Stimulatory effect of xenin-8 on insulin and glucagon secretion in the perfused rat pancreas

Silvestre, Ramona A.; Rodriguez-Gallardo, J.; Egido, Eva M.; Hernández, Raquel; Marco, José

doi:10.1016/s0167-0115(03)00147-2

Cited by 28 publications

(33 citation statements)

References 17 publications

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“…The importance of the C-terminus of xenin-25 in terms of biological activity has been indicated previously. As such, xenin 18-25 was shown to have direct effects on pancreatic hormone secretion (Silvestre et al 2003). We have confirmed these findings in the present study, where xenin 18-25 had equipotent insulinotropic effects to the native peptide.…”

Section: Discussionsupporting

confidence: 89%

“…Despite this, there is a possibility that the recently characterised enzymatic degradation fragments of xenin-25 (Martin et al 2012) may have a physiological role in relation to the overall biological effects of xenin-25. As such, xenin 18-25 was demonstrated to possess insulin-releasing actions in the perfused rat pancreas (Silvestre et al 2003). Consistent with previous observations using clonal pancreatic BRIN-BD11 cells (Taylor et al 2010, Martin et al 2012), xenin-25 induced a concentrationdependent increase in insulin release at physiological and supraphysiological glucose concentrations.…”

Section: Discussionsupporting

confidence: 85%

“…However, the physiological importance of these degradation fragments is largely unknown, and it is conceivable that they could possess important biological functions. 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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confidence: 99%

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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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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 85%

mentioning

confidence: 99%

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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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“…In addition, xenin is now thought to be involved in the regulation of calorie intake (Leckstrom et al 2009) and possibly insulin secretion (Silvestre et al 2003). Thus, the aim of the current study was to evaluate the effects and role of xenin in food intake, glucose homoeostasis and insulin secretion.…”

Section: Discussionmentioning

confidence: 99%

“…infusion of xenin stimulated exocrine pancreatic secretion and also evoked a rise in insulin and glucagon levels as well as an increase in vasoactive intestinal polypeptide and pancreatic polypepide levels . Interestingly, a C-terminally truncated form of xenin, xenin-8, has been shown to exert possible insulinotropic and glucagonotropic actions in the perfused rat pancreas, but lacked somatostatin-releasing effects (Silvestre et al 2003). Furthermore, given that plasma xenin concentrations were significantly elevated during feeding (Feurle et al 2003), and that it is secreted from the same K cell as the incretin hormone glucose-dependent insulinotropic polypeptide (GIP), the possibility of xenin functioning in an incretin-like context is also conceivable.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the degradation and metabolic effects of the gut peptide xenin on insulin secretion, glycaemic control and satiety

Taylor

Irwin²,

McKillop³

et al. 2010

Journal of Endocrinology

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Recently, glucagon-like peptide 1 (GLP1) and glucosedependent insulinotropic polypeptide (GIP) have received much attention regarding possible roles in aetiology and treatment of type 2 diabetes. However, peptides co-secreted from the same enteroendocrine cells are less well studied. The present investigation was designed to characterise the in vitro and in vivo effects of xenin, a peptide co-secreted with GIP from intestinal K-cells. We examined the enzymatic stability, insulin-releasing activity and associated cAMP production capability of xenin in vitro. In addition, the effects of xenin on satiety, glucose homoeostasis and insulin secretion were examined in vivo. Xenin was time dependently degraded (t 1/2 Z162G6 min) in plasma in vitro. In clonal BRIN-BD11 cells, xenin stimulated insulin secretion at 5 . 6 mM (P!0 . 05) and 16 . 7 mM (P!0 . 05 to P!0 . 001) glucose levels compared to respective controls. Xenin also exerted an additive effect on GIP, GLP1 and neurotensin-mediated insulin secretion. In clonal b-cells, xenin did not stimulate cellular cAMP production, alter membrane potential or elevate intra-cellular Ca 2C. In normal mice, xenin exhibited a short-acting (P!0 . 01) satiety effect at high dosage (500 nmol/kg). In overnight fasted mice, acute injection of xenin enhanced glucose-lowering and elevated insulin secretion when injected concomitantly or 30 min before glucose. These effects were not observed when xenin was administered 60 min before the glucose challenge, reflecting the short half-life of the native peptide in vivo. Overall, these data demonstrate that xenin may have significant metabolic effects on glucose control, which merit further study.

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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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Stimulatory effect of xenin-8 on insulin and glucagon secretion in the perfused rat pancreas

Cited by 28 publications

References 17 publications

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

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

Evaluation of the degradation and metabolic effects of the gut peptide xenin on insulin secretion, glycaemic control and satiety

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

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