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.

Role of Intestinal Bitter Sensing in Enteroendocrine Hormone Secretion and Metabolic Control

“…Consistent with the role of BTR signaling in GLP-1 secretion, the effect of DB to slow gastric emptying was abolished by co-administration of probenecid ( 26 ). Similarly, intragastric administration of PTC has been reported to augment plasma GLP-1 concentrations ( 36 ) and slow gastric emptying ( 26 ) in mice. The latter effect was, however, not inhibited by probenecid ( 26 ).…”

“…Consistent with PCR observation, studies using double-labeling immunofluorescence have also shown co-localization of chromogranin A (a cellular marker of enteroendocrine cells) with T2Rs in the mouse small and large intestine ( 42 , 44 ). More specifically, co-expression of GLP-1 with various T2Rs in human enteroendocrine L cell lines (i.e., HuTu-80 and NCI-h716) and in small and large intestinal tissues has been observed ( 21 , 35 , 36 , 39 ). However, the co-expression of T2Rs with enteroendocrine cells containing other hormones is not well characterized in rodents or humans.…”

“…For example, in both NCI-716 and STC-1 cells, berberine, a natural bitter plant alkaloid commonly used as an antibiotic, was shown to dose-dependently stimulate GLP-1 secretion via T2R38 ( 24 , 25 ). Similarly, a specific T2R38 agonist, phenylthiourea, induced GLP-1 secretion from HuTu-80 cells, an effect markedly inhibited by silencing of T2R38 with small interfering RNA ( 36 ), In contrast, 1,10-phenanthroline stimulates GLP-1 via T2R5 ( 39 ), and DB appears to induce GLP-1 secretion via a broad range of BTRs (including T2R4, T2R43, and T2R46 at least), in NCI-h716 cells ( 21 ). Furthermore, blockade of BTRs (e.g., by probenecid), or the downstream pathways relating to BTR signaling, including inositol 1,4,5-trisphophate, phospholipase C β 2 , protein kinase C and/or phosphodiesterase, attenuates GLP-1 secretion induced by bitter tastants ( 21 , 58 , 59 ).…”

“…In rodents, exposure of the gut to BTR agonists has also been shown to augment plasma GLP-1 levels ( 21 , 36 , 58 , 59 ). In acute settings, an intragastric preload of DB prior to enteral glucose administration increased plasma GLP-1 and insulin concentrations ( 21 ), slowed gastric emptying ( 26 , 65 ) and reduced blood glucose ( 21 ).…”

Effect of food ingredients on glucagon‐like peptide‐1 secretion in STC‐1 and HuTu‐80 cells

“…STC-1 is originated from mouse duodenal tumours, while HuTu-80 is originated from a human duodenal adenocarcinoma. Both STC-1 and HuTu-80 cells are able to secrete GLP-1 upon nutrient stimulation, and are often used as cell models for studying GLP-1 secretion (Geraedts et al, 2011;Pham et al, 2016). However, GLP-1 secretion is not always similar among species (Kuhre et al, 2014) and cell lines (Kuhre et al, 2016).…”