Dr. Rickels is the Willard and Rhoda Ware Professor in Diabetes and Metabolic Diseases at the University of Pennsylvania Perelman School of Medicine where Dr. Rickels serves as Director of Clinical Science in the Division of Endocrinology, Diabetes and Metabolism, Director for Translational Research in the Institute for Diabetes, Obesity & Metabolism, and Medical Director for the Pancreatic Islet Cell Transplant Program. Dr. Rickels conducts patient-oriented diabetes research that is focused on understanding the physiology of islet function and replacement and glucose counterregulation in defense against hypoglycemia in type 1 diabetes and pancreatogenic forms of diabetes such as cystic fibrosis-related diabetes. This work has been continuously funded by the National Institutes of Health where Dr. Rickels has served as chair of the metabolics study subcommittee for the Clinical Islet Transplantation (CIT) Consortium, chair of the data and safety monitoring board for the Restoring Insulin Secretion (RISE) Consortium and chairs the publications and presentations committee for the Collaborative Islet Transplant Registry (CITR). Dr. Rickels has served as vice-chair for the Type 1 Diabetes Exchange Clinic Network and Registry, as elected councilor for the International Pancreas and Islet Transplant Association, as Associate Editor of Endocrine Reviews, and currently serves as Associate Editor of Diabetes Care.
Beta-cell function and insulin sensitivity with islet transplant alone and islet-after-kidney transplantation for type 1 diabetes in the Clinical Islet Transplantation (CIT) Consortium
Michael Rickels1, Thomas L Eggerman2, Levent Bayman3, Julie C Qidwai3, Joseph R Naji1, Huong-Lan Nguyen1, Rodolfo Alejandro4, Melena D Bellin5, Peter A Senior6, Lawrence G Hunsicker3.
1University of Pennsylvania, Philadelphia, PA, United States; 2National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, PA, United States; 3University of Iowa, Iowa City, IA, United States; 4University of Miami, Miami, FL, United States; 5University of Minnesota, Minneapolis, MN, United States; 6University of Alberta, Edmonton, AB, Canada
Clinical Islet Transplantation Consortium.
Phase 3 studies of islet transplant alone (ITA)1 and islet-after-kidney (IAK)2 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 & 22 IAK) completed 79 tests before and 203 tests between 75 days and 3 years after islet transplantation. Time dependent impact of each parameter on hazard of islet graft failure defined by mixed-meal tolerance test stimulated C-peptide < 0.3 ng/mL was assessed by joint analysis (mixed model longitudinal & time-to-event). SI increased post-transplant in both cohorts 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 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 renal function between the cohorts or 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.
This analysis was supported by grant 1-SRA-2019-728-A-N (to MRR and LGH) from the Juvenile Diabetes Research Foundation. The Clinical Islet Transplantation Consortium was supported by grants to the University of Pennsylvania (U01DK070430), University of Iowa (U01DK070431), University of Miami (U01DK070460), and University of California San Francisco (U01DK085531) from the National Institute of Diabetes and Digestive and Kidney Diseases, to the University of Alberta (U01AI065191), Uppsala University (U01AI065192), University of Minnesota (U01AI065193), Northwestern University (U01AI089316), and Emory University (U01AI089317) from the National Institute of Allergy and Infectious Diseases.
[1] Hering BJ, Clarke WR, Bridges ND, Eggerman TL, Alejandro R, Bellin MD, Chaloner K, Czarniecki CW, Goldstein JS, Hunsicker LG, Kaufman DB, Korsgren O, Larsen CP, Luo X, Markmann JF, Naji A, Oberholzer J, Posselt AM, Rickels MR, Ricordi C, Robien MA, Senior PA, Shapiro AMJ, Stock PG, Turgeon NA: Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia. Diabetes Care 39(7): 1230-1240, July 2016. PMCID: PMC5317236
[2] Markmann JF, Rickels MR, Eggerman TL, Bridges ND, Lafontant DE, Qidwai J, Foster E, Clarke WR, Kamoun M, Alejandro R, Bellin M, Chaloner K, Czarniecki CW, Goldstein JS, Hering BJ, Hunsicker LG, Kaufman DB, Korsgren O, Larsen CP, Luo X, Naji A, Oberholzer J, Posselt AM, Ricordi C, Senior PA, Shapiro AMJ, Stock PG, Turgeon NA; Clinical Islet Transplantation Consortium: Phase 3 trial of human islet-after-kidney transplantation in type 1 diabetes. American Journal of Transplantation 21(4): 1477-1492, April 2021. PMCID: PMC9074710
