Endocrine Abstracts

Hybrid co-agonist peptides, which activate incretin plus other key receptors, are proving efficacious therapeutic drugs for type-2 diabetes management. Previously we showed that the adipokine apelin-13, operating via the APJ receptor, possesses anti-diabetic therapeutic potential. Here we tested novel acylated and non-acylated hybrid co-agonist peptides (exendin-linker-apelin (ELA)), which simultaneously activate both GLP-1 and APJ receptors. The component peptides exendin-4(1-30), apelin-13 and combined treatments, were examined for their dose-dependent (10-12-10-6 M) insulinotropic actions using pancreatic BRIN-BD11 cells (in presence/absence of specific GLP-1 and APJ receptor antagonists) and isolated islets (10-8-10-6 M). Finally, ELA analogues were examined for their actions on beta-cell proliferation and apoptosis. Exendin-4(1-30), apelin-13 either alone, or combined showed a dose-dependent increase (1.5-4.7-fold, P < 0.05-P < 0.001) in insulin secretion from BRIN-BD11 cells vs 5.6 mM glucose controls. ELA (10-6 M) stimulated insulin secretion (3.5-fold, P < 0.001), which was matched by ELA analogues acylated at position Lys 12 and Lys 38 (3.85- and 3.5-fold, respectively), with receptor antagonists significantly reducing responses (P < 0.01-P < 0.001). Insulinotropic response were identified in isolated mouse islets (3.5–4.5-fold increase) vs glucose controls (P < 0.001). Finally, ELA and its two best acylated analogues showed enhanced dose-dependent (10-8-10-6 M) increases in Ki-67 cell proliferation and a decrease in cytokine-mediated cell apoptosis in BRIN-BD11 cells, vs respective media controls. Overall, hybrid co-agonist acylated and non-acylated ELA peptide analogues, demonstrated potent insulinotropic actions in beta-cells and isolated islets, plus enhanced beta-cell proliferation and reducing beta-cell apoptosis. In conclusion, these ELA co-agonist peptides demonstrated promising anti-diabetic profiles.