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A bitter pill for type 2 diabetes? The activation of bitter taste receptor TAS2R38 can stimulate GLP-1 release from enteroendocrine L-cells

Pham, Hung and Hui, Hongxiang and Morvaridi, Susan and Cai, Jiena and Zhang, Sanqi and Tan, Jun and Wu, Vincent and Levin, Nancy and Knudsen, Beatrice and Goddard, William A., III and Pandol, Stephen J. and Abrol, Ravinder (2016) A bitter pill for type 2 diabetes? The activation of bitter taste receptor TAS2R38 can stimulate GLP-1 release from enteroendocrine L-cells. Biochemical and Biophysical Research Communications, 475 (3). pp. 295-300. ISSN 0006-291X. PMCID PMC4918516.

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The bitter taste receptor TAS2R38 is a G protein coupled receptor (GPCR) that has been found in many extra-oral locations like the gastrointestinal (GI) system, respiratory system, and brain, though its function at these locations is only beginning to be understood. To probe the receptor’s potential metabolic role, immunohistochemistry of human ileum tissues was performed, which showed that the receptor was co-localized with glucagon-like peptide 1 (GLP-1) in L-cells. In a previous study, we had modeled the structure of this receptor for its many taste-variant haplotypes (Tan et al. 2011), including the taster haplotype PAV. The structure of this haplotype was then used in a virtual ligand screening pipeline using a collection of ∼2.5 million purchasable molecules from the ZINC database. Three compounds (Z7, Z3, Z1) were purchased from the top hits and tested along with PTU (known TAS2R38 agonist) in in vitro and in vivo assays. The dose-response study of the effect of PTU and Z7 on GLP-1 release using wild-type and TAS2R38 knockout HuTu-80 cells showed that the receptor TAS2R38 plays a major role in GLP-1 release due to these molecules. In vivo studies of PTU and the three compounds showed that they each increase GLP-1 release. PTU was also chemical linked to cellulose to slow its absorption and when tested in vivo, it showed an enhanced and prolonged GLP-1 release. These results suggest that the GI lumen location of TAS2R38 on the L-cell makes it a relatively safe drug target as systemic absorption is not needed for a TAS2R38 agonist drug to effect GLP-1 release.

Item Type:Article
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URLURL TypeDescription CentralArticle
Goddard, William A., III0000-0003-0097-5716
Abrol, Ravinder0000-0001-7333-6793
Additional Information:© 2016 Elsevier. Received 23 April 2016, Accepted 28 April 2016, Available online 18 May 2016. RA acknowledges support in part from Materials and Process Simulation Center at Caltech when this project started and from start-up funds provided by Cedars-Sinai Medical Center. SJP acknowledges partial support for this project from NIHP01CA163200 and the Department of Veterans Affairs.
Funding AgencyGrant Number
Cedars-Sinai Medical CenterUNSPECIFIED
Department of Veterans AffairsUNSPECIFIED
Subject Keywords:GLP-1; Diabetes; Enteroendocrine L-cell; GPCR structure prediction; Virtual ligand screening; Gut receptors
Issue or Number:3
PubMed Central ID:PMC4918516
Record Number:CaltechAUTHORS:20160602-161244457
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Official Citation:Hung Pham, Hongxiang Hui, Susan Morvaridi, Jiena Cai, Sanqi Zhang, Jun Tan, Vincent Wu, Nancy Levin, Beatrice Knudsen, William A. Goddard III, Stephen J. Pandol, Ravinder Abrol, A bitter pill for type 2 diabetes? The activation of bitter taste receptor TAS2R38 can stimulate GLP-1 release from enteroendocrine L-cells, Biochemical and Biophysical Research Communications, Volume 475, Issue 3, 1 July 2016, Pages 295-300, ISSN 0006-291X, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:67597
Deposited By: George Porter
Deposited On:03 Jun 2016 14:34
Last Modified:03 Oct 2019 10:07

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