Unimolecular GLP-1/Apelin Hybrid Peptides Cause Prominent Appetite Suppression, as Well as Enhancing Insulin...

To characterise the metabolic benefits of a GLP-1/apelin hybrid peptide, namely exendin-4-linker-apelin (ELA), and associated acylated forms, including ELA-Lys¹²(γGluPal), ELA-Lys²⁷(γGluPal) and ELA-Lys³⁸(γGluPal).

Concentration- and receptor-dependent effects of the peptides on insulin secretion and beta-cell turnover were investigated using in vitro systems. Subsequent analyses included assessment of food intake and glucose tolerance in normal mice and rats, as well as high-fat-fed (HFF) mice.

Enzymatic stability of all ELA peptides was initially confirmed in murine plasma. All peptides significantly augmented insulin secretion from BRIN-BD11 cells and isolated islets, linked to engagement of both GLP-1 and apelin receptors, with ELA, ELA-Lys¹²(γGluPal) and ELA-Lys³⁸(γGluPal) being particularly effective. These hybrid peptides also enhanced beta-cell proliferation and reduced cytokine-induced apoptosis. Assessment of effects on feeding behaviour revealed substantial reductions of food intake by ELA, durable for 42 h. Peptide acylation extended the duration of appetite suppressive actions to 63 h. As with in vitro actions, appetite regulatory effects were dependent on engagement of both the GLP-1 and apelin receptors. Studies in rats suggested that ELA-induced inhibition of food intake was not linked to malaise. All peptides significantly improved glucose tolerance in lean and HFF mice, indicating enhanced insulin action and glycaemic control. Acylation extended the duration of glucose-lowering benefits up to 21 h. Effects of ELA on glucose homeostasis appeared to be more reliant on GLP-1, rather than apelin, receptors.

These studies highlight the clear therapeutic applicability of rationally designed GLP-1/apelin hybrid molecules for the treatment of obesity and T2DM.