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

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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.
LanguageEnglish
Article number1179551419855626
Number of pages8
JournalClinical Medicine Insights: Endocrinology and Diabetes
Volume12
Issue number1179551419855626
DOIs
Publication statusPublished - 17 Jun 2019

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Insulin-Secreting Cells
Growth
Dipeptidyl Peptidase 4
Ac-Nal(1)-Cpa(2)-Pal(3,6)-Arg(5)-Ala(10)-lHRH
peptide YY (1-36)
Insulin
Apoptosis
tyrosyltyrosine
Alanine
Neuropeptide Receptors
Cytokines
Glucose

Keywords

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

Cite this

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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",
year = "2019",
month = "6",
day = "17",
doi = "10.1177/1179551419855626",
language = "English",
volume = "12",
number = "1179551419855626",

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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

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)

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U2 - 10.1177/1179551419855626

DO - 10.1177/1179551419855626

M3 - Article

VL - 12

IS - 1179551419855626

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