Correlation between GABA release from rat islet beta-cells and their metabolic state.
Pancreatic beta-cells express glutamate decarboxylase (GAD), which is responsible for the production and release of gamma-aminobutyric acid (GABA). Over a 24-h culture period, total GABA release by purified rat beta-cells is eightfold higher than the cellular GABA content and can thus be used as an index of cellular GAD activity. GABA release is 40% reduced by glucose (58 pmol/10(3) cells at 10 mM glucose vs. 94 pmol at 3 mM glucose, P < 0.05). This suppressive effect of glucose was not observed when glucose metabolism was blocked by mannoheptulose or 2,4-dinitrophenol; it was amplified when ATP-dependent beta-cell activities were inhibited by addition of diazoxide, verapamil, or cycloheximide or by reduction of extracellular calcium levels; it was counteracted when beta-cell functions were activated by nonmetabolized agents, such as glibenclamide, IBMX, glucagon, or glucacon-like peptide-1 (GLP-1), which are known to stimulate calcium-dependent activities, such as hormone release and calcium-dependent ATPases. These observations suggest that GABA release from beta-cells varies with the balance between ATP-producing and ATP-consuming activities in the cells. Less GABA is released in conditions of elevated glucose metabolism, and hence ATP production, but this effect is counteracted by ATP-dependent activities. The notion that increased cytoplasmic ATP levels can suppress GAD activity in beta-cells, and hence GABA production and release, is compatible with previous findings on ATP suppression of brain GAD activity.
Winnock
Frederic
F
Diabetes Research Center, Vrije Universiteit Brussel, B-1090 Brussels, Belgium.
Ling
Zhidong
Z
De Proft
Rene
R
Dejonghe
Sandra
S
Schuit
Frans
F
Gorus
Frans
F
Pipeleers
Daniel
D
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D019297:2,4-Dinitrophenol / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000737:chemistry; D003513:Cycloheximide / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000032:analysis / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008356:Mannoheptulose / Q000494:pharmacology; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014700:Verapamil / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000032:analysis / Q000378:metabolism*
D017077:Culture Media, Conditioned; D010446:Peptide Fragments; D011498:Protein Precursors; D005680:gamma-Aminobutyric Acid; D008356:Mannoheptulose; D052216:Glucagon-Like Peptide 1; D000255:Adenosine Triphosphate; D005934:Glucagon; D003513:Cycloheximide; D014700:Verapamil; D005968:Glutamate Decarboxylase; D005947:Glucose; D003981:Diazoxide; D019297:2,4-Dinitrophenol; D005905:Glyburide; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine