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. 2022 Sep;179(17):4360-4377.
doi: 10.1111/bph.15860. Epub 2022 May 20.

A GLP-1/glucagon (GCG)/CCK2 receptors tri-agonist provides new therapy for obesity and diabetes

Songfeng Zhao  1 , Zhiming Yan  2 , Yue Du  1 , Zeyun Li  1 , Chunli Tang  3 , Lin Jing  3 , Lidan Sun  4 , Qimeng Yang  4 , Xueling Tang  4 , Yongliang Yuan  1 , Jing Han  4 , Neng Jiang  3
Affiliations
Free article

A GLP-1/glucagon (GCG)/CCK2 receptors tri-agonist provides new therapy for obesity and diabetes

Songfeng Zhao et al. Br J Pharmacol. 2022 Sep.
Free article

Abstract

Background and purpose: Glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptor dual agonist have promising therapeutic effects in the treatment of obesity and diabetes. Moreover, GLP-1 and cholecystokinin 2 (CCK2 ) dual agonists have been shown to restore pancreas function and improve glycaemic control in preclinical studies. We describe, for the first time, the beneficial effects of GLP-1/glucagon receptor and GLP-1/CCK2 dual agonists, which can be integrated into one peptide, resulting in significant anti-diabetes and anti-obesity effectiveness.

Experimental approach: The in vitro potency of this novel peptide Xenopus (x) GLP-1/GCG/CCK2 tri-agonist (xGLP/GCG/gastrin) against GLP-1, GCG, CCK1 and CCK2 receptors 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 this tri-agonist 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-1, GCG and CCK2 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 the peptide ZP3022 (GLP-1/CCK-2 dual agonist) and liraglutide. In a short-term study in db/db mice, xGLP/GCG/gastrin treatment had considerable effects, increasing islet numbers, islet areas and insulin content. In a long-term treatment study using db/db mice, xGLP-1/GCG/gastrin showed a significantly and sustained improvement in glucose tolerance and glucose control compared with that of liraglutide, ZP3022, cotadutide (GLP-1/GCG dual agonist) and xGLP/GCG-15.

Conclusions and implications: These results demonstrate the therapeutic potential of xGLP-1/GCG/gastrin for the treatment of obesity and diabetes.

Keywords: diabetes; gastrin; glucagon; glucagon-like peptide-1; obesity.

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References

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