Glial Cell Line-Derived Neurotrophic Factor Increases β-Cell Mass and Improves Glucose Tolerance

Background & Aims: Pancreatic β-cell mass increases in response to increased demand for insulin, but the factors involved are largely unknown. Glial cell line-derived neurotrophic factor (GDNF) is a growth factor that plays a role in the development and survival of the enteric nervous system. We investigated the role of GDNF in regulating β-cell survival. Methods: Studies were performed using the β-TC-6 pancreatic β-cell line, isolated mouse pancreatic β cells, and in vivo in transgenic mice that overexpress GDNF in pancreatic glia. GDNF receptor family α1 and c-Ret receptor expression were assessed by reverse-transcription polymerase chain reaction and immunofluorescence microscopy. Apoptosis was evaluated by assessing caspase-3 cleavage. Phosphoinositol-3-kinase signaling pathway was analyzed by Akt phosphorylation. Glucose homeostasis was assessed by performing intraperitoneal glucose tolerance tests. Insulin sensitivity was assessed using intraperitoneal injection of insulin. Results: We demonstrate the presence of receptors for GDNF, GFRα1, and c-Ret on β cells. GDNF promoted β-cell survival and proliferation and protected them from thapsigargin-induced apoptosis (P<.0001) in vitro. Exposure of β-cells to GDNF also resulted in phosphorylation of Akt and GSK3β. Transgenic mice that overexpress GDNF in glia exhibit increased β-cell mass, proliferation, and insulin content. No differences in insulin sensitivity and c-peptide levels were noted. Compared with wild-type mice, GDNF-transgenic mice have significantly lower blood glucose levels and improved glucose tolerance (P<.01). GDNF-transgenic mice are resistant to streptozotocin-induced β-cell loss (P<.001) and subsequent hyperglycemia. Conclusions: We demonstrate that over expression of GDNF in pancreatic glia improves glucose tolerance and that GDNF may be a therapeutic target for improving β-cell mass.