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

Apr 29, 2022British journal of pharmacology

A combined GLP-1, glucagon, and CCK2 receptor drug as a new treatment for obesity and diabetes

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Abstract

xGLP/GCG/gastrin significantly improved metabolic outcomes in mice models of obesity and diabetes.

xGLP/GCG/gastrin was identified as a potent and selective tri-agonist for GLP-1, glucagon, and cholecystokinin receptors.
In diet-induced obesity mice, xGLP/GCG/gastrin outperformed the dual agonist ZP3022 and liraglutide in reducing body weight and liver fat.
Short-term treatment with xGLP/GCG/gastrin in db/db mice increased the number and size of insulin-producing islets and boosted insulin levels.
Long-term treatment in db/db mice showed xGLP/GCG/gastrin led to significantly better glucose tolerance and control compared to liraglutide and other dual agonists.

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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 (CCK) 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/CCKdual agonists, which can be integrated into one peptide, resulting in significant anti-diabetes and anti-obesity effectiveness. 2 2

EXPERIMENTAL APPROACH: The in vitro potency of this novel peptide Xenopus (x) GLP-1/GCG/CCKtri-agonist (xGLP/GCG/gastrin) against GLP-1, GCG, CCKand CCKreceptors 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. 2 1 2

KEY RESULTS: xGLP/GCG/gastrin was a potent and selective GLP-1, GCG and CCKtri-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. 2

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

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