Sphinganine as a novel stimulator of GLP-1 secretion

Abstract Aims/hypothesis Mechanisms of secretion of the gut hormone glucagon-like peptide-1 (GLP-1) remain incompletely understood yet are relevant for the pathophysiology and treatment of obesity and diabetes. Here, we set out to identify novel triggers. Methods We started with using metabolomics on plasma samples from meal tests in adults, where we identified sphinganine, a sphingolipid, as the strongest predictor of a high GLP-1 response. Sphinganine was next tested in vitro (in GLUTag and NCI-H716 cell lines and human intestinal organoids), ex vivo (in isolated rat intestinal and colon perfusion models) and in vivo (using both single acute administration and prolonged feeding in mice). Results Sphinganine doubled GLP-1 secretion in vitro in multiple cell lines and human intestinal organoids, via G-protein-coupled receptor 40-mediated mechanisms. In isolated intestinal perfusion model in rats, sphinganine increased GLP-1 during luminal administration. However, this effect was only statistically significant in male rats. In vivo, oral administration of sphinganine to mice did not increase GLP-1 acutely or after prolonged feeding. In the prolonged-feeding model, however, it did reduce high-fat-diet-induced weight gain, without changing food intake. Conclusions/interpretation Our data indicate beneficial metabolic effects of sphingolipids and points towards potential therapeutic effects to be explored.