The Influence of γ-Aminobutyric Acid on Hormone Release by the Mouse and Rat Endocrine Pancreas*

Abstract

The present study was aimed at localizing gamma-aminobutyric acid (GABA) and its enzyme of synthesis, glutamic acid decarboxylase (GAD), in the mouse pancreas by immunocytochemical methods. The influence of GABA on hormone release was also studied with normal mouse and rat islets and the isolated perfused rat pancreas. Particular attention was paid to glucagon release to test a recent hypothesis suggesting that GABA mediates the still unexplained glucose-induced inhibition of glucagon release. GABA and GAD were identified only in islet cells and never in the exocrine tissue. Exogenous GABA, baclofen (agonist of GABAB receptors), muscimol (agonist of GABAA receptors), or bicuculline (antagonist of GABAA receptors) did not affect insulin and somatostatin release by isolated mouse or rat islets. GABA was also without effect on glucose-induced electrical activity in mouse B-cells. Glucagon secretion by mouse islets was only slightly inhibited (approximately 20%) by GABA. Since muscimol had a similar effect, and baclofen was ineffective, the inhibition by GABA probably involves GABAA receptor activation. Bicuculline, however, did not antagonize the inhibitory effects of GABA and muscimol, probably because the antagonist alone also decreased glucagon secretion. In contrast to GABA, low (3 mM) and high (20 mM) concentrations of glucose strongly inhibited (approximately 50-65%) glucagon release; this inhibition was not prevented by bicuculline. Similar results were obtained with the perfused rat pancreas; muscimol slightly inhibited glucagon release under various conditions, and bicuculline did not reverse the strong inhibition produced by 16.7 mM glucose. In conclusion, GABA does not affect insulin and somatostatin secretion, but inhibits A-cells, probably by acting on GABAA receptors. It is unlikely, however, that this small inhibitory effect can account for the inhibition of glucagon release produced by glucose.

Secretory Granule-mediated Co-secretion ofl-Glutamate and Glucagon Triggers Glutamatergic Signal Transmission in Islets of Langerhans

“…As to the physiological significance of the glutamatergic and GABAergic signaling in the islets, we propose that these signaling pathways may be involved in negative regulatory mechanism on glucagon secretion, since the secreted GABA in turn binds to GABAA receptors on ␣ cells, causing inhibition of glucagon secretion (25,26,46). Consistent with the idea, stimulation of metabotropic glutamate receptor type 8 (mGluR8), a class III receptor, on ␣ cells, strongly inhibited glucagon secretion under the low glucose condition (11).…”

Coordinate Changes in Histone Modifications, mRNA Levels, and Metabolite Profiles in Clonal INS-1 832/13 β-Cells Accompany Functional Adaptations to Lipotoxicity

“…GABA has previously been shown to suppress GSIS from rat islets (61). However, it has also been suggested that GABA does not influence GSIS but rather has a small suppressive effect on glucagon secretion (62). Overexpression of glutamate decarboxylase, resulting in increased production of GABA, inhibits insulin secretion in a rat model (63).…”

Impact of short-term treatment with benzodiazepines and imidazopyridines on glucose metabolism in healthy subjects

“…In fact, GABA has been reported to affect insulin secretion though both inhibitory and stimulatory effects have been reported in different experimental models [9][10][11][12][13][14][15]. Actually, the apparent absence of a compensatory increase of insulin secretion to the enhanced glucose ΔAUC could support the hypothesis of a partial inhibition of beta-cell responsiveness to glucose load after brotizolam or zolpidem pretreatment.…”

“…Based on this background, the aim of our study was to investigate in vivo in humans, the effects of a short-term modulation of GABA system, known to be involved in the control of insulin secretion [9][10][11][12][13][14][15], through the administration of brotizolam, a benzodiazepine, and zolpidem, an imidazopyridine, on the insulin and the glucose response to an oral glucose tolerance test (OGTT) in healthy subjects. 4 …”