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These data indicate that sustained administration of a stable analogue of xenin-25 exerts a spectrum of beneficial metabolic effects in high-fat-fed mice.

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-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

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Glutamine (gln)-modified analogues of xenin may represent an attractive therapeutic approach for type 2 diabetes.