title: A bitter pill for type 2 diabetes? The activation of bitter taste receptor TAS2R38 can stimulate GLP-1 release from enteroendocrine L-cells.
abstract: 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.
authors.affiliation: Departments of Biomedical Sciences and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Hung
authors.initials: H
authors.lastname: Pham
authors.affiliation: David Geffen School of Medicine, University of California, Los Angeles, CA, USA; International Center for Metabolic Diseases, Southern Medical University, Guangzhou, China.
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Hui
authors.affiliation: Departments of Biomedical Sciences and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Morvaridi
authors.affiliation: International Center for Metabolic Diseases, Southern Medical University, Guangzhou, China.
authors.forename: Jiena
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Medicinal Chemistry, Xi'an Jiaotong University, 710061, China.
authors.forename: Sanqi
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA, USA; Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, 400030, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, University of California, Los Angeles, CA, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Wu
authors.affiliation: GIRx Metabolics Inc., Los Angeles, CA, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Levin
authors.affiliation: Departments of Biomedical Sciences and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Knudsen
authors.affiliation: Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Goddard
authors.affiliation: Departments of Biomedical Sciences and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Veterans Affairs Greater Los Angeles Healthcare System, University of California, Los Angeles, CA, USA; GIRx Metabolics Inc., Los Angeles, CA, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pandol
authors.affiliation: Departments of Biomedical Sciences and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA, USA; GIRx Metabolics Inc., Los Angeles, CA, USA. Electronic address: abrolr@csmc.edu.
authors.forename: Ravinder
authors.initials: R
authors.lastname: Abrol
mesh_terms: D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D019858:Enteroendocrine Cells / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008297:Male; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000032:analysis / Q000378:metabolism*; D000098706:Taste Receptors, Type 2
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D000098706:Taste Receptors, Type 2; D052216:Glucagon-Like Peptide 1
keywords: Diabetes; Enteroendocrine L-cell; GLP-1; GPCR structure prediction; Gut receptors; Virtual ligand screening