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Characterisation of the biological activity of xenin-25 degradation fragment peptides

Martin, CA, Parthsarathy, V, Pathak, V, Gault, Victor, Flatt, Peter and Irwin, Nigel (2014) Characterisation of the biological activity of xenin-25 degradation fragment peptides. Journal of Endocrinology, 221 (2). pp. 193-200. [Journal article]

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DOI: 10.1530/JOE-13-0617.R1

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. The present 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, 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. Intraperitoneal 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 to 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.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
ID Code:28554
Deposited By: Dr Nigel Irwin
Deposited On:17 Feb 2014 15:06
Last Modified:21 May 2014 08:21

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