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Peptide YY (1-36) peptides from phylogenetically ancient fish targeting mammalian neuropeptide Y1 receptors demonstrate potent effects on pancreatic β-cell function, growth and survival.
Diabetes, Obesity and Metabolism ( IF 5.8 ) Pub Date : 2019-12-09 , DOI: 10.1111/dom.13908
Ryan A Lafferty 1 , Neil Tanday 1 , Andrew McCloskey 1 , Pradeep Bompada 2 , Yang De Marinis 2 , Peter R Flatt 1 , Nigel Irwin 1
Affiliation  

AIM To investigate the antidiabetic efficacy of enzymatically stable Peptide YY (PYY) peptides from phylogenetically ancient fish. MATERIALS AND METHODS N-terminally stabilized, PYY (1-36) sequences from Amia calva (bowfin), Oncorhynchus mykiss (trout), Petromyzon marinus (sea lamprey) and Scaphirhynchus albus (sturgeon), were synthesized, and both biological actions and antidiabetic therapeutic efficacy were assessed. RESULTS All fish PYY (1-36) peptides were resistant to dipeptidyl peptidase-4 (DPP-4) degradation and inhibited glucose- and alanine-induced (P < 0.05 to P < 0.001) insulin secretion. In addition, PYY (1-36) peptides imparted significant (P < 0.05 to P < 0.001) β-cell proliferative and anti-apoptotic benefits. Proliferative effects were almost entirely absent in β cells with CRISPR-Cas9-induced knockout of Npyr1. In contrast to human PYY (1-36), the piscine-derived peptides lacked appetite-suppressive actions. Twice-daily administration of sea lamprey PYY (1-36), the superior bioactive peptide, for 21 days significantly (P < 0.05 to P < 0.001) decreased fluid intake, non-fasting glucose and glucagon in streptozotocin (STZ)-induced diabetic mice. In addition, glucose tolerance, insulin sensitivity, pancreatic insulin and glucagon content were significantly improved. Metabolic benefits were linked to positive changes in pancreatic islet morphology as a result of augmented (P < 0.001) proliferation and decreased apoptosis of β cells. Sturgeon PYY (1-36) exerted similar but less impressive effects in STZ mice. CONCLUSION These observations reveal, for the first time, that PYY (1-36) peptide sequences from phylogenetically ancient fish replicate the pancreatic β-cell benefits of human PYY (1-36) and have clear potential for the treatment of type 2 diabetes.

中文翻译:

系统发育古鱼针对哺乳动物神经肽Y1受体的YY(1-36)肽对胰腺β细胞的功能,生长和存活表现出有效的作用。

目的研究系统发育古鱼中酶促稳定的YY肽(PYY)的抗糖尿病作用。材料与方法合成了来自Amia calva(bowfin),Oncorhynchus mykiss(鳟鱼),Petromyzon marinus(sea Lamprey)和Scaphirhynchus albus(st鱼)N末端稳定的PYY(1-36)序列,并具有生物学作用和抗糖尿病药评估治疗效果。结果所有鱼类PYY(1-36)肽均对二肽基肽酶4(DPP-4)降解具有抗性,并抑制葡萄糖和丙氨酸诱导的(P <0.05至P <0.001)胰岛素分泌。此外,PYY(1-36)肽具有显着的(P <0.05至P <0.001)β细胞增殖和抗凋亡优势。CRISPR-Cas9诱导的Npyr1敲除对β细胞几乎没有增殖作用。与人PYY(1-36)相反,鱼衍生肽缺乏食欲抑制作用。每天两次服用超级生物活性肽海七rey鳗PYY(1-36)连续21天(P <0.05至P <0.001),可减少链脲佐菌素(STZ)诱导的糖尿病患者的液体摄入,非空腹血糖和胰高血糖素。老鼠。此外,葡萄糖耐量,胰岛素敏感性,胰腺胰岛素和胰高血糖素含量也得到显着改善。代谢的好处与胰岛形态的积极变化有关,这是由于β细胞增殖增加(P <0.001)和凋亡减少所致。urge鱼PYY(1-36)在STZ小鼠中表现出相似但不那么令人印象深刻的效果。结论这些观察首次揭示了,
更新日期:2019-12-11
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