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

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An Erratum to this article was published on 26 August 2014

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.

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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

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Acknowledgements

This research was supported by Kyung Hee University (KHU-20130547) and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012-0005755 and NRF-2013R1A1A2004960). Some of the data in this paper were presented as a poster abstract at the Fourth International Congress on Prediabetes and Metabolic Syndrome in 2011.

Funding

This work was supported by the Intramural Research Program of the National Institute on Aging/National Institutes of Health and by National Institute on Deafness and Other Communication Disorders/National Institutes of Health (grants DC003055).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

H-JJ designed the study, performed in vitro experiments, analysed the data, and wrote the manuscript. K-SK performed in vivo experiments, analysed and interpreted the data and wrote the manuscript. JME designed the study. All authors contributed to critical revision of the manuscript and approved the final version. H-JJ is the guarantor of this work.

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Correspondence to Hyeung-Jin Jang.

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Kim, KS., Egan, J.M. & Jang, HJ. Denatonium induces secretion of glucagon-like peptide-1 through activation of bitter taste receptor pathways. Diabetologia 57, 2117–2125 (2014). https://doi.org/10.1007/s00125-014-3326-5

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