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

Abstract

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