Background: In the clinical setting, liver is the site currently used for pancreatic islet transplantation (ITX). However, it has been shown that over 50% of the islets can be lost post-infusion. This is most likely associated to nonspecific inflammatory response. One of the specific research priorities to improve the ITX field consists in identifying alternative sites of implantation. The aim of this study is to analyze islet short- and long-term functionality in relation to transplanted mass and location [liver (portal vein, PV) versus kidney capsule (KC)] in comparison to native islets. Material and Methods: Pancreatic islets where isolated from 9-12 weeks old C57BL10 male mice and transplanted in syngeneic streptozotocin-induced diabetic animals. Islets were counted as IEq (islet of an average diameter of 150 μm). Transplant groups included KC 600 (n=8), 1000 (n=7) and PV 600 (n=7), 1000 (n=7), 1200 (n=6), 2000 (n=6). Blood glucose levels and body weight (BW) were monitored. Time of engraftment was recorded. Intra peritoneal glucose tolerance test (IPGTT) was performed at 1 and 6 months post ITX. Two Way ANOVA test (for “IEq” and “transplant site”) was performed to determine statistical difference in short-and long-term functionality. Analysis was performed on individual time points of IPGTT (0, 15, 30, 45, 90, and 120 minutes) and compared between groups. Results: All animals included reversed diabetes within 1week post ITX. Body weight was comparable among groups. When IPGTTs were compared, different IEq among the same implantation site did not reflect difference in functionality, especially long-term. When different implantation sites were compared significant difference was observed at time points 15, 30, 45, 90, and 120 minutes of the IPGTT. KC transplanted islets performed always better as compared to PV islets even when low mass (KC, 600) was compared to high mass (PV, 2000). No statistically significant difference was observed at time 0. KC data were comparable to native islets. Conclusions: This study confirms that KC transplanted islets are functionally comparable to native islets. Islets transplanted PV have an early and late impaired response to glucose challenges even if the transplanted mass is sufficient to reverse diabetes. We believe that preclinical studies should investigate KC feasibility for future clinical application.

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