Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino acid peptide hormone produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption. GLP-1 can act as an enteroglucagon in addition to a glucose-dependent insulinotropic peptide (GIP). It has the ability to lower blood glucose levels in a glucose-dependent manner by enhancing insulin secretion.

Glucagon receptor (GCGR) is a 62 kDa protein activated by glucagon and is a member of the class B G protein-coupled receptor family. In humans, the glucagon receptor is encoded by the GCGR gene. GCGR binds to the signaling molecule glucagon, leading to the activation of acetylate cyclase. So that it initiates a signal transduction pathway that generates cAMP. An increase in intracellular secondary messengers cAMP and calcium levels leads to protein kinase A-dependent activation. At the same time, the GCGR can bind to the ligand and initiate the activation of phospholipase C.

Cotadutide is a potent GLP-1 and GCGR dual agonist.

From: Boland ML, Rhodes CJ, et al. Nat Metab. 2020 May;2(5):413-431.

Cotadutide (MEDI0382) is a potent dual agonist of glucagon-like peptide-1 (GLP-1) and GCGR with EC₅₀ values of 6.9 pM and 10.2 pM, respectively, in CHO cells over-expressing human recombinant GLP-1 or glucagon receptors. In vitro experiments, Cotadutide stimulates a concentration-dependent increase in cAMP accumulation in the rat (INS-1 832/3) and human (EndoC-βH1) β-cell lines with EC₅₀ values of  226 pM and 1051 pM, respectively. Besides, it stimulates rat, mouse and human hepatocytes with EC₅₀ values of 462 pM, 840 pM, 1447 pM, respectively. Also, Cotadutide potentiates glucose-stimulated insulin secretion in the rat (INS-1 832/3) pancreatic β‐cell line and increases glucose output in rat hepatocytes. Moreover, it (100 nM, 2 h) induces mitochondrial turnover and enhances mitochondrial function in mouse primary hepatocytes.

In the diet-induced obesity (DIO) mice model, Cotadutide (10 nmol/kg, s.c., once) can suppress food intake. Besides, Cotadutide (10 or 30 nmol/kg, s.c., once daily for 14-16 weeks) reduces body weight and food intake and improves glucose tolerance in DIO mice. Importantly, it also can reduce hepatic fibrosis and inflammation at 30 nmol/kg for 6 weeks in ob/ob AMLN NASH mice.

In conclusion, it is a potent GLP-1 and GCGR dual agonist for the study of obesity and type 2 diabetes (T2D).

References:

[1] S J Henderson, et al. Diabetes Obes Metab. 2016 Dec;18(12):1176-1190. 

[2] Michelle L Boland, et al. Nat Metab. 2020 May;2(5):413-431.