Zinc-induced activation of GPR39 regulates glucose homeostasis through glucose-dependent insulinotropic polypeptide secretion from enteroendocrine K-cells.

Brian Moran, Michael Miskelly, Yasser Abdel-Wahab, PR Flatt, Aine McKillop

Research output: Contribution to journalArticle

2 Citations (Scopus)
32 Downloads (Pure)

Abstract

The role of Zn2+-sensing receptor GPR39 on glucose homeostasis and incretin regulation was assessed in enteroendocrine L- and K-cells. Anti-hyperglycaemic, insulinotropic and incretin secreting properties of Zn2+ were explored in normal, diabetic and incretin receptor knockout mice. Compared to intraperitoneal injection, oral administration of Zn2+ (50 μmol/kg body weight) with glucose (18 mmol/kg) in lean mice reduced the glycaemic excursion by 25-34% (p < 0.05-p < 0.001) and enhanced glucose-induced insulin release by 46-48% (p < 0.05-p < 0.01). In diabetic mice, orally administered Zn2+ lowered glucose by 24-31% (p < 0.01) and augmented insulin release by 32% (p < 0.01). In glucagon like peptide-1 (GLP-1) receptor knockout mice, Zn2+ reduced glucose by 15-28% (p < 0.05-p < 0.01) and increased insulin release by 35-43% (p < 0.01). In contrast Zn2+ had no effect on responses of glucose-dependent insulinotropic polypeptide (GIP) receptor knockout mice. Consistent with this, Zn2+ had no effect on circulating total GLP-1 whereas GIP release was stimulated by 26% (p < 0.05) in lean mice. Immunocytochemistry demonstrated GPR39 expression on mouse enteroendocrine L- and K-cells, GLUTag cells and pGIP/Neo STC-1 cells. Zn2+ had a direct effect on GIP secretion from pGIPneo STC-1 cells, increasing GIP secretion by 1.3-fold. GPR39 is expressed on intestinal L- and K-cells, and stimulated GIP secretion plays an integral role in mediating enhanced insulin secretion and glucose tolerance following oral administration of Zn2+. This suggests development of potent and selective GPR39 agonists as a therapeutic approach for diabetes.
Original languageEnglish
Pages (from-to)1023-1033
Number of pages11
JournalBiological Chemistry
Volume400
Issue number8
Early online date9 Feb 2019
DOIs
Publication statusE-pub ahead of print - 9 Feb 2019

Keywords

  • G-protein coupled receptors
  • zinc
  • gip
  • glp-1
  • Incretin secretion
  • glucose homeostasis
  • GLP-1
  • incretin secretion
  • GIP

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