βHB inhibits glucose-induced GLP-1 secretion in GLUTag and human jejunal enteroids

Ingestion of nutrients stimulates incretin secretion from enteroendocrine cells (EECs) of the epithelial layer of the gut. Glucagon-like peptide-1 (GLP-1) is one of these incretins that stimulate postprandial insulin release and signal satiety to the brain. Understanding the regulation of incretin secretion might open up new therapeutic options for obesity and type-2 diabetes mellitus. To investigate the inhibitory effect of the ketone body beta-hydroxybutyrate (beta HB) on glucose-induced GLP-1 secretion from EECs, in vitro cultures of murine GLUTag cells and differentiated human jejunal enteroid monolayers were stimulated with glucose to induce GLP-1 secretion. The effect of beta HB on GLP-1 secretion was studied using ELISA and ECLIA methods. GLUTag cells stimulated with glucose and beta HB were analysed using global proteomics focusing on cellular signalling pathways and the results were verified by Western blot. Results demonstrated beta HB had a significant inhibitory effect on glucose-induced GLP-1 secretion at a dose of 100 mM in GLUTag cells. In differentiated human jejunal enteroid monolayers, glucose-induced secretion of GLP-1 was inhibited at a much lower dose of 10 mM beta HB. The addition of beta HB to GLUTag cells resulted in decreased phosphorylation of kinase AKT and transcription factor STAT3 and also influenced the expressions of signalling molecule IRS-2, kinase DGKe and receptor FFAR3. In conclusion, beta HB displays an inhibitory effect on glucose-induced GLP-1 secretion in vitro in GLUTag cells and in differentiated human jejunal enteroid monolayers. This effect may be mediated through multiple downstream mediators of G-protein coupled receptor activation, such as PI3K signalling.

Automated summary

Ingestion of nutrients stimulates the secretion of incretins, such as GLP-1, which regulate postprandial insulin release and satiety. This study investigated the inhibitory effect of beta HB on glucose-induced GLP-1 secretion using cell cultures. The results showed that beta HB significantly inhibited GLP-1 secretion in both murine GLUTag cells and differentiated human jejunal enteroid monolayers. The findings suggest that beta HB may act through multiple downstream mediators to regulate GLP-1 secretion.