Rabbit Anti-Glucagon monoclonal antibody, clone KG1071

Oxyntomodulin (OXM) was identified as a glucagon (GCG) receptor (GCGR) and glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) dual agonist to suppress appetite, increase energy expenditure, and induce body weight loss in obese humans. However, the activities of native OXM to activate GCGR and GLP-1R in vitro were much weaker than the natural ligands. To address this gap, structural modifications were adopted and novel OXM analogues were obtained through chimeric peptide sequence design. One specific analogue with enhanced and balanced GCGR/GLP-1R activations was chemically conjugated with polyethylene glycol (PEG) to achieve sustained release in vivo. This PEGylated analogue was further explored pharmacologically in db/db and diet-induced obese (DIO) mice models. Chronic weekly administration significantly induced hypoglycemic effects and body weight loss with dose dependency, along with normalized adiposity, lipid metabolism, and liver steatosis. Based on its profiles in vitro and in vivo, the analogue has the great potential to develop as a novel anti-diabetic and/or anti-obese candidate. As observed more insulin stimulation and improved insulin resistance, it may be also explored for the treatment of nonalcoholic steatohepatitis (NASH) in the future. (C) 2020 Elsevier Masson SAS. All rights reserved.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors are so called "incretin-based therapies" (IBTs) that represent innovative therapeutic approaches and are commonly used in clinical practice for the treatment of type 2 diabetes mellitus (T2DM). The cardiovascular outcome trials (CVOTs) have provided useful information that has helped to shape changes in clinical practice guidelines for the management of T2DM. At the same time, the mechanisms that may explain the nonglycemic and cardiovascular (CV) benefits of these medications are still being explored. A summary of the main findings from CVOTs performed to-date with particular emphasis on various outcomes and inconsistencies observed in the trials is provided. Overall, available data is favourable to the early deployment of GLP-1RAs in clinical practice, fully in line with recommendations from international scientific guidelines, and based on their effects on glucose metabolism parameters, body weight reduction and CV outcomes. Evidence further suggest that the CV benefits of GLP-1RAs may not be a class effect, with GLP-1 analogues having a greater benefit rather than exendin-based agents. (C) 2020 Elsevier Inc. All rights reserved.