PROJECT SUMMARY This proposal addresses a significant public health question: Does diabetes, the 3rd leading cause of death in the United States (US), impact suitability of donor corneal tissue for transplantation? This question takes on increasing urgency as recent eye bank data suggests donors with diabetes now comprise about 30-35% of the cornea donor pool, a 50-72% increase in just over a decade. The impact of diabetes on keratoplasty outcomes remains unknown, with conflicting evidence from secondary or retrospective analyses of multiple clinical studies. Previous large clinical studies did not show a diabetic donor effect on penetrating keratoplasty (PKP) and Descemet membrane endothelial keratoplasty (DMEK) graft success, yet our recent Cornea Preservation Time Study (CPTS) found the diabetic donor adversely affected graft outcomes following Descemet stripping automated endothelial keratoplasty (DSAEK). Although current standard of care is to use diabetic donor corneas for all types of keratoplasties, some eye banks and surgeons are increasingly avoiding them for DMEK. As both the diabetic donor population and DMEK demand increases, a definitive superiority study evaluating effect of donor diabetes status on graft outcomes will allay and/or define these concerns. The Diabetes Endothelial Keratoplasty Study (DEKS) will address these important questions through a prospective masked clinical trial enrolling 1420 participant-eyes at 30 clinical sites and 15 eye banks across the US. The DEKS will determine if the 3-year graft success rate following DMEK performed with corneas from donors without diabetes is superior to the graft success rate with corneas from donors with diabetes. It will also determine if the 3-year central endothelial cell loss (ECL) after DMEK with corneas from donors without diabetes is less than the central ECL when corneas from donors with diabetes are used. Lastly, the DEKS will explore the relationship of donor diabetes severity, as measured by eye bank-determined diabetes risk categorization scores, post- mortem HbA1c, and skin advanced glycation endproducts and oxidation markers, with DMEK graft outcomes 3 years postoperatively in corneas from diabetic donors. The DEKS could have a major impact on the targeted use of corneas from an increasing number of donors with diabetes with a range of disease severity in a donor pool that must continue to expand to meet the clinical demands of an aging population and DMEK growth.