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. https://doi.org/10.1016/j.bcp.2017.10.002
AuthorsO'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.

KeywordsDiabetes; Obesity; Feeding; Glucose homeostasis; insulin
Year2017
JournalBiochemical pharmacology
PublisherElsevier
ISSN0006-2952
Digital Object Identifier (DOI)https://doi.org/10.1016/j.bcp.2017.10.002
Web address (URL)http://hdl.handle.net/10545/622905
hdl:10545/622905
Publication dates04 Oct 2017
Publication process dates
Deposited16 Aug 2018, 13:55
Permalink -

https://repository.derby.ac.uk/item/93856/acylated-apelin-13-amide-analogues-exhibit-enzyme-resistance-and-prolonged-insulin-releasing-glucose-lowering-and-anorexic-properties

  • 10
    total views
  • 0
    total downloads
  • 0
    views this month
  • 0
    downloads this month

Export as

Related outputs

Exendin-4 stimulates autophagy in pancreatic β-cells via the RAPGEF/EPAC-Ca PPP3/calcineurin-TFEB axis
Zummo, F.P, Krishnanda, S.I, Georgiou, M., O’Harte, F. P. M., Parthsarathy, V., Cullen, K.S, Honkanen-Scott, M, Shaw, J.A.M, Lovat, P.E and Arden, C 2021. Exendin-4 stimulates autophagy in pancreatic β-cells via the RAPGEF/EPAC-Ca PPP3/calcineurin-TFEB axis. Autophagy. 18 (4), pp. 1-17. https://doi.org/10.1080/15548627.2021.1956123
Protein hydrolysates from boarfish (Capros aper) and Atlantic salmon (Salmo salar) skin gelatin improve metabolic control in genetically obese diabetic (ob/ob) mice
Parthsarathy, V., McLaughlin, C.M, Sharkey, S.J, Harnedy-Rothwell, P.A, Lafferty, R.A, Allsopp, P.J, McSorley, E.M, Fitzgerald, R.J and O'Harte, F.P.M 2021. Protein hydrolysates from boarfish (Capros aper) and Atlantic salmon (Salmo salar) skin gelatin improve metabolic control in genetically obese diabetic (ob/ob) mice. Journal of Food Bioactives. 16, pp. 48-57. https://doi.org/10.31665/JFB.2021.16292
Stability to thermal treatment of dipeptidyl peptidase‐IV inhibitory activity of a boarfish (Capros aper) protein hydrolysate when incorporated into tomato‐based products
Harnedy‐Rothwell, P.A., McLaughlin, C.M., Crowe, W., Allsopp, P.J., McSorley, E.M., Devaney, M., Whooley, J., McGovern, B., Parthsarathy, V., O'Harte, F.P.M. and FitzGerald, R.J. 2021. Stability to thermal treatment of dipeptidyl peptidase‐IV inhibitory activity of a boarfish (Capros aper) protein hydrolysate when incorporated into tomato‐based products. International Journal of Food Science and Technology. 56 (1), pp. 158-165. https://doi.org/10.1111/ijfs.14615
Macroalgal protein hydrolysates from Palmaria palmata influence the 'incretin effect' in vitro via DPP-4 inhibition and upregulation of insulin, GLP-1 and GIP secretion
McLaughlin, C.M., Harnedy-Rothwell, P.A., Lafferty, R.A., Sharkey, S., Parthsarathy, V., Allsopp, P.J., McSorley, E.M., FitzGerald, R.J. and O'Harte, F.P.M. 2021. Macroalgal protein hydrolysates from Palmaria palmata influence the 'incretin effect' in vitro via DPP-4 inhibition and upregulation of insulin, GLP-1 and GIP secretion. European Journal of Nutrition. 60 (8), pp. 4439-4452. https://doi.org/10.1007/s00394-021-02583-3
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 and Flatt, Peter R 2020. Chronic apelin analogue administration is more effective than established incretin therapies for alleviating metabolic dysfunction in diabetic db/db mice. Molecular and cellular endocrinology. 504, p. 110695. https://doi.org/10.1016/j.mce.2019.110695
Beneficial long-term antidiabetic actions of N- and C-terminally modified analogues of apelin-13 in diet-induced obese diabetic mice.
Parthsarathy, Vadivel, Hogg, Christopher, Flatt, Peter R. and O'Harte, Finbarr P. M. 2017. Beneficial long-term antidiabetic actions of N- and C-terminally modified analogues of apelin-13 in diet-induced obese diabetic mice. Diabetes Obesity and Metabolism. https://doi.org/10.1111/dom.13068
Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice
Millar, Paul, Pathak, Nupur, Parthsarathy, Vadivel, Bjourson, Anthony J., O'Kane, Maurice, Pathak, Varun, Moffett, Charlotte, Flatt, Peter R. and Gault, Victor A. 2017. Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice. Journal of Endocrinology. https://doi.org/10.1530/JOE-17-0263
Apelin-13 analogues show potent in vitro and in vivo insulinotropic and glucose lowering actions
O'Harte, Finbarr P. M., Parthsarathy, Vadivel, Hogg, Christopher and Flatt, Peter R. 2018. Apelin-13 analogues show potent in vitro and in vivo insulinotropic and glucose lowering actions. Peptides. https://doi.org/10.1016/j.peptides.2017.12.004
Long-term treatment with acylated analogues of apelin-13 amide ameliorates diabetes and improves lipid profile of high-fat fed mice.
O' Harte, F.P.M., Parthsarathy, V., Hogg, C and Flatt, P 2018. Long-term treatment with acylated analogues of apelin-13 amide ameliorates diabetes and improves lipid profile of high-fat fed mice. PLos ONE. 13 (8). https://doi.org/10.1371/journal.pone.0202350
Atlantic salmon (Salmo salar) co-product-derived protein hydrolysates: A source of antidiabetic peptides
Harnedy, Pàdraigín A., Parthsarathy, Vadivel, McLaughlin, Chris M., O'Keeffe, Martina B., Allsopp, Philip J., McSorley, Emeir M., O'Harte, Finbarr P. M. and FitzGerald, Richard J. 2018. Atlantic salmon (Salmo salar) co-product-derived protein hydrolysates: A source of antidiabetic peptides. Food Research International. 106, pp. 598-606. https://doi.org/10.1016/j.foodres.2018.01.025
Boarfish (Capros aper) protein hydrolysate has potent insulinotropic and GLP‐1 secretory activity in vitro and acute glucose lowering effects in mice
Parthsarathy, Vadivel, Mclaughlin, Christopher, Harnedy, Padraigin, Allsopp, Phillip, Crowe, William, McSorley, Emeir, FitzGerald, Dick and O'Harte, Finbarr 2018. Boarfish (Capros aper) protein hydrolysate has potent insulinotropic and GLP‐1 secretory activity in vitro and acute glucose lowering effects in mice. International Journal of Food Science and Technology. 54 (1), pp. 271-281. https://doi.org/10.1111/ijfs.2019.54.issue-1
Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice
Millar, P., Pathak, N., Parthsarathy, V., Bjourson, A.J., O'Kane, M., Pathak, V., Moffett, R.C., Flatt, P.R. and Gault, V.A. 2017. Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice. The Journal of Endocrinology. 234 (3), pp. 255-267. https://doi.org/10.1530/joe-17-0263
An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice
Hasib, Annie, Ng, Tony, Gault, Victor A., Khan, Dawood, Parthsarathy, Vadivel, Flatt, Peter and Irwin, Nigel 2017. An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice. Diabetologia. 60 (2017), pp. 541-552. https://doi.org/10.1007/s00125-016-4186-y
Blue whiting (Micromesistius poutassou) muscle protein hydrolysate with in vitro and in vivo antidiabetic properties
Harnedy, Pàdraigín A., Parthsarathy, Vadivel, McLaughlin, Chris M., O'Keeffe, Martina B., Allsopp, Philip J., McSorley, Emeir M., O'Harte, Finbarr P. M. and Fitzgerald, Richard J. 2017. Blue whiting (Micromesistius poutassou) muscle protein hydrolysate with in vitro and in vivo antidiabetic properties. Journal of Functional Foods. 40 (2018), pp. 137-145. https://doi.org/10.1016/j.jff.2017.10.045
Beneficial long-term antidiabetic actions of N- and C-terminally modified analogues of apelin-13 in diet-induced obese diabetic mice
Parthsarathy, Vadivel, Hogg, Christopher, Flatt, Peter R. and O'Harte, Finbarr P. M. 2017. Beneficial long-term antidiabetic actions of N- and C-terminally modified analogues of apelin-13 in diet-induced obese diabetic mice. Diabetes Obesity and Metabolism. 20 (2), pp. 319-327. https://doi.org/10.1111/dom.13068
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 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
Biological Activity and Antidiabetic Potential of C-Terminal Octapeptide Fragments of the Gut-Derived Hormone Xenin
Martin, Christine M., Parthsarathy, Vadivel, Hasib, Annie, NG, Ming T., McClean, Stephen, Flatt, Peter R., Gault, Victor A. and Irwin, Nigel 2016. Biological Activity and Antidiabetic Potential of C-Terminal Octapeptide Fragments of the Gut-Derived Hormone Xenin. PLos ONE. 11 (3). https://doi.org/10.1371/journal.pone.0152818
A novel chemically modified analogue of xenin-25 exhibits improved glucose-lowering and insulin-releasing properties
Parthsarathy, Vadivel, Irwin, Nigel, Hasib, Annie, Martin, Christine M., McClean, Stephen, Bhat, Vikas K., NG, Ming T., Flatt, Peter R. and Gault, Victor A. 2016. A novel chemically modified analogue of xenin-25 exhibits improved glucose-lowering and insulin-releasing properties. Biochimica et Biophysica Acta. 1860 (4), pp. 757-764. https://doi.org/10.1016/j.bbagen.2016.01.015
Xenin-25[Lys(13)PAL]: a novel long-acting acylated analogue of xenin-25 with promising antidiabetic potential
Gault, Victor A., Martin, Christine M., Flatt, Peter R., Parthsarathy, Vadivel and Irwin, Nigel 2015. Xenin-25[Lys(13)PAL]: a novel long-acting acylated analogue of xenin-25 with promising antidiabetic potential. Acta Diabetologica. 52 (3), pp. 461-471. https://doi.org/10.1007/s00592-014-0681-0
Characterisation of the biological activity of xenin-25 degradation fragment peptides
Martin, C.M., Parthsarathy, V., Pathak, V., Gault, V.A., Flatt, P.R. and Irwin, N. 2014. Characterisation of the biological activity of xenin-25 degradation fragment peptides. The Journal of Endocrinology. 221 (2), pp. 193-200. https://doi.org/10.1530/joe-13-0617
Correction: A Novel Retro-Inverso Peptide Inhibitor Reduces Amyloid Deposition, Oxidation and Inflammation and Stimulates Neurogenesis in the APPswe/PS1ΔE9 Mouse Model of Alzheimer’s Disease
Parthsarathy, V., McClean, P.L., Hölscher, C., Taylor, M., Tinker, C., Jones, G., Kolosov, O., Salvati, E., Gregori, M., Masserini, M. and Allsop, D. 2013. Correction: A Novel Retro-Inverso Peptide Inhibitor Reduces Amyloid Deposition, Oxidation and Inflammation and Stimulates Neurogenesis in the APPswe/PS1ΔE9 Mouse Model of Alzheimer’s Disease. PLos ONE. 8 (9). https://doi.org/10.1371/annotation/57e0a947-8600-4658-b04c-cf7a45c8bd8d
A novel retro-inverso peptide inhibitor reduces amyloid deposition, oxidation and inflammation and stimulates neurogenesis in the APPswe/PS1ΔE9 mouse model of Alzheimer's disease
Parthsarathy, V., McClean, P.L., Hölscher, C., Taylor, M., Tinker, C., Jones, G., Kolosov, O., Salvati, E., Gregori, M., Masserini, M. and Allsop, D. 2013. A novel retro-inverso peptide inhibitor reduces amyloid deposition, oxidation and inflammation and stimulates neurogenesis in the APPswe/PS1ΔE9 mouse model of Alzheimer's disease. PLos ONE. 8 (1). https://doi.org/10.1371/journal.pone.0054769
Chronic treatment with the GLP1 analogue liraglutide increases cell proliferation and differentiation into neurons in an AD mouse model
Parthsarathy, V. and Hölscher, C. 2013. Chronic treatment with the GLP1 analogue liraglutide increases cell proliferation and differentiation into neurons in an AD mouse model. PLos ONE. 8 (3). https://doi.org/10.1371/journal.pone.0058784
The type 2 diabetes drug liraglutide reduces chronic inflammation induced by irradiation in the mouse brain
Parthsarathy, Vadivel and Holscher, Christian 2013. The type 2 diabetes drug liraglutide reduces chronic inflammation induced by irradiation in the mouse brain. European Journal of Pharmacology. 700 (1-3), pp. 42-50. https://doi.org/10.1016/j.ejphar.2012.12.012
The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease
McClean, P.L., Parthsarathy, V,, Faivre, E. and Hölscher, C. 2011. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. The Journal of Neuroscience. 31 (17), pp. 6587-6594. https://doi.org/10.1523/jneurosci.0529-11.2011