Effects of an enzymatically stable C-terminal hexapseudopeptide fragment peptide of xenin-25, ψ-xenin-6, on pancreatic islet function and metabolism

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-BD11 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 betacells, 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 8 hours. 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 250 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.

Enzymatically stable analogue of the gut‐derived peptide xenin on beta‐cell transdifferentiation in high fat fed and insulin‐deficient Ins1Cre/+;Rosa26‐eYFP mice

“…Studies in both rodents and humans have shown that annulling glucagon receptor (GCGR) signalling is a highly effective therapeutic strategy in diabetes 35‐40 . Interestingly, in the acute in vitro and in vivo setting, xenin has been shown to induce glucagon secretion 41,42 . However, in the current study, long‐term treatment with xenin‐25[Lys 13 PAL] evoked substantial reductions in circulating glucagon and pancreatic alpha‐cell area in both STZ and HFF mice, suggesting secretory adaptations in the face of prolonged receptor activation.…”

Ψ-Xenin-6 enhances sitagliptin effectiveness, but does not improve glucose tolerance

“…Ψ-Xenin-6 is a C-terminal hexapeptide of xenin with a reduced pseudopeptide bond (CH 2 NH) positioned between the first two N-terminal amino acid residues that possesses a significantly extended pharmacokinetic profile (Feurle et al 2003). In our hands, Ψ-xenin-6 stimulated insulin secretion from in vitro and ex vivo systems, promoted beta-cell proliferation and survival, augmented glucose homeostasis, insulin secretion and satiety in rodents as well as amplified the insulinotropic actions of GIP (Craig et al 2019). Thus, combination therapy with a DPP-4 inhibitor and Ψ-xenin-6 represents an exciting potential therapeutic option for T2DM.…”

“…or oral) was administered as control at each time point either orally or intraperitoneally, as appropriate. Doses of sitagliptin and Ψ-xenin-6 were chosen based on previous published studies in mice (Gault et al 2015b, Craig et al 2019. Lean control mice (n = 8) were also administered saline vehicle twice daily (orally at 09:30 h and i.p.…”

“…Unlike GIP and GLP-1, xenin is not degraded by DPP-4 (Taylor et al 2010), and thus DPP-4 inhibitors do not alter circulating xenin levels. However, enzymatic degradation fragment peptides of xenin are present in plasma (Martin et al 2012), with some of these shown to retain the parent peptide biological action profile (Martin et al 2014, Craig et al 2019. In this regard, xenin-6 appears to be the shortest xenin form that recapitulates the key physiological actions of xenin at the level of the endocrine pancreas (Craig et al 2019).…”

“…Recent studies in our laboratory (Craig et al 2019) have followed up on the initial characterisation of an enzymatically stabilised xenin-6 form, namely Ψ-xenin-6 (Feurle et al 2003). Ψ-Xenin-6 is a C-terminal hexapeptide of xenin with a reduced pseudopeptide bond (CH 2 NH) positioned between the first two N-terminal amino acid residues that possesses a significantly extended pharmacokinetic profile (Feurle et al 2003).…”