Abstract：
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.
摘要：
GLP-1受体激动剂(GLP-1RAs)是一类对2型糖尿病(T2DM)具有重要治疗价值的创新药物。目前市场上可获得的GLP-1RA是生物大分子肽试剂,其治疗昂贵且不容易口服。因此,小分子GLP-1RAs的开发正成为最受欢迎的降血糖药物研究靶点之一。在这项研究中,我们试图找到一种潜在的口服小分子GLP-1RA,并评估其对大鼠胰腺β细胞胰岛素分泌和小鼠血糖的影响.我们从基因表达综合数据库下载了GSE102194和GSE37936的mRNA表达谱。随后，通过连接图数据库筛选小分子化合物艾地苯醌。分子对接的结果，生物层干涉法,细胞热转移实验表明，艾地苯醌可以与GLP-1R有效结合。此外，ibebenone升高细胞内cAMP水平。放射免疫分析数据显示，艾地苯醌通过GLP-1R的激动作用增强了葡萄糖刺激的胰岛素分泌。此外，C57BL/6，Glp-1r-/-，和hGlp-1r小鼠证明艾地苯醌的降糖作用是由GLP-1R介导的，而艾地苯醌对GLP-1R的激动作用没有物种差异。总之,艾地苯醌通过GLP-1R的激动作用促进胰岛素释放，从而降低小鼠的血糖，表明艾地苯醌可能是一种潜在的GLP-1RA，有望为T2DM等代谢性疾病的防治提供新的治疗策略。
