Nutrient regulation of gamma-aminobutyric acid release from islet beta cells.
Glutamate decarboxylase (GAD) of pancreatic beta cells seems to be involved in the development of autoimmune reactivities which occur in insulin-dependent diabetes mellitus. Little is known about the regulation and role of the GAD activity in normal beta cells. In the betaTC6 line, the enzymatic product, gamma-aminobutyric acid (GABA) was reported to be released under glucose stimulation, thus supporting the concept that GABA transmits a suppressive action of glucose-stimulated beta cells on neighbouring alpha cells. In this study GABA was found to be released from normal rat beta cells. Over 24-h culture periods, the released amounts represented a constant fraction (25% per h) of the cellular GABA content. Cellular GABA content and release were dose-dependently increased by the glutamine concentration in the medium; both values decreased following a sustained (24 h) glucose activation (culture at 10 or 20 mmol/l glucose instead of 3 mmol/l). The variations in the medium GABA content did not parallel the changes in insulin release, indicating that both beta-cell secretory products follow different routes of storage and release. We suggest that beta cells can discharge GABA via exocytosis of microvesicles storing GABA as well as via direct transport from the cytoplasmic pool of newly formed product. Variations in GABA production result in parallel changes in extracellular GABA concentration; the high fractional release of GABA makes it also a likely parameter of the cellular GAD activity. Since chronically elevated glucose levels result in a reduced GABA discharge from the beta cells, it is conceivable that the subsequent decrease in GABA-mediated suppression of the alpha cells is responsible for a higher glucagon release, as observed in diabetes.
Smismans
A
A
Diabetes Research Center, Vrije Universiteit Brussel, Belgium.
Schuit
F
F
Pipeleers
D
D
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003000:Clonidine / Q000494:pharmacology; D003470:Culture Media; D004305:Dose-Response Relationship, Drug; D005968:Glutamate Decarboxylase / Q000378:metabolism; D005973:Glutamine / Q000008:administration & dosage / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology
D003470:Culture Media; D005973:Glutamine; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; D003000:Clonidine; D000109:Acetylcholine; D013755:Tetradecanoylphorbol Acetate