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

ABSTRACT: Paracrine signaling between pancreatic islet ?-cells and ?-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 ?-hydroxybutyrate (GHB), a potent inhibitory neurotransmitter, is generated in ?-cells by an extension of the GABA shunt during glucose stimulation and interacts with ?-cell GHB receptors, thus mediating the suppressive effect of glucose on glucagon release. We also identified glycine, acting via ?-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 ?-cell secretory responses to metabolic fuels.

SUBMITTER: Li C 

PROVIDER: S-EPMC3567647 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature