Improvement in β-Cell Secretory Capacity After Human Islet Transplantation According to the CIT07 Protocol

Abstract

The Clinical Islet Transplantation 07 (CIT07) protocol uses antithymocyte globulin and etanercept induction, islet culture, heparinization, and intensive insulin therapy with the same low-dose tacrolimus and sirolimus maintenance immunosuppression as in the Edmonton protocol. To determine whether CIT07 improves engrafted islet β-cell mass, our center measured β-cell secretory capacity from glucose-potentiated arginine tests at days 75 and 365 after transplantation and compared those results with the results previously achieved by our group using the Edmonton protocol and normal subjects. All subjects were insulin free, with CIT07 subjects receiving fewer islet equivalents from a median of one donor compared with two donors for Edmonton protocol subjects. The acute insulin response to glucose-potentiated arginine (AIRpot) was greater in the CIT07 protocol than in the Edmonton protocol and was less in both cohorts than in normal subjects, with similar findings for C-peptide. The CIT07 subjects who completed reassessment at day 365 exhibited increasing AIRpot by trend relative to that of day 75. These data indicate that engrafted islet β-cell mass is markedly improved with the CIT07 protocol, especially given more frequent use of single islet donors. Although several peritransplant differences may have each contributed to this improvement, the lack of deterioration in β-cell secretory capacity over time in the CIT07 protocol suggests that low-dose tacrolimus and sirolimus are not toxic to islets.

Total Pancreatectomy With Islet Autotransplantation

“…In the 11 subjects transplanted at the University of Pennsylvania, this combination of immunosuppressive, anti-inflammatory, anti-thrombotic, and beta-cell “rest” approaches was associated with an improvement in beta-cell secretory capacity to > 40% of normal despite the transplantation of fewer islets than in the same institution's previous experience with the Edmonton protocol, with 7/11 CIT07 protocol subjects receiving islets from a single donor pancreas, and suggesting a 3-fold gain in islet engraftment efficiency (54). Importantly, when the CIT07 protocol cohort was reassessed at 1 year, they remained insulin-free with a trend toward further improvement in β-cell secretory capacity to > 50% of normal (54), supporting the achievement of a sufficient engrafted β-cell mass capable of resisting metabolic exhaustion over time. While islet autotransplants do not necessitate immunosuppression, use of adjuvant anti-inflammatory agents, heparinization, and aggressive insulin therapy are relevant to TPIAT.…”

Glucose Effectiveness

“…35 Also, insulin secretion is promptly induced during an IVGTT performed on a person with a well-functional islet transplant. 36 In conclusion, functional assessments of transplanted β cells remain challenging, and the predominant effect of glucose effectiveness in rodents is commonly overlooked. Based on the results presented herein, normalization of glucose disposal during an IVGTT should not be interpreted as evidence for active glucose-stimulated insulin release unless substantiated by insulin or c peptide measurements in immediate conjunction with glucose administration.…”

Beta-cell replacement therapy

“…A short culture period to cull nonviable cells and to decrease tissue factor expression and IBMIR is also an important improvement in alloislet transplantation [57]. Importantly, recent advances in islet isolation techniques and characterization have really augmented islet yield and function and may drive further improvements in outcomes after single donor islet allotransplantation by way of an increased functional b-cell mass [53,[58][59][60][61][62]63 && ]. However, unlike islet autotransplants, the function of allotransplants is not as durable over time [10].…”