Vasu Srividya, Ojo Opeolu O, Moffett R Charlotte, Conlon J Michael, Flatt Peter R, Abdel-Wahab Yasser H A
SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, UK.
Cell Growth and Metabolism Section, Diabetes, Endocrinology, and Obesity Branch, NIDDK, National Institutes of Health, Bethesda, MD, 20892, USA.
Amino Acids. 2017 Oct;49(10):1705-1717. doi: 10.1007/s00726-017-2469-3. Epub 2017 Aug 23.
Actions of esculentin-2CHa(1-30) (GFSSIFRGVAKFASKGLGKDLAKLGVDLVA) and its analogues, ([D-Arg, D-Lys, D-Lys]-esculentin-2CHa(1-30) and [Lys-octanoate]-esculentin-2CHa(1-30), were evaluated in high-fat fed NIH Swiss mice with impaired glucose tolerance and insulin resistance. Twice-daily i.p. administration of the esculentin-2CHa(1-30) peptides (75 nmol/kg body weight) or exendin-4 (25 nmol/kg) for 28 days reduced body weight, without altering cumulative energy intake. All peptides reduced blood glucose levels by 6-12 mmol/l concomitant with lower plasma insulin levels, with significance evident from day 6. All peptides improved glucose tolerance, insulin sensitivity, blood glucose profile over 24 h and decreased HbA1 to a similar extent as exendin-4. The peptides also reduced high fat diet-induced increases in plasma GLP-1 and glucagon. None of the peptides altered bone mineral density/content or lean mass but decreased fat mass. Islets isolated from peptide-treated mice exhibited improved glucose-, alanine- and GLP-1-stimulated insulin secretion. Islet morphometric analyses revealed that exendin-4 and the esculentin-2CHa(1-30) peptides significantly reduced islet, beta and alpha cell areas compared to high-fat controls. Esculentin-2CHa(1-30) peptides markedly reduced high fat diet-induced increase in beta cell proliferation and apoptosis. Peptide treatments had beneficial effects on expression of islet genes (Ins1, Slc2a2, Pdx1) and skeletal muscle genes involved in insulin action (Slc2a4, Pdk1, Irs1, Akt1). High-fat diet significantly increased LDL cholesterol which was reduced by the acylated esculentin-2CHa(1-30) analogue. Peptide treatments did not alter circulating concentrations of amylase and marker enzymes of liver function, indicating a lack of toxicity. These data indicate that esculentin-2CHa(1-30) and its analogues may be useful for improvement of blood glucose control and weight loss in type 2 diabetes.
在糖耐量受损和胰岛素抵抗的高脂喂养NIH瑞士小鼠中评估了七叶皂苷素-2CHa(1-30)（GFSSIFRGVAKFASKGLGKDLAKLGVDLVA）及其类似物（[D-精氨酸，D-赖氨酸，D-赖氨酸]-七叶皂苷素-2CHa(1-30)和[赖氨酸-辛酸酯]-七叶皂苷素-2CHa(1-30)）的作用。每天两次腹腔注射七叶皂苷素-2CHa(1-30)肽（75 nmol/kg体重）或艾塞那肽-4（25 nmol/kg），持续28天，可减轻体重，而不改变累积能量摄入。所有肽均可使血糖水平降低至6-12 mmol/l，同时血浆胰岛素水平降低，从第6天起效果显著。所有肽均改善了糖耐量、胰岛素敏感性、24小时血糖谱，并使糖化血红蛋白降低程度与艾塞那肽-4相似。这些肽还降低了高脂饮食诱导的血浆胰高血糖素样肽-1和胰高血糖素的升高。这些肽均未改变骨矿物质密度/含量或瘦体重，但降低了脂肪量。从肽处理的小鼠中分离的胰岛显示出改善的葡萄糖、丙氨酸和胰高血糖素样肽-1刺激的胰岛素分泌。胰岛形态计量学分析显示，与高脂对照组相比，艾塞那肽-4和七叶皂苷素-2CHa(1-30)肽显著减小了胰岛、β细胞和α细胞面积。七叶皂苷素-2CHa(1-30)肽显著降低了高脂饮食诱导的β细胞增殖和凋亡增加。肽处理对胰岛基因（Ins1、Slc2a2、Pdx1）和参与胰岛素作用的骨骼肌基因（Slc2a4、Pdk1、Irs1、Akt1）的表达有有益影响。高脂饮食显著增加了低密度脂蛋白胆固醇，而酰化的七叶皂苷素-2CHa(1-30)类似物可降低其水平。肽处理未改变淀粉酶的循环浓度和肝功能标记酶，表明无毒性。这些数据表明，七叶皂苷素-2CHa(1-30)及其类似物可能有助于改善2型糖尿病患者的血糖控制和体重减轻。
