A recent publication in Nature Metabolism describes findings from a study that looked at the effects of a dual glucagon-like peptide-1 (GLP-1) / glucagon receptor agonist on liver glycogen in individuals with type 2 diabetes (T2D) and overweight or obesity. Edvin Johansson, Senior Director MR Imaging, and Lars Johansson, CSO, are co-authors on the publication alongside colleagues from AstraZeneca, Maastricht UMC, and University of Nottingham.
Glycogen synthesis (glycogenesis), and breakdown (glycogenolysis), are mediated through several mechanisms, including the balance of hormones such as insulin and glucagon. Therefore, it is of interest to look more closely at hepatic glycogen dynamics during the development of drugs targeted towards the glucagon receptor, such as dual GLP-1/glucagon receptor agonists.
In this study, 13C Magnetic Resonance Spectroscopy (MRS) was used to help characterise the mechanism of action and confirm engagement of the glucagon receptor through measurement of liver glycogen. A reduction in liver glycogen through the stimulation of glycogenolysis in the liver, confirmed engagement of the glucagon receptors. This was the first time this method was used to measure treatment effects in a pharmaceutical interventional trial, showing its potential for further understanding of target engagement of the glucagon receptor.
Hitting the intended target of dual and triple incretin hormone receptor agonists
The glucagon receptor is a target of many novel drugs currently in development within the field of metabolic diseases like obesity, T2D, and other downstream organ effects. Many of these drugs are targeting the glucagon receptor in combination with other incretin hormone receptors such as GLP-1 and/or gastric inhibitory polypeptide (GIP) as either dual or triple receptor agonists. There is a need to understand more about these drugs and their effects. Imaging is one way of investigating if the intended target is hit or not, providing information to facilitate decision-making in clinical drug development.
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Title: Cotadutide promotes glycogenolysis in people with overweight or obesity diagnosed with type 2 diabetes
Authors: Parker VER, Robertson D, Erazo-Tapia E, Havekes B, Phielix E, de Ligt M, Roumans KHM, Mevenkamp J, Sjoberg F, Schrauwen-Hinderling VB, Johansson E, Chang YT, Esterline R, Smith K, Wilkinson DJ, Hansen L, Johansson L, Ambery P, Jermutus L, Schrauwen P
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