Peptide Co-Agonists for Combined Activation of the APJ and GLP-1 Receptors with Insulinotropic and Satiety Actions Show Potential for Alleviation of Metabolic Dysfunction in Type 2 Diabetes †

Stable analogues of the adipokine apelin-13 have shown promising therapeutic potential via APJ receptor activation in isolated β-cells and in animal models of obesity-related diabetes. Incretin mimetics such as exenatide that bind to GLP-1 receptors are well-established Type 2 diabetes treatment options. We developed novel hybrid co-agonist peptide analogues incorporating both exendin-4(1-30) covalently linked to apelin (ELA). The dose-dependent (10−12 to 10−6 M) actions of ELA and component peptides were tested on acute (20 min) insulin secretion from cultured pancreatic BRIN-BD11 β-cells at 5.6 mmol/L glucose. In addition, separate tests were performed in the presence or absence of specific APJ and GLP-1 receptor antagonists. The co-agonist ELA peptide showed markedly greater insulinotropic actions (1.6 to 3.3-fold) than equimolar concentrations of either component peptide alone or in combination (p < 0.001). ELA and related acylated analogues (25 nmol/kg i.p. injection) were also tested on cumulative food intake in trained 21 h-fasted adult mice (n = 8), with food intake measured at 30 min intervals up to 180 min. The ELA co-agonist peptides significantly reduced food intake (3.1-fold by 180 min) in mice (p < 0.001) versus saline-treated controls. ELA peptides showed marked improvements in both insulin secretion and appetite control, raising interest in their therapeutic potential.