Following the success obtained with transplantation of fresh human islets under steroid-free immunosuppression, this trial evaluated the transplantation of islets that had undergone a period of in vitro culture and the potential of tumor necrosis factor (TNF-a) blockade to improve islet engraftment. Subjects included 16 patients with type 1 diabetes mellitus (T1DM); half were randomly assigned to receive Infliximab immediately preceding initial infusion. Immunosuppression consisted of daclizumab induction and sirolimus/tacrolimus maintenance. Out of 16 subjects 14 achieved insulin independence with one or two islet infusions; adverse events precluded completion in two. Without supplemental infusions, 11/14 (79%) subjects were insulin independent at 1 year, 6/14 (43%) at 18 months; these same subjects remain insulin independent at 33 ± 6 months. While on immunosuppression, all patients maintained graft function. Out of 14 patients, 8 suffered chronic partial graft loss, likely immunological in nature, 5 of these received supplemental infusions. Currently, 11 subjects remain on immunosuppression, 8 (73%) are insulin independent, two with supplemental infusions. Insulin independent subjects demonstrated normalization of HbA1c, fructosamine and Mean Amplitude of Glycemic Excursions (MAGE) values. No clinical benefit of infliximab was identified. These results demonstrate that transplantation of cultured human islet allografts results in reproducible insulin independence in all subjects under this immunosuppressive regimen, comparable to that of freshly transplanted islets (Edmonton protocol).

The aim of this study was to develop a simple test for the assessment of islet graft dysfunction based on measures involving fasting C-peptide.

There was a varying range of AEs, most of them mild and self-limiting; however, some required urgent medical attention. The majority of patients were able to tolerate and remain on this effective regimen. To date, no deaths, cytomegalovirus disease, graft-versus-host disease, or posttransplant lymphoproliferative disease has been observed.

Background Progressive graft dysfunction (GDF) and loss of insulin independence (II) has been invariably observed in islet transplant recipients under the ‘Edmonton protocol’. To reestablish II we performed supplemental islet infusions (SI) in recipients of allogeneic islet transplant alone, displaying GDF. To improve the engraftment and long-term graft function of SI, exenatide (EXN) and etanercept treatment at islet infusion, and long-term EXN treatment were tested in a non-randomized pilot clinical trial. Methods Patients with GDF received SI under Edmonton-like immunosuppression with daclizumab induction, either without interventions (SI-control; n=5) or with EXN and etanercept treatment (SI-EXN; n=4). Clinical and metabolic profiles were assessed over 18–month follow-up. Results Long-term II (18 months) was observed in 100% of SI-EXN and in 20% of SI-Control (p=0.04). SI-EXN subjects demonstrated restoration of function better than that seen following initial islet infusions. Comparison of SI-EXN and SI-Control groups demonstrated better responses in SI-EXN subjects at three months post SI. Over the 18 months of follow-up, function was sustained in the SI-EXN subjects better than in SI-Controls. Acute effects of exenatide during MMTT and IVGTT results in improved first and second phase insulin release in response to intravenous glucose (IVGTT), and suppressed postprandial hyperglucagonemia after mixed meal tolerance test (MMTT). Conclusion These results suggest that the combination of exenatide and etanercept improve engraftment and long term islet survival and function in subjects undergoing SI. This data however must be interpreted with some caution due to small sample size, lack of randomization and sequential comparison with historical controls.

Islet transplantation represents a feasible therapeutic option for patients with T1DM bearing a stable kidney allograft. Insulin independence at 1 year is lower than what reported in islet transplant alone. Nevertheless, clear benefits in terms of optimal metabolic control and absence of severe hypoglycemia are invariably present.

Background A current limitation of islet transplantation is reduced long term graft function. The glucagon like peptide-1 (GLP-1) receptor agonist, exenatide (Byetta®, Amylin Pharmaceuticals, CA) has properties that could improve existing islet function, prevent further loss of islet mass and possibly even stimulate islet regeneration. Methods This prospective study evaluated the safety, efficacy and metabolic effects of exenatide in subjects with type 1 diabetes mellitus and islet allograft dysfunction requiring exogenous insulin. Results Sixteen subjects commenced exenatide, twelve continue (follow-up 214±57 days; range 108-287), four (25%) discontinued medication due to side effects. At six months, exogenous insulin was significantly reduced with stable glycemic control (0.15±0.02 vs. 0.11±0.025 Units/kg/day; p<0.0001); three subjects discontinued insulin from 4, 5 and 9 U/day respectively, two sustained insulin independence with A1c reduction below graft dysfunction criteria. Post-prandial capillary blood glucose was significantly decreased (129.4±3.8 vs. 118.7±4.6 mg/dL; p<0.001), C-peptide and C-peptide/glucose ratio increased significantly by 5th and 6th months of treatment (ratio-1.09±0.15 vs. 1.52±0.18; p<0.05). Weight loss >3 kg occurred in 8/12 (67%) subjects. Stimulation testing demonstrated improved glucose disposal and C-peptide secretion (glucose area under the curve 52,332±3,219 vs. 2,072±1,965; p=0.002 mg·min-1·dL-1, Mixed Meal Stimulation Index 0.50±0.06 vs 0.66±0.09; P=0.03 pMol·mL-1), with marked suppression of glucagon secretion and progressive increase in amylin secretion. Side effects were more frequent/severe compared to published reports in type 2 diabetes, tolerated doses were lower. Conclusions Exenatide was tolerated in this patient population following appropriate dose titration and there appeared to be gradual but sustained positive effects on glycemic control and islet graft function.

OBJECTIVE -To determine the impact of islet transplantation (ITx) on hypoglycemia awareness in patients with unstable type 1 diabetes and its relation to islet function. RESEARCH DESIGN AND METHODS-A total of 31 ITx recipients were studied. Hypoglycemia unawareness was assessed using the Clarke hypoglycemic score (0 ϭ no hypoglycemia; Ն4 ϭ hypoglycemia unawareness). Subjects were grouped based on graft function: off-insulin (n ϭ 8), graft dysfunction (on-insulin and stimulated C-peptide Ն0.3 ng/ml, n ϭ 13), and graft failure (stimulated C-peptide Ͻ0.3 ng/ml, n ϭ 10, evaluated 11.5 Ϯ 14.5 months after graft failure).RESULTS -The hypoglycemia score improved after ITx when compared with baseline values (before vs. after: 5.29 Ϯ 1.51 vs. 1.35 Ϯ 1.92, P Ͻ 0.001). This result was sustained even after patient stratification based on islet function (pre vs. post off-insulin: 5.63 Ϯ 2.00 vs. no hypoglycemia reported; graft dysfunction: 5.31 Ϯ 1.49 vs. 1.15 Ϯ 1.63, P Ͻ 0.001; and graft failure: 5.00 Ϯ 1.16 vs. 2.70 Ϯ 2.26, P ϭ 0.014).CONCLUSIONS -The improved metabolic control achieved with ITx can restore hypoglycemia awareness in patients with type 1 diabetes, persisting even after islet graft failure.

Background Health related quality of life (HRQoL) is one of the most important outcomes to measure effectiveness of an intervention, especially for islet transplantation in which benefits should outweigh risks of long-term immunosuppression. This study aimed to evaluate long-term effects of islet transplantation and to outline possible influential factors. Methods Forty islet transplant recipients who completed 344 Health Status Questionnaires (HSQ 2.0) and 384 Diabetes quality of life questionnaires (DQoL) between 2000–2007 were retrospectively reviewed. Assessments were analyzed in pre-transplantation period, then every 3 months after the first infusion for 18 months and every 6 months thereafter. The mean follow-up post-transplantation was 40.8±21.9 (9–72) months. Results Sustained improvement in DQoL-impact score was observed at all time-points post-transplantation. Similarly, worry and satisfaction scales were significantly better than pre-transplant evaluation for most time-points. Four-out-of-eight HSQ 2.0 scales demonstrated a significant improvement at some time-points. Longitudinal analysis, after adjustments for potential confounding factors, showed significantly sustained improvement in impact scale up to 72 months. Longer diabetes duration, higher insulin dosage and occurrence of adverse events had negative effects on HRQoL. Single islet infusion or islet after kidney transplant recipients showed the lowest values in HSQ 2.0. In contrast, subjects on exenatide therapy had significantly higher HSQ 2.0 scores. Conclusions Islet transplantation is associated with long-term improvement in HRQoL. Exenatide usage had a positive effect while single islet infusion, islet after kidney transplantation, longer diabetes duration, higher insulin dosage and adverse events had a negative impact on HRQoL scores.