Endocrine Abstracts

Incretin mimetics, alongside associated hybrid co-agonist peptides, which activate GLP-1 and other receptors are leading the way to more effective therapeutic options for management of obesity and type 2 diabetes. The adipokine apelin, which activates the APJ receptor, has shown anti-diabetic and obesity related therapeutic utility following pre-clinical testing. The present study investigated several novel hybrid co-agonist peptides, derived from exendin-linker-apelin (ELA) and apelin-linker-exendin (ALE). Co-agonists were first assessed for their efficacy in lowering plasma glucose following an intraperitoneal glucose tolerance test (ipGTT). The ipGTT (18 mmol/kg) was performed following simultaneous (t=0) or delayed (2, 4, 8, 24 and 36 h prior) i.p. injection with non-acylated ELA or ALE peptides (25 nmol/kg) either in normal healthy male NIH mice (n = 8), or in insulin resistant diet-induced obese (DIO) mice (n = 6) previously fed on a high-fat diet (45% fat) for 12-14 weeks. Additional, ipGTT studies in healthy mice (n = 6-8) were performed with acylated peptide analogues, modified at Lys¹², Lys²⁷ or Lys³⁸ side-chains within the co-agonist ELA sequence. The hybrid analogue ELA showed promising acute in vivo insulinotropic actions when administered to healthy or DIO mice. ELA reduced plasma glucose concentrations in DIO mice immediately after an ipGGT (43% reduction AUC_{0-120 min} glucose, P < 0.001) and retained efficacy (30% reduction AUC_{0-120 min}, P < 0.001) up to 24 h post peptide injection. The reverse analogue ALE, lacked anti-hyperglycaemic efficacy. Acylated ELA(Lys¹²) and ELA(Lys³⁸) analogues retained highly effective glucose-lowering actions with AUC_{0-105 min} values reduced by 40-48% (P < 0.01) vs glucose alone, when administered 4 h in advance of an i.p. glucose load in healthy mice. The ELA(Lys¹²) analogue retained anti-hyperglycaemic activity (27% AUC_{0-105 min} reduction; P < 0.05) up to 24 h after acute administration to mice. In conclusion, hybrid co-agonist acylated and non-acylated ELA peptide analogues, demonstrated sustained improvements in glucose tolerance in normal and DIO mice.