SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, UK.
Laboratory Affiliated To Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Biochemical Sciences, Sapienza University of Rome, Via degli Apuli 9, 00185, Rome, Italy.
Amino Acids. 2018 Jun;50(6):723-734. doi: 10.1007/s00726-018-2551-5. Epub 2018 Mar 17.
Long-standing Type 2 diabetes is associated with loss of both β-cell function and β-cell mass. Peptides derived from the frog-skin host-defense peptide esculentin-1 have been shown to exhibit potent, broad-spectrum antimicrobial activity. The aim of the present study is to determine whether such peptides also show insulinotropic and β-cell protective activities. Esculentin-1a(1-21).NH, esculentin-1b(1-18).NH, and esculentin-1a(1-14).NH produced concentration-dependent stimulations of insulin release from BRIN-BD11 rat clonal β-cells, 1.1B4 human-derived pancreatic β-cells, and isolated mouse islets with no cytotoxicity at concentrations of up to 3 μM. The mechanism of insulinotropic action involved membrane depolarization and an increase in intracellular Ca concentrations. The analogue [D-Lys, D-Ser]esculentin-1a(1-21).NH (Esc(1-21)-1c) was less potent in vitro than the all L-amino acid containing peptides and esculentin-1a(9-21) was inactive indicating that helicity is an important determinant of insulinotropic activity. However, intraperitoneal injection of Esc(1-21)-1c (75 nmol/kg body weight) together with a glucose load (18 mmol/kg body weight) in C57BL6 mice improved glucose tolerance with a concomitant increase in insulin secretion, whereas administration of esculentin-1a(1-21).NH, esculentin-1b(1-18).NH, and esculentin-1a(1-14) was without significant effect on plasma glucose levels. Esc(1-21)-1c (1 µM) protected BRIN-BD11 cells against cytokine-induced apoptosis (P < 0.01) and augmented proliferation of the cells (P < 0.01) to a similar extent as glucagon-like peptide-1. The data demonstrate that the multifunctional peptide Esc(1-21)-1c, as well as showing therapeutic potential as an anti-infective and wound-healing agent, may constitute a template for development of compounds for treatment of patients with Type 2 diabetes.
长期存在的 2 型糖尿病与β细胞功能和β细胞数量的丧失有关。从青蛙皮肤防御肽衍生的肽已被证明具有强大的广谱抗菌活性。本研究旨在确定此类肽是否还具有胰岛素促分泌和β细胞保护活性。Esculentin-1a(1-21).NH、esculentin-1b(1-18).NH 和 esculentin-1a(1-14).NH 从 BRIN-BD11 大鼠克隆β细胞、1.1B4 人源性胰腺β细胞和分离的小鼠胰岛中产生浓度依赖性的胰岛素释放刺激，在高达 3μM 的浓度下没有细胞毒性。胰岛素促分泌作用的机制涉及膜去极化和细胞内 Ca 浓度增加。类似物 [D-Lys, D-Ser]esculentin-1a(1-21).NH (Esc(1-21)-1c) 在体外的效力比所有包含 L-氨基酸的肽都弱，而 esculentin-1a(9-21) 没有活性，表明螺旋性是胰岛素促分泌活性的重要决定因素。然而，在 C57BL6 小鼠中，腹腔内注射 Esc(1-21)-1c（75nmol/kg 体重）和葡萄糖负荷（18mmol/kg 体重）改善了葡萄糖耐量，同时增加了胰岛素分泌，而 esculentin-1a(1-21).NH、esculentin-1b(1-18).NH 和 esculentin-1a(1-14) 对血浆葡萄糖水平没有显著影响。Esc(1-21)-1c（1μM）可保护 BRIN-BD11 细胞免受细胞因子诱导的凋亡（P<0.01），并增强细胞增殖（P<0.01），与胰高血糖素样肽-1 相似。数据表明，多功能肽 Esc(1-21)-1c 不仅具有作为抗感染和伤口愈合剂的治疗潜力，还可能成为开发治疗 2 型糖尿病患者化合物的模板。
