β-Cell Secretory Capacity and Metabolic Control during 5 Years Following Human Islet Transplantation

Presentation Number: OR12-1
Date of Presentation: April 4th, 2017

Michael R. Rickels*, Eileen Markmann, Cornelia Dalton-Bakes, Amy J. Peleckis, Chengyang Liu and Ali Naji
University of Pennsylvania Perelman School of Medicine, Philadelphia, PA

Abstract

Surviving β-cell mass can be monitored following islet transplantation using the β-cell secretory capacity, however, there are no data beyond one-year for allogeneic islet grafts in patients with type 1 diabetes. We measured β-cell secretory capacity from glucose-potentiated arginine tests at day 75 and years 1, 2, 3, and 4 following intrahepatic islet transplantation for type 1 diabetes according to the Clinical Islet Transplantation 07 (CIT07) protocol. Eleven patients received 694,895 ± 48,498 islet equivalents from one (n = 7) or two (n = 4) donor pancreases, became insulin-independent, and completed two-year follow-up, ten of whom enrolled in an extended follow-up (CIT08) protocol until four years following transplantation, with clinical follow-up available until year 5. Maintenance immunosuppression was with low-dose tacrolimus and sirolimus, with three patients converting from sirolimus to mycophenolic acid for adverse effects. Three patients had returned to insulin therapy, one each by the two, three, and four year assessments, with two requiring low-dose basal insulin, and one experiencing islet graft failure due to recurrent autoimmune diabetes as evidenced by the development of de novo autoantibodies against glutamic acid decarboxylase-65 prior to recurrence of hyperglycemia and return to basal-bolus insulin therapy. Except for the patient with graft failure, HbA1c remained < 6.5% over the 5 years of follow-up. Average BMI has stayed between 23-24 kg/m2. During glucose-potentiated arginine testing, acute insulin responses to arginine (AIRarg) decreased over time (P < 0.05) with insulin sensitivity (M/I) increasing (P < 0.05) such that there was no change in the disposition index (DI = AIRarg×M/I), while acute insulin responses to glucose-potentiated arginine (AIRpot) that provides the β-cell secretory capacity remained stable. The patient with recurrent autoimmune diabetes experienced a 58% decrease in AIRpot between the year 2 and year 3 assessments when returning to insulin therapy. These results indicate 70% of islet recipients experienced 5 year insulin-independence associated with transplanted islet β-cell functional adaptation to changes in insulin sensitivity, and with sufficient insulin secretory reserve that is able, in the absence of immunologic recognition of the islet graft, to resist metabolic exhaustion over time despite the requirement for chronic immunosuppressive drug therapy.

 

Nothing to Disclose: MRR, EM, CD, AJP, CL, AN