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

Journal article


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
AuthorsGault, Victor A., Martin, Christine M., Flatt, Peter R., Parthsarathy, Vadivel and Irwin, Nigel
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.

Keywordsdiabetes; obesity; glucose
Year2015
JournalActa Diabetologica
Journal citation52 (3), pp. 461-471
PublisherSpringer
ISSN0940-5429
1432-5233
Digital Object Identifier (DOI)https://doi.org/10.1007/s00592-014-0681-0
Web address (URL)http://hdl.handle.net/10545/622909
hdl:10545/622909
http://europepmc.org/article/med/25374384
Output statusPublished
Publication dates06 Nov 2014
Publication process dates
Deposited16 Aug 2018
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