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Diabetes 53:1038-1045, 2004
© 2004 by the American Diabetes Association, Inc.

Glucose Inhibition of Glucagon Secretion From Rat {alpha}-Cells Is Mediated by GABA Released From Neighboring ß-Cells

Anna Wendt1, Bryndis Birnir1, Karsten Buschard2, Jesper Gromada3, Albert Salehi1, Sabine Sewing3, Patrik Rorsman1, and Matthias Braun1

1 Department of Physiological Sciences, Lund University, Lund, Sweden
2 Bartholin Instituttet, Kommunehospitalet, Copenhagen, Denmark
3 Lilly Research Laboratories, Hamburg, Germany

{gamma}-Aminobutyric acid (GABA) has been proposed to function as a paracrine signaling molecule in islets of Langerhans. We have shown that rat ß-cells release GABA by Ca2+-dependent exocytosis of synaptic-like microvesicles. Here we demonstrate that GABA thus released can diffuse over sufficient distances within the islet interstitium to activate GABAA receptors in neighboring cells. Confocal immunocytochemistry revealed the presence of GABAA receptors in glucagon-secreting {alpha}-cells but not in ß- and {delta}-cells. RT-PCR analysis detected transcripts of {alpha}1 and {alpha}4 as well as ß1–3 GABAA receptor subunits in purified {alpha}-cells but not in ß-cells. In whole-cell voltage-clamp recordings, exogenous application of GABA activated Cl- currents in {alpha}-cells. The GABAA receptor antagonist SR95531 was used to investigate the effects of endogenous GABA (released from ß-cells) on pancreatic islet hormone secretion. The antagonist increased glucagon secretion at 1 mmol/l glucose twofold and completely abolished the inhibitory action of 20 mmol/l glucose on glucagon release. Basal and glucose-stimulated secretion of insulin and somatostatin were unaffected by SR95531. The L-type Ca2+ channel blocker isradipine evoked a paradoxical stimulation of glucagon secretion. This effect was not observed in the presence of SR95531, and we therefore conclude that isradipine stimulates glucagon secretion by inhibition of GABA release.

Address correspondence and reprint requests to Matthias Braun, Department of Physiological Sciences, BMC B11, SE-221 84 Lund, Sweden. E-mail: matthias.braun{at}mphy.lu.se


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2004 by the American Diabetes Association.