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• W4225151834 abstract "Background and Purpose Glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) dual agonists have exerted promising therapeutic effects for the treatment of obesity and diabetes in clinical development. Moreover, GLP-1R and cholecystokinin 2 receptor (CCK-2R) dual agonists have been shown to restore pancreas function and improve glycemic control in many preclinical studies. In the present study, we describe for the first time that the beneficial effects of GLP-1R/GCGR and GLP-1R/CCK-2R dual agonists can be integrated into one peptide, resulting in significant anti-diabetes and anti-obesity effectiveness. Experimental Approach The in vitro potency of a novel GLP-1R/GCGR/CCK-2R tri-agonist (xGLP/GCG/gastrin) against GLP-1R, GCGR, CCK-1R and CCK-2R was determined on cells expressing the corresponding receptors by cAMP accumulation or ERK1/2 phosphorylation assays. The in vivo anti-diabetes and anti-obesity effects of xGLP/GCG/gastrin were studied in both db/db and diet induced obesity (DIO) mice. Key Results xGLP/GCG/gastrin was a potent and selective GLP-1R, GCGR, and CCK-2R tri-agonist. In DIO mice, the metabolic benefits of xGLP-1/GCG/gastrin such as reduction of body weight and hepatic lipid contents were significantly better than those of ZP3022 (GLP-1R/CCK-2R dual agonist) and liraglutide. In the short term study in db/db mice, xGLP/GCG/gastrin treatment exerted considerable effects on increasing islet numbers, islet areas, and insulin content. In the long-term treatment study in db/db mice, xGLP-1/GCG/gastrin displayed a significantly sustained improvement in glucose tolerance and glucose control compared with those of liraglutide, ZP3022, cotadutide (GLP-1R/GCGR dual agonist), and xGLP/GCG-15. Conclusions and Implications These results demonstrate the therapeutic promise of xGLP-1/GCG/gastrin for obesity and diabetes." @default.
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• W4225151834 date "2022-05-20" @default.
• W4225151834 modified "2023-10-16" @default.
• W4225151834 title "A GLP‐1/glucagon (GCG)/CCK ₂ receptors tri‐agonist provides new therapy for obesity and diabetes" @default.
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• W4225151834 doi "https://doi.org/10.1111/bph.15860" @default.
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