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Glucagon-like peptide-1 stimulates GABA formation by pancreatic -cells at the level of glutamate decarboxylase

Diabetes Research Center, Brussels Free University-VUB, and Juvenile Diabetes Research Foundation Center for -Cell Therapy in Diabetes, Brussels, Belgium

Submitted 31 August 2006 ; accepted in final form 19 December 2006

Pancreatic -cells are the major extraneural site of glutamate decarboxylase expression (GAD). During culture of isolated -cells, the GAD product -aminobutyrate (GABA) is rapidly released in the medium, independently of insulin. It is considered as a possible mediator of -cell influences on -cells, acinar cells, and/or infiltrating lymphocytes. In this perspective, we investigated the regulation of GABA release by rat -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 -vinyl-GABA. The stimulatory action of GLP-1 is cAMP dependent, being reproduced by the adenylate cyclase activator forskolin and the cAMP analog N⁶-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 -cells can elevate medium GABA levels in conditions of glucose-driven intracellular GABA breakdown and thus maintain GABA-mediated -cell influences on neighboring cells.

forskolin; -aminobutyric acid; cyclic adenosine 3',5'-monophosphate