Diabetologia

, Volume 57, Issue 10, pp 2117–2125

Denatonium induces secretion of glucagon-like peptide-1 through activation of bitter taste receptor pathways

Article

DOI: 10.1007/s00125-014-3326-5

Cite this article as:
Kim, KS., Egan, J.M. & Jang, HJ. Diabetologia (2014) 57: 2117. doi:10.1007/s00125-014-3326-5

Abstract

Aims/hypothesis

This study was designed to ascertain whether human enteroendocrine cells express bitter taste receptors, and whether activation of these receptors with bitter-tasting ligands induces secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY).

Methods

We used human enteroendocrine NCI-H716 cells, isolated duodenal segments from mice, and whole mice as our experimental systems for investigating stimuli and mechanisms underlying GLP-1- and PYY-stimulated release. We measured hormone levels by ELISA and determined bitter taste receptor expression by real-time quantitative PCR. We adopted a pharmacological approach using inhibitors and enhancers of downstream signalling pathways known to be involved in bitter taste transduction in taste bud cells to investigate these pathways in NCI-H716 cells.

Results

Using a pharmacological approach, we identified signalling pathways triggered by the denatonium benzoate (DB)-activated bitter receptors. This involved activation of α-gustducin (Gαgust)—the specific G-protein subunit that is also present in taste bud cells—reduction of intracellular cAMP levels and enhancement of phospholipase C (PLC) activity, which ultimately led to increased intracellular calcium concentrations and hormone release. Gavage of DB, followed by gavage of glucose, to db/db mice stimulated GLP-1 and subsequent insulin secretion, leading to lower blood glucose levels.

Conclusions/interpretation

Our study demonstrates that activation of gut-expressed bitter taste receptors stimulates GLP-1 secretion in a PLC-dependent manner. In diabetic mice, DB (a ligand of bitter taste receptor cells), when given via gavage, lowers blood glucose levels in diabetic mice after oral glucose administration, through increased secretion of GLP-1.

Keywords

Bitter taste receptor GLP-1 Incretin PYY Type 2 diabetes mellitus α-gustducin 

Abbreviations

AC

Adenylyl cyclase

2APB

2-Aminoethoxydiphenyl borate

[Ca2+]i

Intracellular free Ca2+

DAG

Diacylglycerol

DB

Denatonium benzoate

ERK

Extracellular signal-regulated kinase

Gαgust

α-Gustducin

GLP-1

Glucagon-like peptide-1

HBSS

Hanks’ balanced salt solution

IBMX

3-Isobutyl-1-methylxanthine

IP3

Inositol 1,4,5-trisphosphate

PDE

Phosphodiesterase

PKC

Protein kinase C

PLC

Phospholipase C

PMA

Phorbol 12-myristate 13-acetate

PYY

Peptide YY

siRNA

Small interfering RNA

TAS1Rs

Sweet and umami taste receptors

TAS2Rs

Bitter taste receptors

Supplementary material

125_2014_3326_MOESM1_ESM.pdf (77 kb)
ESM Table 1(PDF 76 kb)
125_2014_3326_MOESM2_ESM.pdf (12 kb)
ESM Table 2(PDF 12 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Ki-Suk Kim
    • 1
  • Josephine M. Egan
    • 2
  • Hyeung-Jin Jang
    • 1
  1. 1.Department of Biochemistry, College of Korean MedicineKyung Hee UniversitySeoulRepublic of Korea
  2. 2.National Institute on AgingNational Institutes of HealthBaltimoreUSA