Article

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

The Children's Hospital of Philadelphia, United States
Journal of Biological Chemistry (Impact Factor: 4.6). 12/2012; DOI: 10.1074/jbc.M112.385682
Source: PubMed

ABSTRACT Paracrine signaling between pancreatic islet beta-cells and alpha-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 employed a metabolomic approach to trace the responses of amino acids and other potential neurotransmitters to stimulation with [U-13C]glucose in both normals 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 gamma-hydroxybutyrate (GHB), a potent inhibitory neurotransmitter, is generated in beta-cells by an extension of the GABA shunt during glucose stimulation and interacts with alpha-cell GHB receptors, thus, mediating the suppressive effect of glucose on glucagon release. We also identified glycine, acting via alpha-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 alpha-cell secretory responses to metabolic fuels.

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