In vivo and in vitro characterization of GL0034, a novel long‐acting glucagon‐like peptide‐1 receptor agonist

Abstract

Aims: To describe the in vitro characteristics and antidiabetic in vivo efficacy of the novel glucagon-like peptide-1 receptor agonist (GLP-1RA) GL0034.Materials and Methods: Glucagon-like peptide-1 receptor (GLP-1R) kinetic binding parameters, cyclic adenosine monophosphate (cAMP) signalling, endocytosis and recycling were measured using HEK293 and INS-1832/3 cells expressing human GLP-1R. Insulin secretion was measured in vitro using INS-1832/3 cells, mouse islets and human islets. Chronic administration studies to evaluate weight loss and glycaemic effects were performed in db/db and diet-induced obese mice.Results: Compared to the leading GLP-1RA semaglutide, GL0034 showed increased binding affinity and potency-driven bias in favour of cAMP over GLP-1R endocytosis and β-arrestin-2 recruitment. Insulin secretory responses were similar for both ligands. GL0034 (6 nmol/kg) led to at least as much weight loss and lowering of blood glucose as did semaglutide at a higher dose (14 nmol/kg).Conclusions: GL0034 is a G protein-biased agonist that shows powerful antidiabetic effects in mice, and may serve as a promising new GLP-1RA for obese patients with type 2 diabetes.

Comparative Analysis of the Anti-Inflammatory Effects of Liraglutide and Dulaglutide

“…Therefore, fragments of the GLP-1 metabolite may be a significant material basis for mediating its cardiovascular protective effects. 45) We observed significant antiinflammatory cardioprotective effects in vitro due to the high degree of homology between liraglutide and dulaglutide. GLP-1RAs have demonstrated superior efficacy and significantly reduce the risk of major adverse cardiovascular events in T2DM patients with preexisting cardiovascular disease.…”

Development of a novel Fc fusion protein dual glucagon‐like peptide‐1 and gastric inhibitory polypeptide receptor agonists

“…Moreover, previous studies showed how G protein selective biased agonism is associated with profound alterations to GLP-1R trafficking, resulting in improved insulinotropic and antidiabetic effects through avoidance of GLP-1R desensitization and downregulation. 34,35 Whether HEC-CG115 has biased selection on signalling transduction, particularly at GLP-1R, will be a subject for future investigation.…”

Sustained metabolic benefits of ΔTRTX‐Ac1, a tarantula venom‐derived peptide, when administered together with exenatide in high‐fat fed mice

“…Although tachyphylaxis has been suggested as a possible limiting factor for GLP-1 drugs, 25 this now seems unlikely and methods to avoid that potential phenomenon are also well described. 26,27 Thus, there can be optimism in terms of persistent beneficial metabolic effects of combined administration of ΔTRTX-Ac1 with exenatide. Moreover, in the current study, combination peptide therapy resulted in notable additive improvements on glucose handling beyond that of either treatment alone, reinforcing this indication.…”

“…This not only corroborates bioactivity of ΔTRTX‐Ac1 in both normal and diabetic rodents, but also suggests that desensitization to the benefits of ΔTRTX‐Ac1 is not a concern. Although tachyphylaxis has been suggested as a possible limiting factor for GLP‐1 drugs, 25 this now seems unlikely and methods to avoid that potential phenomenon are also well described 26,27 . Thus, there can be optimism in terms of persistent beneficial metabolic effects of combined administration of ΔTRTX‐Ac1 with exenatide.…”