AIMS/HYPOTHESIS MicroRNAs (miRNAs) are a novel class of potential biomarkers emerging in many diseases, including type 1 diabetes. Here, we aim to analyse a panel of circulating miRNAs in non-obese diabetic (NOD) mice and individuals with type 1 diabetes. METHODS We adopted standardised methodologies for extracting miRNAs from small sample volumes to evaluate a profiling panel of mature miRNAs in paired plasma and laser-captured microdissected immune-infiltrated islets of recently diabetic and normoglycaemic NOD mice. Moreover, we validated the findings during disease progression and remission after anti-CD3 therapy in NOD mice, as well as in individuals with type 1 diabetes. RESULTS Plasma levels of five miRNAs were downregulated in diabetic vs normoglycaemic mice. Of those, miR-409-3p was also downregulated in situ in the immune islet infiltrates of diabetic mice, suggesting an association with disease pathogenesis. Target-prediction tools linked miR-409-3p to immune- and metabolism-related signalling molecules. In situ miR-409-3p expression correlated with insulitis severity, and CD8+ central memory T cells were found to be enriched in miR-409-3p. Plasma miR-409-3p levels gradually decreased during diabetes development and improved with disease remission after anti-CD3 antibody therapy. Finally, plasma miR-409-3p levels were lower in people recently diagnosed with type 1 diabetes compared with a non-diabetic control group, and levels were inversely correlated with HbA1c levels. CONCLUSIONS/INTERPRETATION We propose that miR-409-3p may represent a new circulating biomarker of islet inflammation and type 1 diabetes severity.

中文翻译：

---

miR-409-3p在NOD糖尿病小鼠的血浆和胰岛免疫浸润中减少，并在1型糖尿病患者中差异表达。

目的/假设MicroRNA（miRNA）是一类新型的潜在生物标志物，出现在许多疾病中，包括1型糖尿病。在这里，我们旨在分析一组非肥胖糖尿病（NOD）小鼠和1型糖尿病个体中的循环miRNA。方法我们采用标准化的方法从少量样品中提取miRNA，以评估配对的血浆和激光捕获的显微切割的免疫浸润的胰岛中成熟的miRNA的分布图，这些胰岛是近期糖尿病和血糖正常的NOD小鼠。此外，我们在NOD小鼠以及1型糖尿病患者中验证了抗CD3治疗后疾病进展和缓解期间的发现。结果在糖尿病小鼠和血糖正常小鼠中，五个miRNA的血浆水平被下调。那些，miR-409-3p在糖尿病小鼠的免疫胰岛浸润液中也被下调，提示与疾病的发病机制有关。靶标预测工具将miR-409-3p与免疫和代谢相关的信号分子连接起来。原位miR-409-3p表达与胰岛素样炎的严重程度相关，并且发现CD8 +中枢记忆T细胞富含miR-409-3p。在糖尿病发展过程中，血浆miR-409-3p水平逐渐降低，并在抗CD3抗体治疗后随着疾病缓解而提高。最后，与非糖尿病对照组相比，最近被诊断出患有1型糖尿病的人的血浆miR-409-3p水平更低，并且该水平与HbA1c水平呈负相关。