Aims/hypothesis  

The role of gamma-aminobutyric acid (GABA) and A-type GABA receptors (GABA_ARs) in modulating islet endocrine function has been actively investigated since the identification of GABA and GABA_ARs in the pancreatic islets. However, the reported effects of GABA_AR 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 GABA_AR antagonist bicuculline. The current–voltage relationship revealed that I_GABA reversed at −42±2.2 mV, independently of glucose concentration. Nevertheless, the glucose concentration critically controlled the membrane potential (V _M), i.e., at low glucose (0 or 2.8 mmol/l) the endogenous V _M of INS-1 cells was below the I_GABA reversal potential and at high glucose (16.7 or 28 mmol/l), the endogenous V _M of INS-1 cells was above the I_GABA 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 GABA_ARs in beta cells regulates insulin secretion in concert with changes in glucose levels.