Regulation of Glucagon Secretion in Normal and Diabetic Human Islets by γ-Hydroxybutyrate and Glycine

Paracrine signaling between pancreatic islet β-cells and α-cells has been proposed to play a role in regulating glucagon responses to elevated glucose and hypoglycemia. To examine this possibility in human islets, we used a metabolomic approach to trace the responses of amino acids and other potenti...

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Veröffentlicht in:The Journal of biological chemistry 2013-02, Vol.288 (6), p.3938-3951
Hauptverfasser: Li, Changhong, Liu, Chengyang, Nissim, Itzhak, Chen, Jie, Chen, Pan, Doliba, Nicolai, Zhang, Tingting, Nissim, Ilana, Daikhin, Yevgeny, Stokes, David, Yudkoff, Marc, Bennett, Michael J., Stanley, Charles A., Matschinsky, Franz M., Naji, Ali
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Sprache:eng
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Zusammenfassung:Paracrine signaling between pancreatic islet β-cells and α-cells has been proposed to play a role in regulating glucagon responses to elevated glucose and hypoglycemia. To examine this possibility in human islets, we used a metabolomic approach to trace the responses of amino acids and other potential neurotransmitters to stimulation with [U-13C]glucose in both normal individuals and type 2 diabetics. Islets from type 2 diabetics uniformly showed decreased glucose stimulation of insulin secretion and respiratory rate but demonstrated two different patterns of glucagon responses to glucose: one group responded normally to suppression of glucagon by glucose, but the second group was non-responsive. The non-responsive group showed evidence of suppressed islet GABA levels and of GABA shunt activity. In further studies with normal human islets, we found that γ-hydroxybutyrate (GHB), a potent inhibitory neurotransmitter, is generated in β-cells by an extension of the GABA shunt during glucose stimulation and interacts with α-cell GHB receptors, thus mediating the suppressive effect of glucose on glucagon release. We also identified glycine, acting via α-cell glycine receptors, as the predominant amino acid stimulator of glucagon release. The results suggest that glycine and GHB provide a counterbalancing receptor-based mechanism for controlling α-cell secretory responses to metabolic fuels. Background: β-Cells regulate α-cells via paracrine mechanisms. Results: A GABA shunt defect impairs glucose suppression of glucagon secretion in diabetic human islets. Glucagon secretion is inhibited by γ-hydroxybutyrate produced by β-cells but is stimulated by glycine via plasma membrane receptors. Conclusion: γ-Hydroxybutyrate and glycine serve as counterbalancing receptor-based regulators of glucagon secretion. Significance: Amino acids and their metabolites are central regulators of α-cell function.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M112.385682