Regulation of glucagon secretion in normal and diabetic human islets by γ-hydroxybutyrate and glycine

J Biol Chem. 2013 Feb 8;288(6):3938-51. doi: 10.1074/jbc.M112.385682. Epub 2012 Dec 24.


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-(13)C]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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / pathology
  • Female
  • Glucagon / metabolism*
  • Glucagon-Secreting Cells / metabolism*
  • Glucagon-Secreting Cells / pathology
  • Glucose / metabolism*
  • Glycine / metabolism*
  • Humans
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Male
  • Middle Aged
  • Receptors, GABA / metabolism
  • Receptors, Glycine / metabolism
  • Sodium Oxybate / metabolism*
  • gamma-Aminobutyric Acid / metabolism


  • Receptors, GABA
  • Receptors, Glycine
  • gamma-Aminobutyric Acid
  • Sodium Oxybate
  • Glucagon
  • Glucose
  • Glycine