Acylated apelin-13 amide analogues exhibit enzyme resistance and prolonged insulin releasing, glucose lowering and anorexic properties
Journal article
O'Harte, Finbarr P M, Parthsarathy, Vadivel, Hogg, Christopher and Flatt, Peter R 2017. Acylated apelin-13 amide analogues exhibit enzyme resistance and prolonged insulin releasing, glucose lowering and anorexic properties. Biochemical pharmacology. 146, pp. 165-173. https://doi.org/10.1016/j.bcp.2017.10.002
| Authors | O'Harte, Finbarr P M, Parthsarathy, Vadivel, Hogg, Christopher and Flatt, Peter R |
|---|---|
| Abstract | 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. |
| Keywords | Adipokine; Apelin-13; feeding; glucose homeostasis insulin release; glucose uptake; obesity; Type 2 diabetes |
| Year | 2017 |
| Journal | Biochemical pharmacology |
| Journal citation | 146, pp. 165-173 |
| Publisher | Elsevier |
| ISSN | 1873-2968 |
| Digital Object Identifier (DOI) | https://doi.org/10.1016/j.bcp.2017.10.002 |
| Web address (URL) | http://hdl.handle.net/10545/624634 |
| hdl:10545/624634 | |
| http://europepmc.org/article/med/28987595 | |
| https://pure.ulster.ac.uk/en/publications/acylated-apelin-13-amide-analogues-exhibit-enzyme-resistance-and--2 | |
| Output status | Published |
| Publication dates | 04 Oct 2017 |
| Publication process dates | |
| Deposited | 01 Apr 2020 |
| Accepted | 02 Oct 2017 |
| Rights | Copyright © 2017 Elsevier Inc. All rights reserved. |
| Contributors | University of Ulster |
| Place of publication | England |
| File | File Access Level Open |
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