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Abstract：
Well-controlled type 1 diabetes (T1DM) is characterized by inflammation and endothelial dysfunction, thus constituting a suitable model of subclinical cardiovascular disease (CVD). miR-199b-5p overexpression in murine CVD has shown proatherosclerotic effects. We hypothesized that miR-199b-5p would be overexpressed in subclinical CVD yet downregulated following metformin therapy. Inflammatory and vascular markers were measured in 29 individuals with T1DM and 20 matched healthy controls (HCs). miR-199b-5p expression in CFU-Hill\'s colonies was analyzed from each study group, and correlations with inflammatory/vascular health indices were evaluated. Significant upregulation of miR-199b-5p was observed in T1DM, which was significantly downregulated by metformin. miR-199b-5p correlated positively with vascular endothelial growth factor-D and c-reactive protein (CRP: nonsignificant). ROC analysis determined miR-199b-5p to define subclinical CVD by discriminating between HCs and T1DM individuals. ROC analyses of HbA1c and CRP showed that the upregulation of miR-199b-5p in T1DM individuals defined subclinical CVD at HbA1c > 44.25 mmol and CRP > 4.35 × 106 pg/mL. Ingenuity pathway analysis predicted miR-199b-5p to inhibit the target genes SIRT1, ETS1, and JAG1. Metformin was predicted to downregulate miR-199b-5p via NFATC2 and STAT3 and reverse its downstream effects. This study validated the antiangiogenic properties of miR-199b-5p and substantiated miR-199b-5p overexpression as a biomarker of subclinical CVD. The downregulation of miR-199b-5p by metformin confirmed its cardio-protective effect.
摘要：
良好控制的1型糖尿病（T1DM）的特征是炎症和内皮功能障碍，从而构成亚临床心血管疾病（CVD）的合适模型。miR-199b-5p在小鼠CVD中的过表达已显示出前动脉粥样硬化作用。我们假设miR-199b-5p在亚临床CVD中过表达，但在二甲双胍治疗后下调。在29名患有T1DM的个体和20名匹配的健康对照(HCs)中测量炎症和血管标志物。从每个研究组分析CFU-Hill's菌落中miR-199b-5p的表达，并评估与炎症/血管健康指数的相关性。在T1DM中观察到miR-199b-5p的显著上调,二甲双胍显著下调。miR-199b-5p与血管内皮生长因子-D和C反应蛋白（CRP：无意义）呈正相关。ROC分析确定miR-199b-5p通过区分HC和T1DM个体来定义亚临床CVD。HbA1c和CRP的ROC分析表明，T1DM个体中miR-199b-5p的上调定义为HbA1c>44.25mmol和CRP>4.35×106pg/mL的亚临床CVD。独创性通路分析预测miR-199b-5p抑制靶基因SIRT1、ETS1和JAG1。预测二甲双胍通过NFATC2和STAT3下调miR-199b-5p并逆转其下游效应。这项研究验证了miR-199b-5p的抗血管生成特性，并证实了miR-199b-5p过表达作为亚临床CVD的生物标志物。二甲双胍下调miR-199b-5p证实了其心脏保护作用。
