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.

Figures

FIG. 1.

Plasma insulin (A and C) and C-peptide (B and D) levels in response to bolus injections of arginine (arrows) administered under fasting and 230 mg/dL hyperglycemic clamp conditions at day 90 posttransplantation in the Edmonton protocol subjects (A and B) and at day 75 posttransplantation in the CIT07 (C, D) protocol subjects. The Edmonton cohort underwent islet transplantation between 2002 and 2003, and the CIT07 cohort underwent islet transplantation between 2008 and 2012. The C-peptide (4) and insulin (11) data for the Edmonton group previously have been reported. The gray shaded area gives the 95% CI for levels in the normal control group.

FIG. 2.

β-Cell secretory capacity measured as the AIRpot in the Edmonton protocol subjects (A) and in the CIT07 protocol subjects (B) over time after transplantation. The Edmonton cohort underwent islet transplantation between 2002 and 2003, and the CIT07 cohort underwent islet transplantation between 2008 and 2012. The hashed area gives the 95% CI for the β-cell secretory capacity in the normal control group. Of the Edmonton protocol subjects, one returned to insulin soon after initial study and lost all islet graft function by 365 days (□), one returned to insulin at 9 months and received a second islet infusion (○), two returned to insulin at 11 months and exhibited declines in β-cell secretory capacity at 365 days (△, ◇), and one initially studied at 365 days remained insulin independent at 730 days with stable β-cell secretory capacity (⌂). All nine of the CIT07 protocol subjects to have reached 365 days remained insulin independent.

FIG. 3.

Plasma glucose (A) and glucose infusion rates (B) during conduct of the glucose-potentiated arginine test, and insulin (C) and C-peptide (D) levels in response to bolus injections of arginine (arrows) administered under fasting and 230 mg/dL hyperglycemic clamp conditions at day 75 and day 365 posttransplantation in the CIT07 protocol subjects. The gray shaded and hashed areas give the 95% CIs for levels in the normal control group.