Journal article

Publication year: 2019

Pages: 110523-

Journal: Molecular and Cellular Endocrinology

Volume number: 496

ISSN: 0303-7207

Open access status: Green

DOI Link: https://doi.org/10.1016/j.mce.2019.110523

Publisher: Elsevier

Abstract: 
Xenin-25 undergoes rapid enzyme metabolism following secretion. Early studies demonstrated bioactivity of a C-terminal hexapeptide fragment of xenin-25, namely xenin-6, which were enhanced through introduction of a reduced N-terminal peptide bond, to yield psi-xenin-6. The present study was undertaken to define the biological actions and potential antidiabetic properties of psi-xenin-6. In vitro enzymatic stability, insulin and glucagon secretory activity, as well as effects on beta-cell survival were determined. Studies in mice were used to assess the impact of psi-xenin-6 on glucose homeostasis and satiety. psi-xenin-6 was resistant to murine plasma degradation. In BRIN-BD11 cells and isolated murine islets, psi-xenin-6 significantly stimulated insulin secretion, and prominently enhanced the insulinotropic actions of GIP. Xenin-6 and psi-xenin-6 had no impact on glucagon secretion, although xenin-6 partially reversed the glucagonotropic action of GIP. Further in vitro investigations revealed that, similar to GLP-1, psi-xenin-6 significantly augmented proliferation of human and rodent clonal beta-cells, whilst also fully protecting against cytokine-induced beta-cell cytotoxicity, with greater potency than xenin-25 and xenin-6. When administered to mice in combination with glucose, psi-xenin-6 significantly reduced glucose levels and enhanced glucose-induced insulin release, with a duration of biological action beyond 8 h. psi-xenin-6 also significantly enhanced the glucose-lowering action of GIP in vivo. In overnight fasted mice, psi-xenin-6 exhibited satiety actions at both 25 and 250 nmol/kg. These data demonstrates that psi-xenin-6 is a metabolically stable C-terminal fragment analogue of xenin-25, with a metabolic action profile that merits further study as a potential antidiabetic compound.

Harvard Citation style: Craig, S., Gault, V., McClean, S., Hamscher, G. and Irwin, N. (2019) Effects of an enzymatically stable C-terminal hexapseudopeptide fragment peptide of xenin-25, psi-xenin-6, on pancreatic islet function and metabolism, Molecular and Cellular Endocrinology, 496, p. 110523. https://doi.org/10.1016/j.mce.2019.110523

APA Citation style: Craig, S., Gault, V., McClean, S., Hamscher, G., & Irwin, N. (2019). Effects of an enzymatically stable C-terminal hexapseudopeptide fragment peptide of xenin-25, psi-xenin-6, on pancreatic islet function and metabolism. Molecular and Cellular Endocrinology. 496, 110523. https://doi.org/10.1016/j.mce.2019.110523