gms | German Medical Science

Introduction: Antiproliferative effects of immunosuppressants used in human islet transplantation interfere with the capability of the beta cells to balance cell renewal and cell loss. Consequently, long-term use of these drugs might contribute to graft dysfunction in islet transplant recipients. New immunosuppressive regimens are required to improve outcomes.

Materials and methods: Syngeneic islets (300 IEQ) were injected into the right liver lobes of C57BL/6 diabetic mice. Osmotic pumps filled with Bromodeoxyuridine (group 1), Bromodeoxyuridine and Tacrolimus (group 2) or Bromodeoxyuridine and Everolimus (group 3) were implanted. Hepatectomy was performed after 4 weeks. Proliferation of beta cells was detected by BrdU incorporation.

Results: In all transplanted animals normoglycemia was restored. Glucose tolerance was significantly improved after 4 weeks in group 1 (90min: P< 0.012; 120min: P<0.045). This effect was not as strong when animals were treated with Tacrolimus. In contrast, mice that recieved Everolimus showed an impaired glucose tolerance. After 4 weeks 36.3% of all beta cells in group 1 underwent at least on cycle of proliferation. In comparison, beta cells of group 2 had a significantly decreased proliferation rate (21.19%), whereas beta cell proliferation in group 3 (38.36%) remained unchanged.

Conclusion: Beta cells of transplanted islets have a strong capability of self renewal when not affected by immunosuppression or immune assault. In this setting maintenance of glucose homeosstasis improves over time indicating an increase in beta cell mass. Exposure to Tacrolimus clearly inhibits beta cells replication. In contrast, Everolimus does not seem to affect beta cell proliferation, although having a negative impact on glucose tolerance. The use of Everolimus might lead to better long-term results in islet transplantation, due to the lacking inhibition of beta cell proliferation.