| Diabetes Mellitus (DM), a disease process of multiple and variable etiology, results in diminished or absent glycemic control. Pancreatic islet transplantation is an emerging treatment option for select patients with type 1 DM who have severely impaired insulin secretion and experience frequent episodes of hypoglycemia unawareness. One opportunity for improved success and wider applicability of the procedure is to curtail the sharp decay in islet graft function observed after transplant. Strategies to improve islet engraftment (initial and long-term graft function) are explored here. Engraftment is dependent on factors falling into four categories: pre-transplant, transplantation-associated, immediate post-transplant, and long-term. In the pre-transplant setting, the storage of islets in a pellet, rather than suspended in culture, for just 30-minutes was severely detrimental to transplant outcome. In the immediate post-transplant period, the administration of incretin-based therapy (exendin-4 and liraglutide) was investigated. When used at an optimal dose, liraglutide and exendin-4 separately had beneficial effects on the function of an islet graft in the mouse model. Liraglutide is a particularly promising therapeutic candidate since it diminished beta-cell apoptosis in the immediate post transplant period and resulted in increased glucose-dependent insulin secretion by transplanted islets. Shifting focus to long-term graft function, the novel immunosuppressive agent AEB-071 (a protein kinase c inhibitor) was investigated. Delayed islet allograft rejection was observed in rats receiving AEB-071 monotherapy. Furthermore, islet allograft rejection was prevented in 80% of recipients who received AEB-071 and cyclosporine concurrently. Together autoimmunity, allograft rejection, and immunosuppressive drug-associated adverse effects are involved in the long-term decay of islet graft function. AEB-071 was investigated in the context of these three factors, and shows favorable pre-clinical outcomes as an immunosuppressive drug candidate for islet transplantation. Overall, several strategies to improve islet engraftment are presented here. Both incretin-based therapies and immunosuppression with a protein kinase c inhibitor (AEB-071) are highlighted to be potentially beneficial strategies worthy of investigation in clinical islet transplantation. |
