Department of Internal Medicine, Linyi Jiaotong Hospital, Linyi, China.
Department of Cardiology, Linyi People's Hospital, Linyi, China.
J Cell Physiol. 2019 Apr;234(4):4997-5010. doi: 10.1002/jcp.27300. Epub 2018 Oct 20.
Vascular calcification is highly prevalent in patients with type 2 diabetes mellitus (T2DM), one of the most common chronic diseases with high morbidity and mortality. In recent years, microRNAs have been widely reported as potential biomarkers for the diagnosis and treatment of T2DM. We hypothesized that miR-128-3p is associated with cardiovascular calcification and insulin resistance (IR) in rats with T2DM by targeting ISL1 via the Wnt pathway. Microarray analysis was adopted to identify differentially expressed genes related to T2DM. T2DM models were induced in rats. Blood samples from normal and T2DM rats were used to detect islet β-cell function, islet sensitivity, and calcium content. Next, islet tissues were obtained to identify the expression of miR-128-3p, ISL1, and the Wnt signaling pathway- and apoptosis-related genes. Finally, apoptosis of islet β-cells was determined by flow cytometry. Through microarray analysis of GSE27382 and GSE23343, ISL1 was found to be downregulated in T2DM. In blood samples from T2DM rats, basic biochemical indicators, IR, and calcium content were increased, and islet sensitivity and islet β-cell function were decreased. Furthermore, upregulation of miR-128-3p and ISL1 gene silencing promoted the expression of Wnt-1, β-catenin, GSK-3β, and Bax and the phosphorylation of β-catenin and GSK-3β, inhibited c-fos, PDX-1, and Bcl-2 expression, and enhanced cell apoptosis. The key findings of our study demonstrate that miR-128-3p aggravates cardiovascular calcification and IR in T2DM rats by downregulating ISL1 through the activation of the Wnt pathway. Thus, miR-128-3p may serve as a potential target for the treatment of T2DM.
血管钙化在 2 型糖尿病（T2DM）患者中非常普遍，T2DM 是最常见的慢性病之一，具有高发病率和死亡率。近年来，microRNAs 被广泛报道为 T2DM 的诊断和治疗的潜在生物标志物。我们假设 miR-128-3p 通过 Wnt 通路靶向 ISL1 与 T2DM 大鼠的心血管钙化和胰岛素抵抗（IR）有关。采用微阵列分析鉴定与 T2DM 相关的差异表达基因。在大鼠中诱导 T2DM 模型。使用正常和 T2DM 大鼠的血液样本检测胰岛β细胞功能、胰岛敏感性和钙含量。接下来，获得胰岛组织以鉴定 miR-128-3p、ISL1 和 Wnt 信号通路和凋亡相关基因的表达。最后，通过流式细胞术测定胰岛β细胞的凋亡。通过 GSE27382 和 GSE23343 的微阵列分析，发现 ISL1 在 T2DM 中下调。在 T2DM 大鼠的血液样本中，基本生化指标、IR 和钙含量增加，胰岛敏感性和胰岛β细胞功能降低。此外，上调 miR-128-3p 和沉默 ISL1 基因促进了 Wnt-1、β-catenin、GSK-3β 和 Bax 的表达以及 β-catenin 和 GSK-3β 的磷酸化，抑制了 c-fos、PDX-1 和 Bcl-2 的表达，并增强了细胞凋亡。我们的研究的主要发现表明，miR-128-3p 通过激活 Wnt 通路下调 ISL1 加重 T2DM 大鼠的心血管钙化和 IR。因此，miR-128-3p 可能成为治疗 T2DM 的潜在靶点。
