Ojo Opeolu O, Srinivasan Dinesh K, Owolabi Bosede O, Vasu Srividya, Conlon J Michael, Flatt Peter R, Abdel-Wahab Yasser H A
SAAD Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, United Kingdom; School of Sport, Health and Bioscience, University of East London, Stratford, E15 4LZ, United Kingdom.
SAAD Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, United Kingdom.
PLoS One. 2015 Oct 29;10(10):e0141549. doi: 10.1371/journal.pone.0141549. eCollection 2015.
The frog skin host-defense peptide esculentin-2CHa (GFSSIFRGVA10KFASKGLGK D20LAKLGVDLVA30CKISKQC) displays antimicrobial, antitumor, and immunomodulatory properties. This study investigated the antidiabetic actions of the peptide and selected analogues. Esculentin-2CHa stimulated insulin secretion from rat BRIN-BD11 clonal pancreatic β-cells at concentrations greater than 0.3 nM without cytotoxicity by a mechanism involving membrane depolarization and increase of intracellular Ca2+. Insulinotropic activity was attenuated by activation of KATP channels, inhibition of voltage-dependent Ca2+ channels and chelation of extracellular Ca2+. The [L21K], [L24K], [D20K, D27K] and [C31S,C37S] analogues were more potent but less effective than esculentin-2CHa whereas the [L28K] and [C31K] analogues were both more potent and produced a significantly (P < 0.001) greater maximum response. Acute administration of [L28K]esculentin-2CHa (75 nmol/kg body weight) to high fat fed mice with obesity and insulin resistance enhanced glucose tolerance and insulin secretion. Twice-daily administration of this dose of [L28K]esculentin-2CHa for 28 days had no significant effect on body weight, food intake, indirect calorimetry or body composition. However, mice exhibited decreased non-fasting plasma glucose (P < 0.05), increased non-fasting plasma insulin (P < 0.05) as well as improved glucose tolerance and insulin secretion (P < 0.01) following both oral and intraperitoneal glucose loads. Impaired responses of isolated islets from high fat fed mice to established insulin secretagogues were restored by [L28K]esculentin-2CHa treatment. Peptide treatment was accompanied by significantly lower plasma and pancreatic glucagon levels and normalization of α-cell mass. Circulating triglyceride concentrations were decreased but plasma cholesterol and LDL concentrations were not significantly affected. The data encourage further investigation of the potential of esculentin-2CHa related peptides for treatment of patients with type 2 diabetes.
蛙皮宿主防御肽天蚕抗菌肽-2CHa（GFSSIFRGVA10KFASKGLGK D20LAKLGVDLVA30CKISKQC）具有抗菌、抗肿瘤和免疫调节特性。本研究调查了该肽及其选定类似物的抗糖尿病作用。天蚕抗菌肽-2CHa在浓度大于0.3 nM时可刺激大鼠BRIN-BD11克隆胰腺β细胞分泌胰岛素，且无细胞毒性，其作用机制涉及膜去极化和细胞内Ca2+增加。KATP通道激活、电压依赖性Ca2+通道抑制以及细胞外Ca2+螯合可减弱促胰岛素活性。[L21K]、[L24K]、[D20K, D27K]和[C31S,C37S]类似物比天蚕抗菌肽-2CHa更有效但作用稍弱，而[L28K]和[C31K]类似物既更有效，产生的最大反应也显著更大（P < 0.001）。对患有肥胖症和胰岛素抵抗的高脂喂养小鼠急性给予[L28K]天蚕抗菌肽-2CHa（75 nmol/kg体重）可增强葡萄糖耐量和胰岛素分泌。以该剂量的[L28K]天蚕抗菌肽-2CHa每日两次给药28天，对体重、食物摄入量、间接量热法或身体组成无显著影响。然而，小鼠在口服和腹腔注射葡萄糖负荷后，非空腹血浆葡萄糖降低（P < 0.05），非空腹血浆胰岛素增加（P < 0.05），葡萄糖耐量和胰岛素分泌改善（P < 0.01）。[L28K]天蚕抗菌肽-2CHa处理可恢复高脂喂养小鼠分离胰岛对既定胰岛素促分泌剂的受损反应。肽处理伴随着血浆和胰腺胰高血糖素水平显著降低以及α细胞质量恢复正常。循环甘油三酯浓度降低，但血浆胆固醇和低密度脂蛋白浓度未受到显著影响。这些数据鼓励进一步研究天蚕抗菌肽-2CHa相关肽治疗2型糖尿病患者的潜力。
