Glucagon-like peptide-1 stimulates GABA formation by pancreatic beta-cells at the level of glutamate decarboxylase.
Pancreatic beta-cells are the major extraneural site of glutamate decarboxylase expression (GAD). During culture of isolated beta-cells, the GAD product gamma-aminobutyrate (GABA) is rapidly released in the medium, independently of insulin. It is considered as a possible mediator of beta-cell influences on alpha-cells, acinar cells, and/or infiltrating lymphocytes. In this perspective, we investigated the regulation of GABA release by rat beta-cells during a 24-h culture period. Glucose was previously reported to inhibit GABA release by diverting cellular GABA to mitochondrial breakdown through activation of GABA transferase (GABA-T). In the present study, glucagon-like peptide-1 (GLP-1) was shown to stimulate GABA formation at the level of GAD, its effect being suppressed by the GAD inhibitor allylglycine and remaining unaltered by the GABA-T inhibitor gamma-vinyl-GABA. The stimulatory action of GLP-1 is cAMP dependent, being reproduced by the adenylate cyclase activator forskolin and the cAMP analog N(6)-benzoyladenosine-3',5'-cAMP and inhibited by a PKA inhibitor. It is dependent on protein synthesis and associated with an increased expression of GAD67 but not GAD65. The GLP-1-induced stimulation of GAD activity in beta-cells can elevate medium GABA levels in conditions of glucose-driven intracellular GABA breakdown and thus maintain GABA-mediated beta-cell influences on neighboring cells.
Wang
Chen
C
Diabetes Research Center, Brussels Free University-VUB, Laarbeeklaan 103, B-1090 Brussels, Belgium.
Mao
Rui
R
Van de Casteele
Mark
M
Pipeleers
Daniel
D
Ling
Zhidong
Z
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000201:enzymology / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis*
D007527:Isoenzymes; D005576:Colforsin; D005680:gamma-Aminobutyric Acid; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D000262:Adenylyl Cyclases; D002118:Calcium