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

Gastroenterology. 2008 Mar;134(3):727-37. doi: 10.1053/j.gastro.2007.12.033. Epub 2008 Feb 1.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Blood Glucose / metabolism*
  • Cell Line
  • Cell Proliferation* / drug effects
  • Cell Survival
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Experimental / prevention & control*
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism*
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / genetics
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / metabolism
  • Glucose Intolerance / metabolism*
  • Glucose Intolerance / pathology
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Insulin / blood
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Mice
  • Mice, Transgenic
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-ret / genetics
  • Proto-Oncogene Proteins c-ret / metabolism
  • Signal Transduction
  • Thapsigargin / pharmacology
  • Time Factors
  • Up-Regulation


  • Blood Glucose
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Insulin
  • Thapsigargin
  • Proto-Oncogene Proteins c-ret
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3