Effects of an enzymatically stable C-terminal hexapseudopeptide fragment peptide of xenin-25, ψ-xenin-6, on pancreatic islet function and metabolism.
Mol Cell Endocrinol
; 496: 110523, 2019 10 01.
Article
en En
| MEDLINE
| ID: mdl-31352038
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 Ψ-xenin-6. The present study was undertaken to define the biological actions and potential antidiabetic properties of Ψ-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 Ψ-xenin-6 on glucose homeostasis and satiety. Ψ-xenin-6 was resistant to murine plasma degradation. In BRIN-BD11â¯cells and isolated murine islets, Ψ-xenin-6 significantly stimulated insulin secretion, and prominently enhanced the insulinotropic actions of GIP. Xenin-6 and Ψ-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, Ψ-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, Ψ-xenin-6 significantly reduced glucose levels and enhanced glucose-induced insulin release, with a duration of biological action beyond 8â¯h. Ψ-xenin-6 also significantly enhanced the glucose-lowering action of GIP in vivo. In overnight fasted mice, Ψ-xenin-6 exhibited satiety actions at both 25 and 250â¯nmol/kg. These data demonstrates that Ψ-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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Glucagón
/
Neurotensina
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Células Secretoras de Insulina
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Secreción de Insulina
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Hipoglucemiantes
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Mol Cell Endocrinol
Año:
2019
Tipo del documento:
Article
País de afiliación:
Reino Unido