Biological Activity and Antidiabetic Potential of C-Terminal Octapeptide Fragments of the Gut-Derived Hormone Xenin

MA Martin, Vadivel Parthsarathy, A Hasib, Tony NG, Stephen McClean, Peter Flatt, Victor A Gault, Nigel Irwin

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Xenin is a peptide that is co-secreted with the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), from intestinal K-cells in response to feeding. Studies demonstrate that xenin has appetite suppressive effects and modulates glucose-induced insulin secretion. The present study was undertaken to determine the bioactivity and antidiabetic properties of two C-terminal fragment xenin peptides, namely xenin 18-25 and xenin 18-25 Gln. In BRIN-BD11 cells, both xenin fragment peptides concentration-dependently stimulated insulin secretion, with similar efficacy as the parent peptide. Neither fragment peptide had any effect on acute feeding behaviour at elevated doses of 500 nmol/kg bw. When administered together with glucose to normal mice at 25 nmol/kg bw, the overall insulin secretory effect was significantly enhanced in both xenin 18-25 and xenin 18-25 Gln treated mice, with better moderation of blood glucose levels. Twice daily administration of xenin 18-25 or xenin 18-25 Gln for 21 days in high fat fed mice did not affect energy intake, body weight, circulating blood glucose or body fat stores. However, circulating plasma insulin concentrations had a tendency to be elevated, particularly in xenin 18-25 Gln mice. Both treatment regimens significantly improved insulin sensitivity by the end of the treatment period. In addition, sustained treatment with xenin 18-25 Gln significantly reduced the overall glycaemic excursion and augmented the insulinotropic response to an exogenous glucose challenge on day 21. In harmony with this, GIP-mediated glucose-lowering and insulin-releasing effects were substantially improved by twice daily xenin 18-25 Gln treatment. Overall, these data provide evidence that C-terminal octapeptide fragments of xenin, such as xenin 18-25 Gln, have potential therapeutic utility for type 2 diabetes.
Original languageEnglish
Article numbere0152818
Pages (from-to)1-14
Number of pages14
JournalPLoS ONE
Volume11
Issue number3
Early online date31 Mar 2016
DOIs
Publication statusE-pub ahead of print - 31 Mar 2016

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Keywords

  • Xenin
  • diabetes
  • analogue
  • antihyperglycaemic
  • peptide fragments

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