Endocrine Abstracts

Incretin mimetics and associated hybrid co-agonist peptides remain a driving force in improving metabolic control and managing type 2 diabetes and obesity. Additionally, the adipokine apelin which targets the APJ receptor, has displayed positive anti-diabetic and obesity effects in pre-clinical trials. To harness these beneficial effects, two novel dual-agonist unimolecular peptides were developed based on the amino acid sequence of GLP-1 and apelin and named Exendin-Linker-Apelin (ELA) and Apelin-Linker-Exendin (ALE). Of these two hybrid peptides, ELA proved more efficacious in all pre-clinical trials and was used going forward alongside a range of acylated analogues to prolong therapeutic effects. Cumulative food intake was measured in 21 h fasted trained normal (n = 8) mice at 30, 60, 90, 120, 150, and 180 min following i.p. injection of saline vehicle (0.9% w/v NaCl) or test peptides (each at 25 nmol/kg bw). ELA and associated Lys ¹², Lys ²⁷ and Lys ³⁸ hybrid peptides resulted in an immediate reduction in food intake compared to saline controls (P < 0.001). Furthermore, when test peptides were administered at t=-6 h, whilst ELA significantly inhibited food intake (P < 0.001), the acylated analogues had a greater satiety inhibiting effect compared to non-acylated ELA (P > 0.001). ELA, Lys ¹² and Lys ³⁸ maintained their satiety inhibiting effects when peptide administration was delayed by 21 h (P < 0.001). Finally, Lys ³⁸ maintained this satiety reducing effect up to 63 h post injection (P < 0.05), thereby demonstrating that these acylated analogues may be protected from elimination and display improved plasma stability. In conclusion, hybrid co-agonist acylated and non-acylated ELA peptide analogues, demonstrated significant reductions in food intake that may suggest application for the treatment of obesity, or obesity-related forms of metabolic dysregulation such as type 2 diabetes.