Human GLP1R Stable Cell Line - HEK293

The incidence of diabetic cognitive impairment is increasing year by year and is gradually becoming a research hotspot. Studies have shown that glucagon-like peptide-1 receptor (GLP-1R) agonists can improve cognitive impairment in diabetic patients. Here, researchers explored whether small molecule GLP-1R agonists derived from traditional Chinese medicine could improve diabetic cognitive impairment. The study found that mollugin can bind to GLP-1R, promote Ca²⁺ influx in β-TC-6 cells, and increase insulin secretion and cAMP content. Mollugin also enhanced the viability of PC12 cells, reduced apoptosis, and lowered reactive oxygen species (ROS) levels in high glucose (HG)/hydrogen peroxide (H₂O₂)-damaged PC12 cells. Furthermore, mollugin shortened the escape latency in type 2 diabetic mice, improved neuronal damage, and reduced the expression of Pik3ca, Akt1, and Mapk1 mRNA in brain cortical tissue. These results suggest that mollugin may improve cognitive impairment in type 2 diabetic mice by activating the GLP-1R/cAMP/PKA signaling pathway.

Previous studies suggested that small molecules might have an affinity for GLP-1R, but it was not yet determined whether they were agonists or antagonists. To further confirm whether these small molecules could activate GLP-1R, researchers used calcium imaging technology to detect the effect of these small molecules on intracellular Ca2+ concentration in GLP1R Stable Cell Line - HEK293 (GLP-1R-HEK293) cells. Ca2+, as a second messenger, can reflect the binding of extracellular signals to cell surface receptors. The study showed that nobiletin, isosinensetin and mollugin can significantly promote calcium influx in GLP-1R-HEK293 cells (Figure 1A–G). To further determine the effect of these small molecules on GLP-1R, researchers measured their effect on insulin secretion in β cells. As shown in Figure 1H, these small molecules in 10 μM could promote insulin secretion by β cells in the presence of 1.38 mM glucose, as the positive drug liraglutide did, and the stimulatory effect of mollugin was the most significant. These preliminary results suggest that mollugin, isosinensetin and nobiletin may be GLP-1R agonists.

Figure 1. Calcium imaging of small molecules on GLP-1R-HEK293 cells. (Wang Z, et al., 2023)