Characterisation of the biological activity of xenin-25 degradation fragment peptides Christine M A Martin, Vadivel Parthsarathy, Varun Pathak, Victor A Gault, Peter R Flatt and Nigel Irwin SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK Correspondence should be addressed to N Irwin Email n.irwin@ulster.ac.uk Abstract Xenin-25, a peptide co-secreted with the incretin hormone glucose-dependent insulino- tropic polypeptide (GIP), possesses promising therapeutic actions for obesity-diabetes. However, native xenin-25 is rapidly degraded by serum enzymes to yield the truncated metabolites: xenin 9–25, xenin 11–25, xenin 14–25 and xenin 18–25. This study has examined the biological activities of these fragment peptides. In vitro studies using BRIN-BD11 cells demonstrated that native xenin-25 and xenin 18–25 possessed significant (P!0.05 to P!0.001) insulin-releasing actions at 5.6 and 16.7 mM glucose, respectively, but not at 1.1 mM glucose. In addition, xenin 18–25 significantly (P!0.05) potentiated the insulin-releasing action of the stable GIP mimetic (D-Ala 2 )GIP. In contrast, xenin 9–25, xenin 11–25 and xenin 14–25 displayed neither insulinotropic nor GIP-potentiating actions. Moreover, xenin 9–25, xenin 11–25 and xenin 14–25 significantly (P!0.05 to P!0.001) inhibited xenin-25 (10 K6 M)-induced insulin release in vitro. I.p. administration of xenin-based peptides in combination with glucose to high fat-fed mice did not significantly affect the glycaemic excursion or glucose-induced insulin release compared with controls. However, when combined with (D-Ala 2 )GIP, all xenin peptides significantly (P!0.01 to P!0.001) reduced the overall glycaemic excursion, albeit to a similar extent as (D-Ala 2 )GIP alone. Xenin-25 and xenin 18–25 also imparted a potential synergistic effect on (D-Ala 2 ) GIP-induced insulin release in high fat-fed mice. All xenin-based peptides lacked significant satiety effects in normal mice. These data demonstrate that the C-terminally derived fragment peptide of xenin-25, xenin 18–25, exhibits significant biological actions that could have therapeutic utility for obesity-diabetes. Key Words " glucose-dependent insulinotropic polypeptide (GIP) " high fat-fed mice " bioactivity " xenin-25 Journal of Endocrinology (2014) 221, 193–200 Introduction Xenin-25 is a 25 amino acid gastrointestinal hormone secreted from the same enteroendocrine K-cells from which the incretin hormone glucose-dependent insulino- tropic polypeptide (GIP) is secreted (Anlauf et al. 2000). Key advances in the understanding of xenin-25 physiology have demonstrated that xenin-25 not only affects gut motility and feeding behaviour (Cline et al. 2007, Leckstrom et al. 2009) but also acts as an independent insulinotropic agent (Taylor et al. 2010) and a potentiator of GIP-induced insulin secretion (Wice et al. 2010, Martin et al. 2012). However, there is still a dearth of information regarding the biological profile of Journal of Endocrinology Research C M A MARTIN and others Xenin-25 fragment peptides 221 :2 193–200 http://joe.endocrinology-journals.org Ñ 2014 Society for Endocrinology DOI: 10.1530/JOE-13-0617 Printed in Great Britain Published by Bioscientifica Ltd. Downloaded from Bioscientifica.com at 03/05/2023 11:24:34AM via free access