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, (Lys⁸GluPAL)apelin-13 amide, pGlu(Lys⁸GluPAL)apelin-13 amide, Lys⁸GluPAL(Tyr¹³)apelin-13 and Lys⁸GluPAL(Val¹³)apelin-13. Fatty acid modification extended the half-life of native apelin-13 to >24 h in vitro. pGlu(Lys⁸GluPAL)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). (Lys⁸GluPAL)apelin-13 amide (1.9-fold) and Lys⁸GluPAL(Tyr¹³)apelin-13 (1.7-fold) were less effective, whereas Lys⁸GluPAL(Val¹³)apelin-13 had an inhibitory effect on Insulin secretion. Similarly, pGlu(Lys⁸GluPAL)apelin-13 amide was most potent in increasing beta-cell intracellular CA²⁺ 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(Lys⁸GluPAL)apelin-13 amide and (Lys⁸GluPAL)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(Lys⁸GluPAL)apelin-13 amide and (Lys⁸GluPAL)apelin-13 amide also inhibited feeding (28-40%, p < .001), whereas Lys⁸GluPAL(Val¹³)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.

Adipokine; Apelin-13; Feeding; Glucose homeostasis insulin release; Glucose uptake; Obesity; Type 2 diabetes.