Lafferty Ryan A, Gault Victor A, Flatt Peter R, Irwin Nigel
SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, UK.
Diabetes Research Group, University of Ulster, Coleraine, UK.
Clin Med Insights Endocrinol Diabetes. 2019 Jun 17;12:1179551419855626. doi: 10.1177/1179551419855626. eCollection 2019.
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, (PLP)PYY(1-36) and PYY(1-36)(LysPAL), with further structural modifications to enhance NPYR1 specificity. As expected, (PLP)PYY(1-36) was fully resistant to DPP-4-mediated degradation in vitro, whereas PYY(1-36) and PYY(1-36)(LysPAL) were both liable to DPP-4 breakdown. PYY(1-36) and (PLP)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)(LysPAL) 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 M, for (PLP)PYY(1-36) and PYY(1-36)(LysPAL) in BRIN BD11 cells. Regarding the protection of beta-cells against cytokine-induced apoptosis, PYY(1-36) induced clear protective effects. Both (PLP)PYY(1-36) and PYY(1-36)(LysPAL) 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 M) protected against cytokine-induced apoptosis, but (PLP)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.
近期研究已确定肽酪氨酰酪氨酸（PYY）对胰腺β细胞功能及存活具有有益作用。这些效应与PYY（1 - 36）激活神经肽Y1受体（NPYR1s）有关。然而，PYY（1 - 36）易被二肽基肽酶 - 4（DPP - 4）快速降解，导致NPYR1活性丧失。因此，本研究的目的是开发2种酶稳定性的PYY（1 - 36）类似物，即（PLP）PYY（1 - 36）和PYY（1 - 36）（LysPAL），并进行进一步的结构修饰以增强NPYR1特异性。正如预期的那样，（PLP）PYY（1 - 36）在体外对DPP - 4介导的降解完全具有抗性，而PYY（1 - 36）和PYY（1 - 36）（LysPAL）都易于被DPP - 4分解。PYY（1 - 36）和（PLP）PYY（1 - 36）可使BRIN BD11细胞的葡萄糖刺激胰岛素分泌（GSIS）显著降低，但只有PYY（1 - 36）能减少丙氨酸刺激的胰岛素分泌。相比之下，PYY（1 - 36）（LysPAL）对GSIS或丙氨酸诱导的胰岛素释放没有影响。所有3种PYY肽均显著增强了BRIN BD11和1.1B4β细胞系的增殖，尽管仅在最高检测浓度（10 μM）时，（PLP）PYY（1 - 36）和PYY（1 - 36）（LysPAL）对BRIN BD11细胞才有此作用。关于β细胞免受细胞因子诱导凋亡的保护作用，PYY（1 - 36）具有明显的保护作用。（PLP）PYY（1 - 36）和PYY（1 - 36）（LysPAL）对BRIN BD11细胞的凋亡均有一定保护作用，但效果明显不如PYY（1 - 36）。同样，在1.1B4细胞中，两种PYY类似物（10 μM）均可保护细胞免受细胞因子诱导的凋亡，但（PLP）PYY（见补充材料和方法）。所有3种PYY肽对过夜禁食小鼠的再进食均无影响。这些数据强调了PYY（1 - 36）对β细胞的益处，并突出了合成稳定、生物活性、NPYR1特异性的PYY（1 - 36）类似物所面临的挑战。
