Regulation of pancreatic islet cell survival and replication by gamma-aminobutyric acid

Diabetologia. 2007 Apr;50(4):764-73. doi: 10.1007/s00125-007-0601-8. Epub 2007 Feb 22.

Abstract

Aims/hypothesis: Pancreatic islets have evolved remarkable, though poorly understood mechanisms to modify beta cell mass when nutrient intake fluctuates or cells are damaged. We hypothesised that appropriate and timely adjustments in cell number occur because beta cells release proliferative signals to surrounding cells when stimulated by nutrients and 'bleed' these growth factors upon injury.

Materials and methods: In rat pancreatic islets, we measured DNA content, insulin content, insulin secretion after treatment, immunoblots of apoptotic proteins and the uptake of nucleoside analogues to assess the ability of gamma-aminobutyric acid (GABA), which is highly concentrated in beta cells, to act as a growth and survival factor. This focus is supported by work from others demonstrating that GABA increases cell proliferation in the developing nervous system, acts as a survival factor for differentiated neurons and, interestingly, protects plants under stress.

Results: Our results show that DNA, insulin content and insulin secretion are higher in freshly isolated islets treated with GABA or GABA B receptor agonists. Exposure to GABA upregulated the anti-apoptotic protein B-cell chronic lymphocytic leukaemia XL and limited activation of caspase 3 in islets. The cellular proliferation rate in GABA-treated islets was twice that of untreated controls.

Conclusions/interpretation: We conclude that GABA serves diverse purposes in the islet, meeting a number of functional criteria to act as an endogenous co-regulator of beta cell mass.

Publication types

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

MeSH terms

  • Animals
  • Cell Proliferation
  • Cell Survival
  • DNA / metabolism
  • Immunohistochemistry
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology*
  • Islets of Langerhans / metabolism
  • Male
  • Microscopy, Confocal
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A / metabolism
  • Receptors, GABA-B / metabolism
  • Thymidine / chemistry
  • Up-Regulation
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Insulin
  • Receptors, GABA-A
  • Receptors, GABA-B
  • gamma-Aminobutyric Acid
  • DNA
  • Thymidine