Musale Vishal, Moffett R Charlotte, Conlon J Michael, Flatt Peter R, Abdel-Wahab Yasser H
Diabetes Research Group, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, Northern Ireland, BT52 1SA, UK.
Diabetes Research Group, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, Northern Ireland, BT52 1SA, UK.
Peptides. 2021 Feb;136:170472. doi: 10.1016/j.peptides.2020.170472. Epub 2020 Dec 15.
The antidiabetic actions of [A14K]PGLa-AM1, an analog of peptide glycine-leucine-amide-AM1 isolated from skin secretions of the octoploid frog Xenopus amieti, were investigated in genetically diabetic-obese db/db mice. Twice daily administration of [A14K]PGLa-AM1 (75 nmol/kg body weight) for 28 days significantly (P < 0.05) decreased circulating blood glucose and HbA1c and increased plasma insulin concentrations leading to improvements in glucose tolerance. The elevated levels of triglycerides, LDL and cholesterol associated with the db/db phenotype were significantly reduced by peptide administration. Elevated plasma alanine transaminase, aspartic acid transaminase, and alkaline phosphatase activities and creatinine concentrations were also significantly decreased. Peptide treatment increased pancreatic insulin content and improved the responses of isolated islets to established insulin secretagogues. No significant changes in islet β-cell and α-cell areas were observed in [A14K]PGLa-AM1 treated mice but the loss of large and medium-size islets was prevented. Peptide administration resulted in a significant (P < 0.01) increase in islet expression of the gene encoding Pdx-1, a major transcription factor in islet cells determining β-cell survival and function, resulting in increased expression of genes involved with insulin secretion (Abcc8, Kcnj11, Slc2a2, Cacn1c) together with the genes encoding the incretin receptors Glp1r and Gipr. In addition, the elevated expression of insulin signalling genes (Slc2a4, Insr, Irs1, Akt1, Pik3ca, Ppm1b) in skeletal muscle associated with the db/db phenotype was downregulated by peptide treatment These data suggest that the anti-diabetic properties of [A14K]PGLa-AM1 are mediated by molecular changes that enhance both the secretion and action of insulin.
对从八倍体青蛙非洲爪蟾皮肤分泌物中分离出的肽甘氨酸 - 亮氨酸 - 酰胺 - AM1类似物[A14K]PGLa - AM1的抗糖尿病作用，在遗传性糖尿病肥胖db/db小鼠中进行了研究。每天两次给予[A14K]PGLa - AM1（75 nmol/kg体重），持续28天，显著（P < 0.05）降低了循环血糖和糖化血红蛋白（HbA1c）水平，并提高了血浆胰岛素浓度，从而改善了葡萄糖耐量。与db/db表型相关的甘油三酯、低密度脂蛋白（LDL）和胆固醇水平升高，通过给予该肽显著降低。血浆丙氨酸转氨酶、天冬氨酸转氨酶、碱性磷酸酶活性以及肌酐浓度的升高也显著降低。肽处理增加了胰腺胰岛素含量，并改善了分离胰岛对既定胰岛素促分泌剂的反应。在接受[A14K]PGLa - AM1处理的小鼠中，未观察到胰岛β细胞和α细胞面积有显著变化，但防止了大中型胰岛的丢失。给予该肽导致胰岛中编码Pdx - 1的基因表达显著（P < 0.01）增加，Pdx - 1是胰岛细胞中决定β细胞存活和功能的主要转录因子，导致参与胰岛素分泌的基因（Abcc8、Kcnj11、Slc2a2、Cacn1c）以及编码肠促胰岛素受体Glp1r和Gipr的基因表达增加。此外肽处理下调了与db/db表型相关的骨骼肌中胰岛素信号基因（Slc2a4、Insr、Irs1、Akt1、Pik3ca、Ppm1b）的高表达。这些数据表明，[A14K]PGLa - AM1的抗糖尿病特性是由增强胰岛素分泌和作用的分子变化介导的。
