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

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.

Correlation between gut microbiota and glucagon-like peptide-1 in patients with gestational diabetes mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) places both the mother and offspring at high risk of complications. Increasing evidence suggests that the gut microbiota plays a role in the pathogenesis of GDM. However, it is still unclear whether the gut microbiota is related to blood biochemical traits, particularly glucagon-like peptide-1 (GLP-1), in GDM patients. AIM: To explore the correlation between the gut microbiota and blood biochemical traits, particularly GLP-1, in GDM patients. METHODS: The V4 region of the 16S ribosomal ribonucleic acid (rRNA) gene was sequenced based on the fecal samples of 35 pregnant women with GDM and was compared to that of 25 pregnant women with normal glucose tolerance (NGT). RESULTS: The results showed that Ruminococcaceae_UCG-002, Ruminococcaceae_UCG-005, Clostri-dium_sensu_stricto_1, and Streptococcus were more abundant in the NGT group than in the GDM group. Bacteroides and Lachnoclostridium were more abundant in the GDM group than in the NGT group. Spearman's correlation analysis was performed to identify the relationships between microbiota genera and blood biochemical traits. Paraprevotella, Roseburia, Faecalibacterium, and Ruminococcaceae_UCG-002 were significantly negatively correlated with glucose. Ruminococcaceae_UCG-002 was significantly negatively correlated with hemoglobin A1c. Bacteroides was significantly positively correlated with glucose. Sutterella, Oscillibacter, and Bifidobacterium were significantly positively correlated with GLP-1. A random forest model showed that 20 specific genera plus glucose provided the best discriminatory power, as indicated by the area under the receiver operating characteristic curve (0.94). CONCLUSION: The results of this study reveal novel relationships between the gut microbiome, blood bio-chemical traits, particularly GLP-1, and GDM status. These findings suggest that some genera are crucial for controlling blood glucose-related indices and may be beneficial for GDM treatment. Alteration in the microbial composition of the gut may potentially serve as a marker for identifying individuals at risk of GDM.