Denatonium induces secretion of glucagon-like peptide-1 through activation of bitter taste receptor pathways
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- Kim, KS., Egan, J.M. & Jang, HJ. Diabetologia (2014) 57: 2117. doi:10.1007/s00125-014-3326-5
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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).
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.
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.
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.
KeywordsBitter taste receptor GLP-1 Incretin PYY Type 2 diabetes mellitus α-gustducin
Intracellular free Ca2+
Extracellular signal-regulated kinase
Hanks’ balanced salt solution
Protein kinase C
Phorbol 12-myristate 13-acetate
Small interfering RNA
Sweet and umami taste receptors
Bitter taste receptors