Journal
JOURNAL OF ENDOCRINOLOGY
Volume 221, Issue 2, Pages 193-200Publisher
BIOSCIENTIFICA LTD
DOI: 10.1530/JOE-13-0617
Keywords
glucose-dependent insulinotropic polypeptide (GIP); high fat-fed mice; bioactivity; xenin-25
Categories
Funding
- Department of Education and Learning, Northern Ireland
- SAAD Trading and Contracting Company
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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(-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-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.
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