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  • Title: Glial cell line-derived neurotrophic factor increases beta-cell mass and improves glucose tolerance.
    Author: Mwangi S, Anitha M, Mallikarjun C, Ding X, Hara M, Parsadanian A, Larsen CP, Thule P, Sitaraman SV, Anania F, Srinivasan S.
    Journal: Gastroenterology; 2008 Mar; 134(3):727-37. PubMed ID: 18241861.
    Abstract:
    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 alpha1 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, GFRalpha1, and c-Ret on beta cells. GDNF promoted beta-cell survival and proliferation and protected them from thapsigargin-induced apoptosis (P<.0001) in vitro. Exposure of beta-cells to GDNF also resulted in phosphorylation of Akt and GSK3beta. Transgenic mice that overexpress GDNF in glia exhibit increased beta-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 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.
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