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

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    Authors
    Parthsarathy, Vadivel cc
    Irwin, Nigel
    Hasib, Annie
    Martin, Christine M.
    McClean, Stephen
    Bhat, Vikas K.
    NG, Ming T.
    Flatt, Peter R.
    Gault, Victor A.
    Issue Date
    2016-01-21
    
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    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.
    Citation
    Parthsarathy, Vadivel, Irwin, Nigel, Hasib, A, Martin, CM, McClean, Stephen, Bhat, VK, NG, Tony, Flatt, Peter 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.
    Publisher
    Elsevier
    Journal
    Biochimica et Biophysica Acta
    URI
    http://hdl.handle.net/10545/622908
    DOI
    10.1016/j.bbagen.2016.01.015
    Additional Links
    http://uir.ulster.ac.uk/33791/
    Type
    Journal article
    ISSN
    0304-4165
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.bbagen.2016.01.015
    Scopus Count
    Collections
    Environmental Sustainability Research Centre

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