GLP-1R mediates idebenone-reduced blood glucose in mice.

GLP-1 receptor agonists (GLP-1RAs) are an innovative class of drugs with significant therapeutic value for type 2 diabetes mellitus (T2DM). The GLP-1RAs currently available on the market are biologic macromolecular peptide agents that are expensive to treat and not easy to take orally. Therefore, the development of small molecule GLP-1RAs is becoming one of the most sought-after research targets for hypoglycemic drugs. In this study, we sought to find a potential oral small molecule GLP-1RA and to evaluate its effect on insulin secretion in rat pancreatic β cells and on blood glucose in mice. We downloaded the mRNA expression profiles of GSE102194 and GSE37936 from the Gene Expression Omnibus database. Subsequently, the small molecule compound idebenone was screened through the connectivity map database. The results of molecular docking, biolayer interferometry, and cellular thermal shift assay indicated that idebenone could bind potently with GLP-1R. Furthermore, ibebenone elevated intracellular cAMP levels. The radioimmunoassay data showed that idebenone enhanced glucose-stimulated insulin secretion via agonism of GLP-1R. Moreover, the results of oral glucose tolerance tests in C57BL/6, Glp-1r, and hGlp-1r mice demonstrated that the glucose-lowering effects of idebenone were mediated by GLP-1R and that there were no species differences in the agonistic effect of idebenone on GLP-1R. In summary, idebenone reduces blood glucose in mice by promoting insulin release through agonism of GLP-1R, suggesting that idebenone is probably a potential GLP-1RA, which is expected to provide a new therapeutic strategy for the prevention and treatment of metabolic diseases such as T2DM.