Degradation, insulin secretion, glucose-lowering and GIP additive actions of a palmitate-derivatised analogue of xenin-25

Martin, Christine M.; Gault, Victor; McClean, Stephen; Flatt, Peter R.; Irwin, Nigel

doi:10.1016/j.bcp.2012.04.015

Cited by 44 publications

(58 citation statements)

References 20 publications

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“…Development of a specific assay to directly measure (DAla 2 )GIP/xenin-8-Gln in plasma would be useful to determine the pharmacokinetic profile of the hybrid peptide. Moreover, methodology such as peptide acylation or PEGylation may help to extend the biological half-life of (DAla 2 )GIP/xenin-8-Gln [29,36]. Notably, the biological effects of (DAla 2 )GIP/xenin-8-Gln were equal, or indeed enhanced, when compared with either parent peptide administered at the same dose.…”

Section: Resultsmentioning

confidence: 99%

An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

Hasib

Gault

et al. 2016

Diabetologia

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Aims/hypothesis Glucose-dependent insulinotropic polypeptide (GIP) and xenin, regulatory gut hormones secreted from enteroendocrine K cells, exert important effects on metabolism. In addition, xenin potentiates the biological actions of GIP. The present study assessed the actions and therapeutic utility of a (DAla 2 )GIP/xenin-8-Gln hybrid peptide, in comparison with the parent peptides (DAla 2 )GIP and xenin-8-Gln. Methods Following confirmation of enzymatic stability, insulin secretory activity of (DAla 2 )GIP/xenin-8-Gln was assessed in BRIN-BD11 beta cells. Acute and persistent glucose-lowering and insulin-releasing effects were then examined in vivo. Finally, the metabolic benefits of twice daily injection of (DAla 2 )GIP/xenin-8-Gln was determined in high-fat-fed mice.

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Section: Resultsmentioning

confidence: 99%

An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

Hasib

Gault

et al. 2016

Diabetologia

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“…Notwithstanding this, the various biological actions of xenin-25 established to date have aroused significant interest in the possible therapeutic action of stable, enzyme-resistant, xenin-based analogues for the therapy of obesity-diabetes (Martin et al 2012). This is particularly applicable given that xenin-25 could restore the welldocumented compromised insulin-releasing action of GIP in type 2 diabetes (Nauck et al 1993).…”

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confidence: 99%

“…Similar to most regulatory peptides, native xenin-25 is efficiently degraded by plasma enzymes once secreted into the bloodstream (Taylor et al 2010, Martin et al 2012. Recently, the degradation products and enzymatic cleavage sites for native xenin-25 have been determined through the use of electrospray ionisation tandem mass spectrometry (ESI-MS/MS) sequencing, algorithms and databases (Martin et al 2012).…”

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“…Recently, the degradation products and enzymatic cleavage sites for native xenin-25 have been determined through the use of electrospray ionisation tandem mass spectrometry (ESI-MS/MS) sequencing, algorithms and databases (Martin et al 2012). Thus, the plasma enzymatic degradation fragment peptides of native xenin-25 include xenin 9-25, xenin 11-25, xenin 14-25 and xenin 18-25 (Martin et al 2012). However, the physiological importance of these degradation fragments is largely unknown, and it is conceivable that they could possess important biological functions.…”

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confidence: 99%

“…In this regard, xenin 18-25 (also named xenin-8) was originally identified in dogs (Feurle et al 1997) and demonstrated to have insulinotropic effects in the perfused rat pancreas (Silvestre et al 2003). Despite this, a novel, fully enzymatic resistant form of native xenin-25 was shown to have significantly improved biological activity compared with the native peptide, including enhanced insulin-releasing actions (Martin et al 2012).…”

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

Martin

Parthsarathy

Pathak

et al. 2014

Journal of Endocrinology

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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 K6 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. Key Words" glucose-dependent insulinotropic polypeptide (GIP)" high fat-fed mice " bioactivity " xenin-25

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Emerging therapeutic potential for xenin and related peptides in obesity and diabetes

Craig

Gault

Irwin

2018

Diabetes Metabolism Res

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Xenin-25 is a 25-amino acid peptide hormone co-secreted from the same enteroendocrine K-cell as the incretin peptide glucose-dependent insulinotropic polypeptide. There is no known specific receptor for xenin-25, but studies suggest that at least some biological actions may be mediated through interaction with the neurotensin receptor. Original investigation into the physiological significance of xenin-25 focussed on effects related to gastrointestinal transit and satiety. However, xenin-25 has been demonstrated in pancreatic islets and recently shown to possess actions in relation to the regulation of insulin and glucagon secretion, as well as promoting beta-cell survival. Accordingly, the beneficial impact of xenin-25, and related analogues, has been assessed in animal models of diabetes-obesity. In addition, studies have demonstrated that metabolically active fragment peptides of xenin-25, particularly xenin-8, possess independent therapeutic promise for diabetes, as well as serving as bioactive components for the generation of multi-acting hybrid peptides with antidiabetic potential. This review focuses on continuing developments with xenin compounds in relation to new therapeutic approaches for diabetes-obesity.

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Degradation, insulin secretion, glucose-lowering and GIP additive actions of a palmitate-derivatised analogue of xenin-25

Cited by 44 publications

References 20 publications

An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

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

Emerging therapeutic potential for xenin and related peptides in obesity and diabetes

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