γ-Hydroxybutyrate does not mediate glucose inhibition of glucagon secretion.
(2020) Journal of Biological Chemistry — Vol. 295, n° 16, p. 5419-5426 (2020)
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Helander, Anders 
Tengholm, Anders
- Abstract
- Hypersecretion of glucagon from pancreatic α-cells strongly contributes to diabetic hyperglycemia. Moreover, failure of α-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 α-cell-intrinsic and intraislet paracrine signaling. Among paracrine factors, glucose-stimulated release of the GABA metabolite γ-hydroxybutyric acid (GHB) from pancreatic β-cells might mediate glucose suppression of glucagon release via GHB receptors on α-cells. However, the direct effects of GHB on α-cell signaling and glucagon release have not been investigated. Here, we found that GHB (4-10 μm) lacked effects on the cytoplasmic concentrations of the secretion-regulating messengers Ca and cAMP in mouse α-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.
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Citations
Yu, Q., Lai, B. K., Ahooghalandari, P., Helander, A., Gylfe, E., Gilon, P., & Tengholm, A. (2020). γ-Hydroxybutyrate does not mediate glucose inhibition of glucagon secretion. Journal of Biological Chemistry, 295(16), 5419-5426. https://doi.org/10.1074/jbc.RA119.009577 (Original work published 2020)