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

      O'Harte, Finbarr P M; Parthsarathy, Vadivel; Hogg, Christopher; Flatt, Peter R; University of Ulster (Elsevier, 2017-10-04)
      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.
    • Chronic apelin analogue administration is more effective than established incretin therapies for alleviating metabolic dysfunction in diabetic db/db mice.

      O'Harte, Finbarr P M; Parthsarathy, Vadivel; Flatt, Peter R; University of Ulster (Elsevier, 2020-01-03)
      Stable apelin-13 peptide analogues have shown promising acute antidiabetic effects in mice with diet-induced obesity diabetes. Here the efficacy of (pGlu)apelin-13 amide (apelin amide) and the acylated analogue (pGlu)(Lys8GluPAL)apelin-13 amide (apelin FA), were examined following chronic administration in db/db mice, a genetic model of degenerative diabetes. Groups of 9-week old male db/db mice (n = 8) received twice daily injections (09:00 and 17:00 h; i.p.) or saline vehicle, apelin amide, apelin FA, or the established incretin therapies, exendin-4(1-39) or liraglutide, all at 25 nmol/kg body weight for 21 days. Control C57BL/6J mice were given saline twice daily. No changes in body weight or food intake were observed with either apelin or liraglutide treatments, but exendin-4 showed a reduction in cumulative food intake (p < 0.01) compared with saline-treated db/db mice. Apelin analogues and incretin mimetics induced sustained improvements of glycaemia (p < 0.05 to p < 0.001, from day 9-21), lowered HbA1c at 21 days (p < 0.05) and raised plasma insulin concentrations. The treatments also improved OGTT and ipGTT with enhanced insulin responses compared with saline-treated control db/db mice (p < 0.05 to p < 0.001). Apelin amide was superior to incretin mimetics in lowering plasma triglycerides by 34% (p < 0.05). Apelin analogues unlike both incretin mimetics reduced pancreatic α-cell area (p < 0.05 to p < 0.01) and all peptide treatments enhanced pancreatic insulin content (p < 0.05 to p < 0.01). In conclusion, longer-term administration of apelin-13 analogues, induced similar and in some respects more effective metabolic improvements than incretin mimetics in db/db mice, providing a viable alternative approach for counteracting metabolic dysfunction for mild and more degenerative forms of the disease.