358-OR: ß-Cell Function and Insulin Sensitivity with Islet Alone and Islet-after-Kidney Transplantation for Type 1 Diabetes in the Clinical Islet Transplantation (CIT) Consortium

Phase 3 studies of islet transplant alone (ITA) and islet-after-kidney (IAK) transplantation in type 1 diabetes were completed by the CIT Consortium using the same procedures for islet manufacturing and induction immunosuppression but differing in maintenance immunosuppression. Both studies met their criteria for safety and efficacy over 2 and 3 year planned follow-up, respectively. The insulin sensitivity index, S_I, was derived from an insulin-modified frequently sampled intravenous glucose tolerance (FSIGT) test using the minimal model approach before (repeated annually) and after islet transplantation, with post-transplant tests also used to assess β-cell function from the acute insulin response to glucose (AIR_g) and the disposition index (D_I = AIR_g S_I). Seventy subjects (48 ITA and 22 IAK) completed 79 tests before and 203 tests between 75 days and 3 years after islet transplantation. S_I increased post-transplant in both groups and displayed an apparent hyperbolic relationship with post-transplant AIR_g. Post-transplant S_I was greater in ITA vs. IAK (P < 0.001). Log-transformed AIR_g and S_I indicate that S_I is ∼24% lower at any given AIR_g for IAK than ITA. Neither AIR_g nor D_I was significantly different between ITA and IAK post-transplant. Log-transformed AIR_g and D_I demonstrate significant prediction of islet graft failure (defined by mixed-meal tolerance test stimulated C-peptide < 0.3 ng/mL) such that each log increase of AIR_g and D_I reduces the hazard of islet graft failure by 45% and 42%, respectively. These results indicate that while insulin sensitivity improved after islet transplantation, post-transplant measures of β-cell function may better predict islet graft survival. Whether the differences in maintenance immunosuppression (low-dose tacrolimus and sirolimus, ITA; tacrolimus and mycophenolic acid, IAK) may explain the greater insulin sensitivity in ITA vs. IAK requires further study.