greater reduction in insulin use (80.1% + or - 4.3% vs. 54.2% + or - 2.8%, P<0.001) even if insulin independence was not achieved., Conclusions: Peritransplant intensive insulin and heparin enhances islet transplantation outcomes likely related in part to mitigation of the effects of the instant blood-mediated inflammatory reaction, combined with islet rest and avoidance of inflammation. It would be important to further investigate the effects of peritransplant insulin and heparin infusions on islet engraftment.

Background: The ability of supplemental islet infusions (SII) to restore insulin independence in islet transplant recipients with graft dysfunction has been attributed to the coadministration of exenatide. However, improving islet transplant outcomes could explain the success of SII. We aimed to determine the effect on islet graft function and insulin independence of SII using these new protocols, without the use of exenatide., Methods: Seventeen islet transplant recipients underwent SIIs after developing graft dysfunction requiring insulin use. For induction therapy, four subjects received daclizumab induction therapy, whereas 13 subjects received thymoglobulin and etanercept. Maintenance immunosuppression consisted of sirolimus+tacrolimus or tacrolimus+cellcept., Results: SII was performed 49.3+/-4.8 months (mean+/-SEM) after the preceding islet transplant. Subjects received significantly lower islet mass with their SII compared with initial transplant(s) (6076+/-492 vs. 9071+/-796 IEQ/kg; P=0.003). Fifteen of the 17 subjects (88.2%) became insulin independent 2.4+/-0.5 months after SII. Insulin-independent duration after SII exceeded that of the initial transplant(s) (24.8+/-2.2 vs. 14.2+/-2.6 months by Kaplan-Meier analysis, P=0.009). Subjects show improved glycemic control after SII (HbA1c 7.0%+/-0.2% pre-SII vs. 6.1%+/-0.2% post-SII, P=0.005) and did not become immunosensitized., Conclusion: Using current protocols, SII in the absence of exenatide results in impressive insulin-independence rates and the durability of insulin independence seems to be promising. However, a beneficial effect of exenatide should not be discounted until tested in randomized controlled studies.

Background: An accurate monitoring would help understanding the fate of islet grafts after transplantation., Methods: This work assessed the feasibility of needle biopsy monitoring after intraportal islet transplantation (n=16), and islet graft morphology was studied with the addition of autopsy samples (n=2). Pancreas autopsy samples from two nondiabetic individuals were used as control., Results: Islet tissue was found in five needle samples (31%). Sampling success was related to size (100% sampling for the four biopsies of 1.8 cm in length or higher, P

The health-related quality of life (HRQL; Health Utilities Index Mark 2) and the fear of hypoglycemia (Hypoglycemia Fear Survey) were assessed after islet transplant; the impact of a single islet infusion and of the metabolic outcome were determined. A control group included 166 patients with type 1 diabetes. Islet transplant had no impact on overall HRQL. Prior to transplant, islet recipients had more fear of hypoglycemia than controls (P<0.000001), but this improved up to 36 months after transplant (P<0.00001, pretransplant vs. each time point). With a single islet infusion, this fear improved substantially (P<0.00001), but improved further with subsequent islet infusions (P