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Transgenic mice over expressing Glial Derived Neurotrophic Factor have increased beta cell mass

The role of the enteric nervous system in regulating β‐cell survival is unknown. Glial cell line‐derived neurotrophic factor (GDNF) is a growth factor that plays a critical role in the development and survival of the enteric nervous system. We demonstrate the presence of receptors for GDNF, GFRα1 and RET, on β‐cells. GDNF promoted β‐cell survival and proliferation and protected them from thapsigargin‐induced apoptosis (P<0.0001). GDNF activated the PI‐3‐kinase pathway in β‐TC‐6 cells resulting in phosphorylation of Akt and GSK3β. Transgenic mice that overexpress GDNF in glia demonstrate increased β‐cell mass (2.5 fold increase in transgenic mice vs. WT mice p<0.001). The GDNF transgenic mice had increased β‐cell proliferation, insulin content, plasma insulin, and c‐peptide levels. Compared to wild‐type mice they have significantly lower blood glucose levels and improved glucose tolerance (p<0.01). GDNF transgenic mice are resistant to streptozotocin‐induced β‐cell apoptosis (p<0.05) and subsequent hyperglycemia. Mouse islets cultured with GDNF showed improved islet transplantation survival. GDNF and its signaling pathway may provide novel therapeutic targets for improving β‐cell survival and mass.