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, Nigel Irwin

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Xenin-25, a peptide co-secreted with the incretin hormone glucose-dependent insulinotropic 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-Ala²)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 (10⁻⁶ 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-Ala²)GIP, all xenin peptides significantly (P<0.01 to P<0.001) reduced the overall glycaemic excursion, albeit to a similar extent as (D-Ala²)GIP alone. Xenin-25 and xenin 18-25 also imparted a potential synergistic effect on (D-Ala²)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.

Original languageEnglish
Pages (from-to)193-200
JournalThe Journal of endocrinology
Volume221
Issue number2
Early online date11 Feb 2014
DOIs
Publication statusPublished - May 2014

Keywords

  • Animals
  • Cells, Cultured
  • Diet, High-Fat
  • Drug Evaluation, Preclinical
  • Hypoglycemic Agents
  • Insulin
  • Male
  • Mice
  • Neurotensin
  • Peptide Fragments
  • Proteolysis
  • Satiation
  • Journal Article
  • Research Support, Non-U.S. Gov't

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