title: A Glycine-Insulin Autocrine Feedback Loop Enhances Insulin Secretion From Human β-Cells and Is Impaired in Type 2 Diabetes.
abstract: The secretion of insulin from pancreatic islet β-cells is critical for glucose homeostasis. Disrupted insulin secretion underlies almost all forms of diabetes, including the most common form, type 2 diabetes (T2D). The control of insulin secretion is complex and affected by circulating nutrients, neuronal inputs, and local signaling. In the current study, we examined the contribution of glycine, an amino acid and neurotransmitter that activates ligand-gated Cl(-) currents, to insulin secretion from islets of human donors with and without T2D. We find that human islet β-cells express glycine receptors (GlyR), notably the GlyRα1 subunit, and the glycine transporter (GlyT) isoforms GlyT1 and GlyT2. β-Cells exhibit significant glycine-induced Cl(-) currents that promote membrane depolarization, Ca(2+) entry, and insulin secretion from β-cells from donors without T2D. However, GlyRα1 expression and glycine-induced currents are reduced in β-cells from donors with T2D. Glycine is actively cleared by the GlyT expressed within β-cells, which store and release glycine that acts in an autocrine manner. Finally, a significant positive relationship exists between insulin and GlyR, because insulin enhances the glycine-activated current in a phosphoinositide 3-kinase-dependent manner, a positive feedback loop that we find is completely lost in β-cells from donors with T2D.
authors.affiliation: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Yan-Do
authors.affiliation: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Duong
authors.affiliation: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jocelyn E
authors.initials: JE
authors.lastname: Manning Fox
authors.affiliation: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Dai
authors.affiliation: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Kunimasa
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Shara
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Austin
authors.initials: A
authors.lastname: Bautista
authors.affiliation: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Mourad
authors.initials: M
authors.lastname: Ferdaoussi
authors.affiliation: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Lyon
authors.affiliation: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Xichen
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Cheley
authors.affiliation: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada pmacdonald@ualberta.ca.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: MacDonald
authors.affiliation: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Matthias
authors.initials: M
authors.lastname: Braun
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology; D004594:Electrophysiology; D005998:Glycine / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018009:Receptors, Glycine / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D007328:Insulin; D018009:Receptors, Glycine; D002118:Calcium; D005998:Glycine