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DOI: 10.2337/db06-0173
© 2006 by the American Diabetes Association
Sirolimus Is Associated With Reduced Islet Engraftment and Impaired ß-Cell Function
1 Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York
2 Rangos Research Center, Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Address correspondence and reprint requests to H. Henry Dong, Rangos Research Center, Children’s Hospital of Pittsburgh, 3460 5th Ave., Rm. 6111, Pittsburgh, PA 15213. E-mail: dongh{at}pitt.edu
Abbreviations:
AUC, area under the curve; FFA, free fatty acid; FPLC, fast-performance liquid chromatography; PDX-1, pancreas duodenum homeobox-1; STZ, streptozotocin
Successful islet transplantation depends on the infusion of sufficiently large quantities of islets, but only a fraction of transplanted islets can survive and become engrafted, and yet the underlying mechanism remains unclear. In this study, we examined the effect of sirolimus, a key component of the immunosuppressive regimen in clinical islet transplantation, on islet engraftment and function. To distinguish the effect of sirolimus on immune rejection from its effect on islet engraftment, we used a syngeneic model. Diabetic mice were transplanted with 250 islets under the renal capsule, followed by treatment with sirolimus or vehicle for 14 days. Thirty days posttransplantation, islet grafts were retrieved for the determination of insulin content and vascular density. Compared with mock-treated controls, diabetic recipient mice receiving sirolimus exhibited impaired blood glucose profiles and reduced glucose-stimulated insulin secretion, correlating with reduced intragraft insulin content and decreased vascular density. Islets exposed to sirolimus for 24 h in culture displayed significantly diminished glucose-stimulated insulin release, coinciding with decreased pancreas duodenum homeobox-1 and GLUT2 expression in cultured islets. Furthermore, sirolimus-treated diabetic recipient mice, as opposed to mock-treated controls, were associated with dyslipidemia. These data suggest that sirolimus, administered in the early posttransplantation phase, is a confounding factor for reduced islet engraftment and impaired ß-cell function in transplants.
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