Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 179, Issue 17, Pages 4360-4377Publisher
WILEY
DOI: 10.1111/bph.15860
Keywords
diabetes; gastrin; glucagon; glucagon-like peptide-1; obesity
Categories
Funding
- National Natural Science Foundation of China [31600265, 82173663, 31970371, 81903874]
- Open Project Program of Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University [GKLBCN202106-03]
- Basic Public Welfare Research Project of Zhejiang Province [LGD19H070002]
- Youth Foundation of Guangxi Medical University [GXMUYSF202105]
- Guangxi Science and Technology Base and Talent Special Project [AD21220076]
- Guangxi Postdoctoral Research Fund
- Guangxi Medical University Training Program for Distinguished Young Scholars
- Guangxi Science Fund for Distinguished Young Scholars [2022GXNSFFA035030]
- Special Funds for Science and Technology Development under the Guidance of the Central Government [ZY20198020]
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This study demonstrates the therapeutic potential of dual agonists targeting GLP-1/glucagon and GLP-1/CCK2 receptors in the treatment of obesity and diabetes. The newly developed peptide, xGLP-1/GCG/gastrin, showed significant anti-diabetes and anti-obesity effects in both in vitro and in vivo experiments.
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.
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