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 (GABA A Rs) in modulating islet endocrine function has been actively investigated since the identification of GABA and GABA A Rs in the pancreatic islets. However, the reported effects of GABA A R 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 patchclamp 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 A R 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 A Rs in beta cells regulates insulin secretion in concert with changes in glucose levels.

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“…Furthermore, GABA also might be beneficial in the reducing the risk of diabetes due to it potentiation of insulin secretion from the pancreas [164].…”

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“…In peripheral tissues, GABAacts not only as a neurotransmitter in the enteric andparasympathetic nervous systems but also as a hormonein non-neuronal tissues (Erdö, 1992). In the endocrinepancreas, GABA is produced by β-cells and once released,activates ionotropic GABAA and metabotropic GABABreceptors in both α-and β-cells (Bonaventura et al, 2008;Dong et al, 2006). Through a paracrine signal, GABAreleased from β-cells inhibits glucagon release from α-cells (Bailey et al, 2007), whereas an autocrine signal increasesor decreases insulin secretion from β-cells, depending onextracellular glucose levels (Dong et al, 2006).…”

“…In the endocrinepancreas, GABA is produced by β-cells and once released,activates ionotropic GABAA and metabotropic GABABreceptors in both α-and β-cells (Bonaventura et al, 2008;Dong et al, 2006). Through a paracrine signal, GABAreleased from β-cells inhibits glucagon release from α-cells (Bailey et al, 2007), whereas an autocrine signal increasesor decreases insulin secretion from β-cells, depending onextracellular glucose levels (Dong et al, 2006). GABA isproduced through the conversion of L-glutamate by theenzyme glutamate decarboxylase and different types ofbacteria produce GABA as a response to adverse acidicenvironmental conditions (Cotter et al, 2001;Jung andKim, 2003;Sanders et al, 1998).…”

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“…12 GABA and GABAA receptors are found in nonneuronal cells of visceral organs. 13 It is known that GABA is a transmitter of enteric interneurons and it regulates the gastrointestinal tract functions.…”