Glial cell line-derived neurotrophic factor increases β-cell mass and improves glucose tolerance

Background & Aims: Pancreatic beta-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 beta-cell survival. Methods: Studies were performed using the beta-TC-6 pancreatic beta-cell line, isolated mouse pancreatic beta-cells, and in vivo in transgenic mice that overexpress GDNF in pancreatic glia. GDNF receptor family alpha 1 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, GFR alpha 1, and c-Ret on P cells. GDNF promoted beta-cell survival and proliferation and protected them from thapsigargin-induced apoptosis (P < .0001) in vitro. Exposure of A-cells to GDNF also resulted in phosphorylation of Akt and GSK3 beta. Transgenic mice that overexpress GDNF in glia exhibit increased P-cell mass, proliferation, and insulin content. No differences in insulin sensitivity and c-peptide levels were noted. Compared with wildtype mice, GDNF-transgenic mice have significantly lower blood glucose levels and improved glucose tolerance (P < .01). GDNF-transgenic mice are resistant to streptozotocin-induced beta-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)beta-cell mass.