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.