title: Regulation of glucagon secretion in normal and diabetic human islets by γ-hydroxybutyrate and glycine.
abstract: 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.
authors.affiliation: Division of Endocrinology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. li@email.chop.edu
authors.forename: Changhong
authors.initials: C
authors.lastname: Li
authors.forename: Chengyang
authors.initials: C
authors.lastname: Liu
authors.forename: Itzhak
authors.initials: I
authors.lastname: Nissim
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Pan
authors.initials: P
authors.lastname: Chen
authors.forename: Nicolai
authors.initials: N
authors.lastname: Doliba
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhang
authors.forename: Ilana
authors.initials: I
authors.lastname: Nissim
authors.forename: Yevgeny
authors.initials: Y
authors.lastname: Daikhin
authors.forename: David
authors.initials: D
authors.lastname: Stokes
authors.forename: Marc
authors.initials: M
authors.lastname: Yudkoff
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bennett
authors.forename: Charles A
authors.initials: CA
authors.lastname: Stanley
authors.forename: Franz M
authors.initials: FM
authors.lastname: Matschinsky
authors.forename: Ali
authors.initials: A
authors.lastname: Naji
mesh_terms: D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000378:metabolism*; D005998:Glycine / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018079:Receptors, GABA / Q000378:metabolism; D018009:Receptors, Glycine / Q000378:metabolism; D012978:Sodium Oxybate / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018079:Receptors, GABA; D018009:Receptors, Glycine; D005680:gamma-Aminobutyric Acid; D012978:Sodium Oxybate; D005934:Glucagon; D005947:Glucose; D005998:Glycine