Anti-aging Glycopeptide Protects Human Islets Against Tacrolimus-related Injury and Facilitates Engraftment in Mice Authors: Gala-Lopez

Clinical islet transplantation has become an established treatment modality for selected patients with Type 1 diabetes. However, a large proportion of transplanted islets is lost through multiple factors including immunosuppressant-related toxicity, often requiring more than one donor to achieve insulin independence. Based on the cytoprotective capabilities of antifreeze proteins (AFP) we hypothesize that supplementation of islets with synthetic AFP analogue, Anti-aging Glycopeptide (AAGP) would enhance posttransplant engraftment and function, and would protect against tacrolimus (Tac) toxicity. In vitro and in vivo islet Tac exposure elicited significant but reversible reduction in insulin secretion in both mouse and human islets. Supplementation with AAGP resulted in improvement of islet survival (Tac + vs. Tac+AAGP, 31.5% vs. 67.6%, p<0.01) coupled with better insulin secretion (AUC: Tac + vs. Tac+AAGP, 7.3 vs. 129.2 mmol/L/60 min, p<0.001). The addition of AAGP reduced oxidative stress, enhanced insulin exocytosis, improved apoptosis and also improved engraftment in mice by decreasing expression of IL-1β, IL-6, keratinocyte chemokine and TNF-α. Finally, transplant efficacy was superior in the Tac+AAGP group, and was similar to islets not exposed to tacrolimus, despite receiving continuous treatment for a limited time. Thus, supplementation with AAGP during culture improves islet potency and attenuates longterm tacrolimus induced graft dysfunction. Page 4 of 42 Diabetes