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, SI, 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 (AIRg) and the disposition index (DI = AIRg SI). Seventy subjects (48 ITA and 22 IAK) completed 79 tests before and 203 tests between 75 days and 3 years after islet transplantation. SI increased post-transplant in both groups and displayed an apparent hyperbolic relationship with post-transplant AIRg. Post-transplant SI was greater in ITA vs. IAK (P < 0.001). Log-transformed AIRg and SI indicate that SI is ∼24% lower at any given AIRg for IAK than ITA. Neither AIRg nor DI was significantly different between ITA and IAK post-transplant. Log-transformed AIRg and DI 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 AIRg and DI 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.
M.R. Rickels: Consultant; Self; Semma Therapeutics, Inc. Research Support; Self; Xeris Pharmaceuticals, Inc. T. Eggerman: None. L. Bayman: None. J. Qidwai: None. J. Naji: None. H.T. Nguyen: None. R. Alejandro: None. M. Bellin: Research Support; Self; Dexcom, Inc., Viacyte, Inc. Other Relationship; Self; Insulet Corporation. P. Senior: Research Support; Self; Allergan, Novo Nordisk. L.G. Hunsicker: Advisory Panel; Self; Allergan plc., Bristol-Myers Squibb.
National Institutes of Health; JDRF (1-SRA-2019-728-A-N)