Acylated apelin-13 amide analogues exhibit enzyme resistance and prolonged insulin releasing, glucose lowering and anorexic properties.

The adipokine, apelin has many biological functions but its activity is curtailed by rapid plasma degradation. Fatty acid derived apelin analogues represent a new and exciting avenue for the treatment of obesity-diabetes. This study explores four novel fatty acid modified apelin-13 analogues, namely, (LysGluPAL)apelin-13 amide, pGlu(LysGluPAL)apelin-13 amide, LysGluPAL(Tyr)apelin-13 and LysGluPAL(Val)apelin-13. Fatty acid modification extended the half-life of native apelin-13 to >24 h in vitro. pGlu(LysGluPAL)apelin-13 amide was the most potent insulinotropic analogue in BRIN-BD11 cells and isolated islets with maximal stimulatory effects of up to 2.7-fold (p < .001). (LysGluPAL)apelin-13 amide (1.9-fold) and LysGluPAL(Tyr)apelin-13 (1.7-fold) were less effective, whereas LysGluPAL(Val)apelin-13 had an inhibitory effect on insulin secretion. Similarly, pGlu(LysGluPAL)apelin-13 amide was most potent in increasing beta-cell intracellular Ca concentrations (1.8-fold, p < .001) and increasing glucose uptake in 3T3-L1 adipocytes (2.3-fold, p < .01). Persistent biological action was observed with both pGlu(LysGluPAL)apelin-13 amide and (LysGluPAL)apelin-13 amide significantly reducing blood glucose (39-43%, p < .01) and enhancing insulin secretion (43-56%, p < .001) during glucose tolerance tests in diet-induced obese mice. pGlu(LysGluPAL)apelin-13 amide and (LysGluPAL)apelin-13 amide also inhibited feeding (28-40%, p < .001), whereas LysGluPAL(Val)apelin-13 increased food intake (8%, p < .05) in mice. These data indicate that novel enzymatically stable analogues of apelin-13 may be suitable for future development as therapeutic agents for obesity-diabetes.