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N- and C-terminally structurally modified peptide analogues of apelin-13 are more stable than the native peptide and retain bioactivity.Apelin-13 analogues produce a strong dose-dependent insulinotropic response in cultured pancreatic BRIN-BD11 cells and isolated mouse islets.Apelin-13 peptide analogues stimulate cAMP and a rise in intracellular Ca2+ in BRIN-BD11 cells.Apelin-13 analogues improve acute glucose tolerance in normal and diet-induced-obese mice, as well as inhibiting food intake in normal mice.Apelin-13 peptide analogues have a desirable range of anti-diabetic actions, which demonstrates their potential for drug development.Nine structurally modified apelin-13 analogues were assessed for their in vitro and acute in vivo antidiabetic potential. Stability was assessed in mouse plasma and insulinotropic efficacy tested in cultured pancreatic BRIN-BD11 cells and isolated mouse pancreatic islets. Intracellular Ca2+ and cAMP production in BRIN-BD11 cells was determined, as was glucose uptake in 3T3-L1 adipocytes. Acute antihyperglycemic effects of apelin analogues were assessed following i.p. glucose tolerance tests (ipGGT, 18 mmol/kg) in normal and diet-induced-obese (DIO) mice and on food intake in normal mice. Apelin analogues all showed enhanced in vitro stability (up to 5.8-fold, t½ = 12.8 h) in mouse plasma compared to native apelin-13 (t½ = 2.1 h). Compared to glucose controls, stable analogues exhibited enhanced insulinotropic responses from BRIN-BD11 cells (up to 4.7-fold, p < 0.001) and isolated mouse islets (up to 5.3-fold) for 10−7 M apelin-13 amide (versus 7.6-fold for 10−7 M GLP-1). Activation of APJ receptors on BRIN-BD11 cells increased intracellular Ca2+ (up to 3.0-fold, p < 0.001) and cAMP (up to 1.7-fold, p < 0.01). Acute ipGTT showed improved insulinotropic and glucose disposal responses in normal and DIO mice (p < 0.05 and p < 0.01, respectively). Apelin-13 amide and (pGlu)apelin-13 amide were the most effective analogues exhibiting acute, dose-dependent and persistent biological actions. Both analogues stimulated insulin-independent glucose uptake by differentiated adipocytes (2.9–3.3-fold, p < 0.05) and inhibited food intake (26–33%, p < 0.001), up to 180 min in mice, versus saline. In contrast, (Ala13)apelin-13 and (Val13)apelin-13 inhibited insulin secretion, suppressed beta-cell signal transduction and stimulated food intake in mice. Thus, stable analogues of apelin-13 have potential for diabetes/obesity therapy.