Glial Cell Line-Derived Neurotrophic Factor Enhances Human Islet Posttransplantation Survival

Background. Development of pretransplantation islet culture strategies that preserve or enhance beta-cell viability would eliminate the requirement for the large numbers of islets needed to restore insulin independence in type 1 diabetes patients. We investigated whether glial cell line-derived neurotrophic factor (GDNF) could improve human islet survival and posttransplantation function in diabetic mice. Methods. Human islets were cultured in medium supplemented with or without GDNF (100 ng/mL) and in vitro islet survival and function assessed by analyzing beta-cell apoptosis and glucose stimulated insulin release. In vivo effects of GDNF were assessed in streptozotocin-induced diabetic nude mice transplanted under the kidney capsule with 2000 islet equivalents of human islets precultured in medium supplemented with or without GDNF. Results. In vitro, human islets cultured for 2 to 10 days in medium supplemented with GDNF showed lower beta-cell death, increased Akt phosphorylation, and higher glucose-induced insulin secretion than islets cultured in vehicle. Human islets precultured in medium supplemented with GDNF restored more diabetic mice to normoglycemia and for a longer period after transplantation than islets cultured in vehicle. Conclusions. Our study shows that GDNF has beneficial effects on human islet survival and could be used to improve islet posttransplantation survival.