A novel chemically modified analogue of xenin-25 exhibits improved glucose-lowering and insulin-releasing properties

Journal article


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
AuthorsParthsarathy, Vadivel, Irwin, Nigel, Hasib, Annie, Martin, Christine M., McClean, Stephen, Bhat, Vikas K., NG, Ming T., Flatt, Peter R. and Gault, Victor A.
Abstract

BACKGROUND: Xenin-25 is a K-cell derived gut peptide with insulin-releasing activity which is rapidly degraded following release into the circulation. We hypothesized that substitution of all naturally-occurring Lys and Arg residues with Gln would lead to prolonged enzyme resistance and enhanced biological efficacy.

METHODS: Peptide stability was assessed using murine plasma, in vitro insulin-releasing actions evaluated in BRIN-BD11 cells and acute glucose-lowering and insulin-releasing actions examined in high fat fed mice. For sub-chronic studies, a range of metabolic parameters and pancreatic histology were assessed in high fat fed mice which had received saline vehicle or xenin-25(gln) twice-daily for 21days.

RESULTS: In contrast to native xenin-25, xenin-25(gln) was resistant to plasma-mediated degradation and significantly stimulated insulin secretion in BRIN-BD11 cells. Acute administration of xenin-25(gln) in high fat fed mice significantly reduced blood glucose and increased plasma insulin concentrations. Twice-daily administration of xenin-25(gln) in high fat fed mice did not affect food intake, body weight or circulating insulin concentrations but significantly decreased blood glucose from day 9 onwards. Furthermore, glucose tolerance, glucose-mediated insulin secretion, insulin sensitivity and GIP-stimulated insulin-release were significantly enhanced in xenin-25(gln)-treated mice. Pancreatic immunohistochemistry revealed decreased alpha cell area with increased beta cell area and beta-to-alpha cell ratio in xenin-25(gln)-treated mice. In addition, xenin-25(gln) exerted similar beneficial actions in ob/ob mice as demonstrated by reduced blood glucose, superior glycaemic response and glucose-mediated insulin release.

CONCLUSIONS: Xenin-25(gln) is resistant to plasma-mediated degradation and exerts sustained and beneficial metabolic actions in high fat fed and ob/ob mice.

GENERAL SIGNIFICANCE: Glutamine (gln)-modified analogues of xenin may represent an attractive therapeutic approach for type 2 diabetes.

Keywordsglucose homeostasis; gut; insulin; diabetes
Year2016
JournalBiochimica et Biophysica Acta
Journal citation1860 (4), pp. 757-764
PublisherElsevier
ISSN0304-4165
Digital Object Identifier (DOI)https://doi.org/10.1016/j.bbagen.2016.01.015
Web address (URL)http://hdl.handle.net/10545/622908
hdl:10545/622908
http://europepmc.org/article/med/26802310
Output statusPublished
Publication dates21 Jan 2016
Publication process dates
Deposited16 Aug 2018
Permalink -

https://repository.derby.ac.uk/item/925v6/a-novel-chemically-modified-analogue-of-xenin-25-exhibits-improved-glucose-lowering-and-insulin-releasing-properties

  • 20
    total views
  • 0
    total downloads
  • 0
    views this month
  • 0
    downloads this month

Export as

Related outputs

Peptide Co-Agonists for Combined Activation of the APJ and GLP-1 Receptors with Insulinotropic and Satiety Actions Show Potential for Alleviation of Metabolic Dysfunction in Type 2 Diabetes †
O' Harte, S., Parthsarathy, V., Craig, S., Palmer, E. and Irwin, N. 2023. Peptide Co-Agonists for Combined Activation of the APJ and GLP-1 Receptors with Insulinotropic and Satiety Actions Show Potential for Alleviation of Metabolic Dysfunction in Type 2 Diabetes †. 1st International Meeting Molecules 4 Life. MDPI. https://doi.org/10.3390/msf2023023001
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
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. https://doi.org/10.1016/j.bcp.2017.10.002
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
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