Screening Of Modulators And Inhibitors Of GLP-1 From Natural Products

Glucagon like peptide-1(GLP-1)is mainly secreted by L cells in the colon and ileum,which has the effect of stimulating insulin secretion and stimulating the proliferation of islet beta cells.It has been clinically used for type II diabetes,and its analogues have been marketed as therapeutic drugs,but it is expensive and inconvenient in use.Therefore,searching for small molecule modulators that can significantly enhance GLP-1 has potential social and economic benefits.In this study,a high efficiency,sensitive and visualized in vitro screening system was established by using the GLP1R/U2OS cell line as a model with high content detection equipment.More than 40 kinds of crude extracts and monomeric compounds of traditional Chinese medicines such as Panax notoginseng(Burk.)F.H.Chen,Schefflera arboricola Hayata and Dysosma versipellis Hance M.Cheng ex Ying supplied by the Yunnan Institute of Materia Medica were screened by this system.First total of 165 samples including 124 crude extracts E1-E124 and 41compounds of C1 to C41 were screened.Through the preliminary screening of high content cell imaging system,5 samples with GLP-1 modulators activity were isolated,which were extracts E95 and E99,compound of C1,C18 and C23.Except E99,the R~2 was 66%the others were more than 94%.The minimum effective concentration of each sample is 5.7?g/ml,24?g/ml,11?g/ml,3.9?g/ml and 39?g/ml.Among all samples,total of 26 potential inhibitors were identified,including 18 extracts and 6compounds.The inhibition rate was 19%to 49%,of which E49 inhibition rate reached at 49%.Secondly,the modulator candidates were investigated furtherly.The results showed that the modulator candidates of E95,E99,C1,C18 and C23 have no agonist activity toward GLP-1 receptor alone.The invetigation results showed that E95,E99 and C23 are the modulators of GLP-1,the minimum effective concentration is 13.03?g/ml,49.37?g/ml and 39.06?g/ml,respectively.The optimum concentration is 22.8?g/ml,197.5?g/ml and 39.06?g/ml respectively,and the activity can be increased to 43.4%,42.53%and 31.30%respectively.In conclusion,this study total of 5 GLP-1 candidate modulators have been identifed from 165 natural product samples,and finally confirmed that three could significantly increase the activity of GLP-1,which provided a practical basis for further research and development of new diabetes drugs...