Laboratório de Carboidratos e Radioimunoensios - LIM/18, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
Heart Institute (InCor) and Division of Clinical Immunology and Allergy - LIM60, University of São Paulo School of Medicine, São Paulo, Brazil.
Front Immunol. 2019 Jul 23;10:1637. doi: 10.3389/fimmu.2019.01637. eCollection 2019.
MicroRNAs (miRs) are master regulators of post-transcriptional gene expression, and they are often dysregulated in individuals suffering from diabetes. We investigated the roles of miR-101-3p and miR-204-5p, both of which negatively regulate insulin secretion and cell survival and are highly expressed in pancreatic β cells, in the context of type 1 diabetes (T1D) pathogenesis. Using quantitative real time PCR, we evaluated serum levels of miR-101-3p and miR-204-5p in four groups, including recent-onset T1D patients (T1D group; = 50), individuals with normal glucose levels expressing one islet autoantibody (Ab) (single Ab group; = 26) or multiple autoantibodies (multiple Ab group; = 12), and healthy controls (control group; = 43). An analysis was performed to identify potential target genes of these miRNAs and to delineate enriched pathways. The relative expression of serum miR-101-3p was approximately three times higher in the multiple Ab and T1D groups than that in the single Ab and control groups ( < 0.0001). When considering all groups together, miR-101-3p expression was positively correlated with the level of islet autoantibodies GADA ( = 0.267; = 0.0027) and IA-2A ( = 0.291; = 0.001), and the expression of the miRNA was not correlated with levels of ZnT8A ( = 0.125; = 0.183). miR-101-3p expression did not correlate with HbA1c ( = 0.178; = 0.052) or glucose levels ( = 0.177; = 0.051). No significant differences were observed in miR-204-5p expression among the analyzed groups. Computational analysis of the miR-101-3p target gene pathways indicated a potential activation of the HGF/c-Met, Ephrin receptor, and STAT3 signaling pathways. Our study demonstrated that the circulating levels of miR-101-3p are higher in T1D patients and in individuals with normal glucose levels, testing positive for multiple autoantibodies, indicating that miR-101-3p precedes loss of glucose homeostasis. The pathogenic role of miR-101-3p in T1D may involve multiple molecular pathways.
微小 RNA（miRs）是转录后基因表达的主要调控因子，它们在患有糖尿病的个体中通常失调。我们研究了 miR-101-3p 和 miR-204-5p 的作用，这两种 miRNA 都能负调控胰岛素分泌和细胞存活，并且在胰岛 β 细胞中高度表达，在 1 型糖尿病（T1D）发病机制中发挥作用。使用定量实时 PCR，我们评估了包括近期诊断为 T1D 患者（T1D 组；n = 50）、葡萄糖水平正常且仅表达一种胰岛自身抗体（Ab）（单 Ab 组；n = 26）或多种自身抗体（多 Ab 组；n = 12）和健康对照者（对照组；n = 43）在内的四组人群血清中 miR-101-3p 和 miR-204-5p 的水平。进行了 分析以鉴定这些 miRNA 的潜在靶基因，并描绘富含的途径。与单 Ab 和对照组相比，多 Ab 和 T1D 组血清中 miR-101-3p 的相对表达水平约高 3 倍（<0.0001）。当综合考虑所有组时，miR-101-3p 的表达与胰岛自身抗体 GADA（r = 0.267；P = 0.0027）和 IA-2A（r = 0.291；P = 0.001）水平呈正相关，而 miRNA 的表达与 ZnT8A 水平无相关性（r = 0.125；P = 0.183）。miR-101-3p 的表达与 HbA1c（r = 0.178；P = 0.052）或葡萄糖水平（r = 0.177；P = 0.051）均无相关性。在分析的各组中，miR-204-5p 的表达无显著差异。miR-101-3p 靶基因途径的计算分析表明，HGF/c-Met、Ephrin 受体和 STAT3 信号通路可能被潜在激活。我们的研究表明，T1D 患者和葡萄糖水平正常但检测出多种自身抗体的个体中，miR-101-3p 的循环水平较高，表明 miR-101-3p 先于葡萄糖稳态丧失。miR-101-3p 在 T1D 中的致病作用可能涉及多个分子途径。
