Effects of 2 Novel PYY(1-36) Analogues, ((PLP34)-L-3-P-31)PYY(1-36) and PYY(1-36)(Lys(12)PAL), on Pancreatic Beta-Cell Function, Growth, and Survival

Ryan Lafferty; Victor A Gault; PR Flatt; Nigel Irwin

doi:10.1177/1179551419855626

Effects of 2 Novel PYY(1-36) Analogues, ((PLP34)-L-3-P-31)PYY(1-36) and PYY(1-36)(Lys(12)PAL), on Pancreatic Beta-Cell Function, Growth, and Survival

Ryan Lafferty, Victor A Gault, PR Flatt, Nigel Irwin

Research output: Contribution to journal › Article › peer-review

28 Citations (Scopus)

43 Downloads (Pure)

Abstract

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.

Original language	English
Article number	1179551419855626
Number of pages	8
Journal	Clinical Medicine Insights: Endocrinology and Diabetes
Volume	12
Issue number	1179551419855626
DOIs	https://doi.org/10.1177/1179551419855626
Publication status	Published (in print/issue) - 17 Jun 2019

Bibliographical note

Funding Information:
FuNdING: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a PhD studentship (awarded to R.A.L.) from the Department for the Economy (DfE) Northern Ireland and University of Ulster strategic research funding.

Publisher Copyright:
© The Author(s) 2019.

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

Keywords

PYY
DPP-4
amino acid substitution
acylation
insulin secretion
Beta cell
beta-cell
peptide YY (PYY)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1177/1179551419855626

ClinMedInsights_PYYAuthor Accepted Manuscript, 497 KB

Cite this

@article{0fcaedb3350b484b8386755a0a533c56,

title = "Effects of 2 Novel PYY(1-36) Analogues, ((PLP34)-L-3-P-31)PYY(1-36) and PYY(1-36)(Lys(12)PAL), on Pancreatic Beta-Cell Function, Growth, and Survival",

abstract = "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.",

keywords = "PYY, DPP-4, amino acid substitution, acylation, insulin secretion, Beta cell, beta-cell, peptide YY (PYY)",

author = "Ryan Lafferty and Gault, {Victor A} and PR Flatt and Nigel Irwin",

note = "Funding Information: FuNdING: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a PhD studentship (awarded to R.A.L.) from the Department for the Economy (DfE) Northern Ireland and University of Ulster strategic research funding. Publisher Copyright: {\textcopyright} The Author(s) 2019. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2019",

month = jun,

day = "17",

doi = "10.1177/1179551419855626",

language = "English",

volume = "12",

journal = "Clinical Medicine Insights: Endocrinology and Diabetes ",

issn = "1179-5514",

publisher = "SAGE Publications",

number = "1179551419855626",

}

Effects of 2 Novel PYY(1-36) Analogues, ((PLP34)-L-3-P-31)PYY(1-36) and PYY(1-36)(Lys(12)PAL), on Pancreatic Beta-Cell Function, Growth, and Survival. / Lafferty, Ryan; Gault, Victor A ; Flatt, PR et al.
In: Clinical Medicine Insights: Endocrinology and Diabetes , Vol. 12, No. 1179551419855626, 1179551419855626, 17.06.2019.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Effects of 2 Novel PYY(1-36) Analogues, ((PLP34)-L-3-P-31)PYY(1-36) and PYY(1-36)(Lys(12)PAL), on Pancreatic Beta-Cell Function, Growth, and Survival

AU - Lafferty, Ryan

AU - Gault, Victor A

AU - Flatt, PR

AU - Irwin, Nigel

N1 - Funding Information: FuNdING: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a PhD studentship (awarded to R.A.L.) from the Department for the Economy (DfE) Northern Ireland and University of Ulster strategic research funding. Publisher Copyright: © The Author(s) 2019. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2019/6/17

Y1 - 2019/6/17

N2 - 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.

AB - 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.

KW - PYY

KW - DPP-4

KW - amino acid substitution

KW - acylation

KW - insulin secretion

KW - Beta cell

KW - beta-cell

KW - peptide YY (PYY)

UR - http://www.scopus.com/inward/record.url?scp=85067840193&partnerID=8YFLogxK

U2 - 10.1177/1179551419855626

DO - 10.1177/1179551419855626

M3 - Article

C2 - 31244528

SN - 1179-5514

VL - 12

JO - Clinical Medicine Insights: Endocrinology and Diabetes

JF - Clinical Medicine Insights: Endocrinology and Diabetes

IS - 1179551419855626

M1 - 1179551419855626

ER -

Effects of 2 Novel PYY(1-36) Analogues, ((PLP34)-L-3-P-31)PYY(1-36) and PYY(1-36)(Lys(12)PAL), on Pancreatic Beta-Cell Function, Growth, and Survival

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this