Gamma-aminobutyric acid up- and downregulates insulin secretion from beta cells in concert with changes in glucose concentration

Abstract

Aims/hypothesis: The role of gamma-aminobutyric acid (GABA) and A-type GABA receptors (GABAARs) in modulating islet endocrine function has been actively investigated since the identification of GABA and GABAARs in the pancreatic islets. However, the reported effects of GABAAR activation on insulin secretion from islet beta cells have been controversial. Methods: This study examined the hypothesis that the effect of GABA on beta cell insulin secretion is dependent on glucose concentration. Results: Perforated patch-clamp recordings in INS-1 cells demonstrated that GABA, at concentrations ranging from 1 to 1,000 μmol/l, induced a transmembrane current (I GABA) which was sensitive to the GABAAR antagonist bicuculline. The current-voltage relationship revealed that IGABA reversed at -42±2.2 mV, independently of glucose concentration. Nevertheless, the glucose concentration critically controlled the membrane potential (VM), i.e., at low glucose (0 or 2.8 mmol/l) the endogenous VM of INS-1 cells was below the IGABA reversal potential and at high glucose (16.7 or 28 mmol/l), the endogenous VM of INS-1 cells was above the IGABA reversal potential. Therefore, GABA dose-dependently induced membrane depolarisation at a low glucose concentration, but hyperpolarisation at a high glucose concentration. Consistent with electrophysiological findings, insulin secretion assays demonstrated that at 2.8 mmol/l glucose, GABA increased insulin secretion in a dose-dependent fashion (p<0.05, n=7). This enhancement was blocked by bicuculline (p<0.05, n=4). In contrast, in the presence of 28 mmol/l glucose, GABA suppressed the secretion of insulin (p<0.05, n=5). Conclusions/interpretation: These findings indicate that activation of GABAARs in beta cells regulates insulin secretion in concert with changes in glucose levels. © Springer-Verlag 2006.