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

Jul 14, 2014Diabetologia

Denatonium triggers release of a digestion hormone by activating bitter taste signals

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Abstract

Activation of gut-expressed bitter taste receptors stimulates GLP-1 secretion in a PLC-dependent manner.

Human enteroendocrine cells express bitter taste receptors.
The bitter ligand denatonium benzoate activates specific signaling pathways associated with these receptors.
Activation leads to reduced levels of a signaling molecule (cAMP) and increased phospholipase C activity.
This sequence of events results in elevated intracellular calcium concentrations and hormone release.
In diabetic mice, gavage of denatonium benzoate followed by glucose intake enhances GLP-1 and insulin secretion, lowering blood glucose levels.

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

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