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    Xenin-25[Lys(13)PAL]: a novel long-acting acylated analogue of xenin-25 with promising antidiabetic potential

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    Authors
    Gault, Victor A.
    Martin, Christine M.
    Flatt, Peter R.
    Parthsarathy, Vadivel cc
    Irwin, Nigel
    Issue Date
    2015-06-01
    
    Metadata
    Show full item record
    Abstract
    AIMS: Xenin-25 is co-secreted with glucose-dependent insulinotropic polypeptide (GIP) from intestinal K-cells following a meal. Xenin-25 is believed to play a key role in glucose homoeostasis and potentiate the insulinotropic effect of GIP.METHODS: This study investigated the effects of sub-chronic administration of the stable and longer-acting xenin-25 analogue, xenin-25[Lys(13)PAL] (25 nmol/kg), in diabetic mice fed with a high-fat diet.RESULTS: Initial studies confirmed the significant persistent glucose-lowering (p < 0.05) and insulin-releasing (p < 0.05) actions of xenin-25[Lys(13)PAL] compared with native xenin-25. Interestingly, xenin-25 retained significant glucose-lowering activity in GIP receptor knockout mice. Twice-daily intraperitoneal (i.p.) injection of xenin-25[Lys(13)PAL] for 14 days had no significant effect on food intake or body weight in high-fat-fed mice. Non-fasting glucose and insulin levels were also unchanged, but overall glucose levels during an i.p. glucose tolerance and oral nutrient challenge were significantly (p < 0.05) lowered by xenin-25[Lys(13)PAL] treatment. These changes were accompanied by significant improvements in i.p. (p < 0.05) and oral (p < 0.001) nutrient-stimulated insulin concentrations. No appreciable changes in insulin sensitivity were observed between xenin-25[Lys(13)PAL] and saline-treated high-fat mice. However, xenin-25[Lys(13)PAL] treatment restored notable sensitivity to the biological actions of exogenous GIP injection. Consumption of O2, production of CO2, respiratory exchange ratio and energy expenditure were not altered by 14-day twice-daily treatment with xenin-25[Lys(13)PAL]. In contrast, ambulatory activity was significantly (p < 0.05 to p < 0.001) increased during the dark phase in xenin-25[Lys(13)PAL] mice compared with high-fat controls.
    Citation
    Gault, Victor, Martin, CM, Flatt, Peter, V, Parthsarathy 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
    Publisher
    Springer
    Journal
    Acta Diabetologica
    URI
    http://hdl.handle.net/10545/622909
    DOI
    10.1007/s00592-014-0681-0
    Additional Links
    http://uir.ulster.ac.uk/31872/
    Type
    Journal article
    ISSN
    0940-5429
    EISSN
    1432-5233
    ae974a485f413a2113503eed53cd6c53
    10.1007/s00592-014-0681-0
    Scopus Count
    Collections
    Environmental Sustainability Research Centre

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