γ-Hydroxybutyrate does not mediate glucose inhibition of glucagon secretion

Hypersecretion of glucagon from pancreatic alpha-cells strongly contributes to diabetic hyperglycemia. Moreover, failure of alpha-cells to increase glucagon secretion in response to falling blood glucose concentrations compromises the defense against hypoglycemia, a common complication in diabetes therapy. However, the mechanisms underlying glucose regulation of glucagon secretion are poorly understood and likely involve both alpha-cell-intrinsic and intra-islet paracrine signaling. Among paracrine factors, glucose-stimulated release of the GABA metabolite gamma-hydroxybutyric acid (GHB) from pancreatic beta-cells might mediate glucose suppression of glucagon release via GHB receptors on alpha-cells. However, the direct effects of GHB on alpha-cell signaling and glucagon release have not been investigated. Here, we found that GHB (4-10 muM) lacked effects on the cytoplasmic concentrations of the secretion-regulating messengers Ca(2+) and cAMP in mouse alpha-cells. Glucagon secretion from perifused mouse islets was also unaffected by GHB at both 1 and 7 mM glucose. The GHB receptor agonist 3-chloropropanoic acid and the antagonist NCS-382 had no effects on glucagon secretion and did not affect stimulation of secretion induced by a drop in glucose from 7 to 1 mM. Inhibition of endogenous GHB formation with the GABA transaminase inhibitor vigabatrin also failed to influence glucagon secretion at 1 mM glucose and did not prevent the suppressive effect of 7 mM glucose. In human islets, GHB tended to stimulate glucagon secretion at 1 mM glucose, an effect mimicked by 3-chloropropanoic acid. We conclude that GHB does not mediate the inhibitory effect of glucose on glucagon secretion.