IRCCS MultiMedica, via G. Fantoli 16/15, 20138, Milan, Italy.
Institute for Endocrinology and Experimental Oncology 'G. Salvatore', C.N.R, via Pansini 5, 80131, Naples, Italy.
Diabetologia. 2020 Dec;63(12):2699-2712. doi: 10.1007/s00125-020-05237-x. Epub 2020 Jul 29.
AIMS/HYPOTHESIS: We aimed to analyse the association between plasma circulating microRNAs (miRNAs) and the immunometabolic profile in children with type 1 diabetes and to identify a composite signature of miRNAs/immunometabolic factors able to predict type 1 diabetes progression.
Plasma samples were obtained from children at diagnosis of type 1 diabetes (n = 88) and at 12 (n = 32) and 24 (n = 30) months after disease onset and from healthy control children with similar sex and age distribution (n = 47). We quantified 60 robustly expressed plasma circulating miRNAs by quantitative RT-PCR and nine plasma immunometabolic factors with a recognised role at the interface of metabolic and immune alterations in type 1 diabetes. Based on fasting C-peptide loss over time, children with type 1 diabetes were stratified into the following groups: those who had lost >90% of C-peptide compared with diagnosis level; those who had lost <10% of C-peptide; those showing an intermediate C-peptide loss. To evaluate the modulation of plasma circulating miRNAs during the course of type 1 diabetes, logistic regression models were implemented and the correlation between miRNAs and immunometabolic factors was also assessed. Results were then validated in an independent cohort of children with recent-onset type 1 diabetes (n = 18). The prognostic value of the identified plasma signature was tested by a neural network-based model.
Plasma circulating miR-232724 clusters (miR-23a-3p, miR-23b-3p, miR-24-3p, miR-27a-3p and miR-27b-3p) were upmodulated upon type 1 diabetes progression, showed positive correlation with osteoprotegerin (OPG) and were negatively correlated with soluble CD40 ligand, resistin, myeloperoxidase and soluble TNF receptor in children with type 1 diabetes but not in healthy children. The combination of plasma circulating miR-23a-3p, miR-23b-3p, miR-24-3p, miR-27b-3p and OPG, quantified at disease onset, showed a significant capability to predict the decline in insulin secretion 12 months after disease diagnosis in two independent cohorts of children with type 1 diabetes.
CONCLUSIONS/INTERPRETATIONS: We have pinpointed a novel miR-23a-3p/miR-23b-3p/miR-24-3p/miR-27b-3p/OPG plasma signature that may be developed into a novel blood-based method to better stratify patients with type 1 diabetes and predict C-peptide loss.
目的/假设：我们旨在分析血浆循环 microRNAs (miRNAs) 与 1 型糖尿病患儿免疫代谢特征之间的关联，并确定能够预测 1 型糖尿病进展的 miRNA/免疫代谢因子复合特征。
从 1 型糖尿病患儿（n=88）发病时、12 个月（n=32）和 24 个月（n=30）时以及具有相似性别和年龄分布的健康对照儿童（n=47）中获得血浆样本。我们通过定量 RT-PCR 定量了 60 种稳定表达的血浆循环 miRNAs，并检测了在 1 型糖尿病代谢和免疫改变界面具有公认作用的 9 种血浆免疫代谢因子。根据空腹 C 肽随时间的丢失情况，1 型糖尿病患儿分为以下几组：与诊断水平相比，C 肽丢失>90%；C 肽丢失<10%；C 肽丢失处于中间水平。为了评估 1 型糖尿病病程中血浆循环 miRNAs 的调节，我们实施了逻辑回归模型，并评估了 miRNAs 与免疫代谢因子之间的相关性。结果在另一组近期诊断的 1 型糖尿病患儿（n=18）中得到验证。通过基于神经网络的模型测试鉴定的血浆特征的预后价值。
在 1 型糖尿病进展过程中，血浆循环 miR-232724 簇（miR-23a-3p、miR-23b-3p、miR-24-3p、miR-27a-3p 和 miR-27b-3p）上调，与骨保护素（OPG）呈正相关，与可溶性 CD40 配体、抵抗素、髓过氧化物酶和可溶性 TNF 受体呈负相关，在 1 型糖尿病患儿中而非在健康儿童中呈负相关。在两个独立的 1 型糖尿病患儿队列中，在发病时定量检测血浆循环 miR-23a-3p、miR-23b-3p、miR-24-3p、miR-27b-3p 和 OPG 的组合，具有显著的能力来预测疾病诊断后 12 个月胰岛素分泌的下降。
结论/解释：我们已经确定了一个新的 miR-23a-3p/miR-23b-3p/miR-24-3p/miR-27b-3p/OPG 血浆特征，该特征可能被开发为一种新的基于血液的方法，以更好地对 1 型糖尿病患者进行分层，并预测 C 肽的丢失。
