Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Cells. 2020 Feb 19;9(2):481. doi: 10.3390/cells9020481.
Diabetes mellitus is a metabolic disorder approaching epidemic proportions. Non-alcoholic fatty liver disease (NAFLD) regularly coexists with metabolic disorders, including type 2 diabetes, obesity, and cardiovascular disease. Recently, we demonstrated that the voltage-dependent anion channel 1 (VDAC1) is involved in NAFLD. VDAC1 is an outer mitochondria membrane protein that serves as a mitochondrial gatekeeper, controlling metabolic and energy homeostasis, as well as crosstalk between the mitochondria and the rest of the cell. It is also involved in mitochondria-mediated apoptosis. Here, we demonstrate that the VDAC1-based peptide, R-Tf-D-LP4, affects several parameters of a NAFLD mouse model in which administration of streptozotocin (STZ) and high-fat diet 32 (STZ/HFD-32) led to both type 2 diabetes (T2D) and NAFLD phenotypes. We focused on diabetes, showing that R-Tf-D-LP4 peptide treatment of STZ/HFD-32 fed mice restored the elevated blood glucose back to close to normal levels, and increased the number and average size of islets and their insulin content as compared to untreated controls. Similar results were obtained when staining the islets for glucose transporter type 2. In addition, the R-Tf-D-LP4 peptide decreased the elevated glucose levels in a mouse displaying obese, diabetic, and metabolic symptoms due to a mutation in the obese (ob) gene. To explore the cause of the peptide-induced improvement in the endocrine pancreas phenotype, we analyzed the expression levels of the proliferation marker, Ki-67, and found it to be increased in the islets of STZ/HFD-32 fed mice treated with the R-Tf-D-LP4 peptide. Moreover, peptide treatment of STZ/HFD-32 fed mice caused an increase in the expression of β-cell maturation and differentiation PDX1 transcription factor that enhances the expression of the insulin-encoding gene, and is essential for islet development, function, proliferation, and maintenance of glucose homeostasis in the pancreas. This increase occurred mainly in the β-cells, suggesting that the source of their increased number after R-Tf-D-LP4 peptide treatment was most likely due to β-cell proliferation. These results suggest that the VDAC1-based R-Tf-D-LP4 peptide has potential as a treatment for diabetes.
糖尿病是一种代谢紊乱疾病，其发病率呈上升趋势。非酒精性脂肪性肝病（NAFLD）常与代谢紊乱同时存在，包括 2 型糖尿病、肥胖和心血管疾病。最近，我们证明电压依赖性阴离子通道 1（VDAC1）参与了 NAFLD 的发生。VDAC1 是一种线粒体外膜蛋白，作为线粒体的门卫，控制着代谢和能量平衡，以及线粒体与细胞其他部分之间的交流。它还参与线粒体介导的细胞凋亡。在这里，我们证明基于 VDAC1 的肽 R-Tf-D-LP4 可影响 STZ 和高脂肪饮食 32（STZ/HFD-32）诱导的 2 型糖尿病（T2D）和 NAFLD 表型的 NAFLD 小鼠模型的多个参数。我们专注于糖尿病，结果表明，R-Tf-D-LP4 肽治疗 STZ/HFD-32 喂养的小鼠可将升高的血糖恢复到接近正常水平，并增加胰岛的数量和平均大小及其胰岛素含量，与未治疗的对照组相比。当用葡萄糖转运蛋白 2 对胰岛进行染色时，也得到了类似的结果。此外，该 R-Tf-D-LP4 肽还降低了肥胖、糖尿病和代谢症状突变的肥胖（ob）基因小鼠中升高的血糖水平。为了探讨肽诱导的内分泌胰腺表型改善的原因，我们分析了增殖标志物 Ki-67 的表达水平，发现 R-Tf-D-LP4 肽处理的 STZ/HFD-32 喂养的小鼠胰岛中 Ki-67 的表达增加。此外，肽处理 STZ/HFD-32 喂养的小鼠引起 PDX1 转录因子的β细胞成熟和分化的表达增加，该转录因子增强胰岛素编码基因的表达，是胰岛发育、功能、增殖和维持胰腺葡萄糖内稳态所必需的。这种增加主要发生在β细胞中，表明 R-Tf-D-LP4 肽处理后其数量增加的来源很可能是β细胞增殖。这些结果表明，基于 VDAC1 的 R-Tf-D-LP4 肽具有作为糖尿病治疗的潜力。
