Peptide YY (PYY) is a gastrointestinal hormone released from the enteroendocrine cell upon food intake. The N-terminal truncated form, PYY3-36, exerts anorexic effects. In this study we want to investigate the kinetics of PYY1-36 and PYY3-36 and to examine whether a C-terminally degraded metabolite, PYY3-34, is formed after infusion of PYY.

开始日期2014-05-01

申办/合作机构

Hvidovre University Hospital

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100 项与 PYY1-36 相关的临床结果

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100 项与 PYY1-36 相关的转化医学

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100 项与 PYY1-36 相关的专利（医药）

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项与 PYY1-36 相关的文献（医药）

2020-10-01·Metabolism1区 · 医学

Generation and characterisation of C-terminally stabilised PYY molecules with potential in vivo NPYR2 activity

1区 · 医学

Article

作者: Lafferty, Ryan A ; Irwin, Nigel ; Tanday, Neil ; Flatt, Peter R

BACKGROUNDActivation of neuropeptide Y2 receptors (NPYR2) by the N-terminally truncated, dipeptidyl peptidase-4 (DPP-4) generated, Peptide YY (PYY) metabolite, namely PYY(3-36), results in satiating actions. However, PYY(3-36) is also subject to C-terminal enzymatic cleavage, which annuls anorectic effects.METHODSSubstitution of l-Arg³⁵ with d-Arg³⁵ in the DPP-4 stable sea lamprey PYY(1-36) peptide imparts full C-terminal stability. In the current study, we have taken this molecule and introduced DPP-4 susceptibility by Iso³ substitution.RESULTSAs expected, [Iso³]sea lamprey PYY(1-36) and [Iso³](d-Arg³⁵)sea lamprey PYY(1-36) were N-terminally degraded to respective PYY(3-36) metabolites in plasma. Only [Iso³](d-Arg³⁵)sea lamprey PYY(1-36) was C-terminally stable. Both peptides possessed similar insulinostatic and anti-apoptotic biological actions to native PYY(1-36) in beta-cells. Unlike native PYY(1-36) and [Iso³](d-Arg³⁵)sea lamprey PYY(1-36), [Iso³]sea lamprey PYY(1-36) displayed some proliferative actions in Npyr1 knockout beta-cells. In addition, [Iso³]sea lamprey PYY(1-36) induced more rapid NPYR2-dependent appetite suppressive effects in mice than its C-terminally stable counterpart. Twice daily administration of either peptide to high fat fed (HFF) mice resulted in significant body weight reduction and improvements in circulating triglyceride levels. [Iso³]sea lamprey PYY(1-36) treatment also prevented elevations in glucagon. Both peptides, and especially [Iso³]sea lamprey PYY(1-36), improved glucose tolerance. The treatment interventions also partially reversed the deleterious effects of sustained high fat feeding on pancreatic islet morphology.CONCLUSIONThe present study confirms that sustained NPYR2 receptor activation by [Iso³](d-Arg³⁵)sea lamprey induced significant weight lowering actions. However, identifiable benefits of this peptide over [Iso³]sea lamprey PYY(1-36), which was not protected against C-terminal degradation, were not pronounced.

2020-05-01·Biochimica et Biophysica Acta (BBA) - General Subjects3区 · 生物学

Development and characterisation of a peptidergic N-and C-terminally stabilised mammalian NPY1R agonist which protects against diabetes induction

3区 · 生物学

Article

作者: Lafferty, Ryan A ; Irwin, Nigel ; Tanday, Neil ; Flatt, Peter R

BACKGROUNDPYY (1-36) peptides from phylogenetically ancient fish, such as sea lamprey, have previously been shown to function as specific neuropeptide Y1 receptor (NPYR1) agonists. Although, sea lamprey PYY (1-36) is N-terminally stable, we reveal in this study that the peptide is subject to endopeptidase mediated C-terminal dipeptide degradation. In an attempt to prevent this, (d-Arg³⁵)-sea lamprey PYY (1-36) was developed.METHODSIn vitro bioassays assessed enzymatic stability, insulinostatic activity as well as beta-cell anti-apoptotic actions of (d-Arg³⁵)-sea lamprey PYY (1-36). Follow-up studies examined the impact of twice daily administration of sea lamprey PYY (1-36) or (d-Arg³⁵)-sea lamprey PYY (1-36) in multiple low dose STZ-induced diabetic mice.RESULTS(d-Arg³⁵)-sea lamprey PYY (1-36) was fully resistant to plasma enzymatic degradation. The peptide possessed similar significant insulinostatic, as well as positive anti-apoptotic biological actions, as the parent peptide. Sea lamprey PYY (1-36) and (d-Arg³⁵)-sea lamprey PYY (1-36) delayed diabetes progression in STZ mice. Both treatment interventions induced a significant decrease in body weight, food and fluid intake as well as glucose and glucagon concentrations. In addition, glucose tolerance, plasma and pancreatic insulin were partially normalised. (d-Arg³⁵)-sea lamprey PYY (1-36) was significantly more effective than sea lamprey PYY (1-36) in terms of enhancing glucose-stimulate insulin release. Both treatments improved pancreatic islet morphology, linked to decreased apoptosis of beta-cells.CONCLUSIONWe present (d-Arg³⁵)-sea lamprey PYY (1-36) as the first-in-class N- and C-terminally stable PYY (1-36) peptide analogue.GENERAL SIGNIFICANCEEnzymatically stable, long-acting PYY (1-36) peptides highlight the therapeutic benefits of sustained activation of NPYR1's in diabetes.

2019-01-01·Clinical Medicine Insights: Endocrinology and Diabetes

Effects of 2 Novel PYY(1-36) Analogues, (P³L³¹P³⁴)PYY(1-36) and PYY(1-36)(Lys¹²PAL), on Pancreatic Beta-Cell Function, Growth, and Survival

Article

作者: Irwin, Nigel ; Lafferty, Ryan A ; Flatt, Peter R ; Gault, Victor A

Recent studies have identified a beneficial role for peptide tyrosine tyrosine (PYY) on pancreatic beta-cell function and survival. These effects are linked to the activation of neuropeptide Y1 receptors (NPYR1s) by PYY(1-36). However, PYY(1-36) is subject to rapid degradation by dipeptidyl peptidase-4 (DPP-4), resulting is the loss of NPYR1 activity. Therefore, the aim of this study was to develop 2 enzymatically stable PYY(1-36) analogues, namely, (P3L31P34)PYY(1-36) and PYY(1-36)(Lys12PAL), with further structural modifications to enhance NPYR1 specificity. As expected, (P3L31P34)PYY(1-36) was fully resistant to DPP-4-mediated degradation in vitro, whereas PYY(1-36) and PYY(1-36)(Lys12PAL) were both liable to DPP-4 breakdown. PYY(1-36) and (P3L31P34)PYY(1-36) induced significant reductions in glucose-stimulated insulin secretion (GSIS) from BRIN BD11 cells, but only PYY(1-36) diminished alanine-stimulated insulin secretion. In contrast, PYY(1-36)(Lys12PAL) had no impact on GSIS or alanine-induced insulin release. All 3 PYY peptides significantly enhanced proliferation in BRIN BD11 and 1.1B4 beta-cell lines, albeit only at the highest concentration examined, 10-6 M, for (P3L31P34)PYY(1-36) and PYY(1-36)(Lys12PAL) in BRIN BD11 cells. Regarding the protection of beta-cells against cytokine-induced apoptosis, PYY(1-36) induced clear protective effects. Both (P3L31P34)PYY(1-36) and PYY(1-36)(Lys12PAL) offered some protection against apoptosis in BRIN BD11 cells, but were significantly less efficacious than PYY(1-36). Similarly, in 1.1B4 cells, both PYY analogues (10-6 M) protected against cytokine-induced apoptosis, but (P3L31P34)PYY(1-36) was significantly less effective than PYY(1-36). All 3 PYY peptides had no impact on refeeding in overnight fasted mice. These data underline the beta-cell benefits of PYY(1-36) and highlight the challenges of synthesising stable, bioactive, NPYR1-specific, PYY(1-36) analogues.

100 项与 PYY1-36 相关的药物交易

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


EASD2018	N/A	-	-	PYY(1-36)	夢淵獵襯醖糧衊鹽餘衊(構膚積選網淵鬱襯積壓) = 艱築鏇窪製範築醖選構窪選餘醖襯憲糧蓋觸繭 (鹽鹽繭鹽願糧蓋遞繭艱 )	-	2018-10-04
				PYY(1-36)	夢淵獵襯醖糧衊鹽餘衊(構膚積選網淵鬱襯積壓) = 願壓壓夢鏇鏇獵願衊壓窪選餘醖襯憲糧蓋觸繭 (鹽鹽繭鹽願糧蓋遞繭艱 )