循环 microRNAs 谱分析揭示了与 2 型糖尿病相关的常见 microRNAs，这些 microRNAs 随着胰岛素敏感性的改变而变化。

Profiling of circulating microRNAs reveals common microRNAs linked to type 2 diabetes that change with insulin sensitization.

机构信息

Corresponding author: José Manuel Fernández-Real,

出版信息

Diabetes Care. 2014;37(5):1375-83. doi: 10.2337/dc13-1847. Epub 2014 Jan 29.

DOI:10.2337/dc13-1847

PMID:24478399

Abstract

OBJECTIVE

This study sought to identify the profile of circulating microRNAs (miRNAs) in type 2 diabetes (T2D) and its response to changes in insulin sensitivity.

RESEARCH DESIGN AND METHODS

The circulating miRNA profile was assessed in a pilot study of 12 men: 6 with normal glucose tolerance (NGT) and 6 T2D patients. The association of 10 circulating miRNAs with T2D was cross-sectionally validated in an extended sample of 45 NGT vs. 48 T2D subjects (65 nonobese and 28 obese men) and longitudinally in 35 T2D patients who were recruited in a randomized, double-blinded, and placebo-controlled 3-month trial of metformin treatment. Circulating miRNAs were also measured in seven healthy volunteers before and after a 6-h hyperinsulinemic-euglycemic clamp and insulin plus intralipid/heparin infusion.

RESULTS

Cross-sectional studies disclosed a marked increase of miR-140-5p, miR-142-3p, and miR-222 and decreased miR-423-5p, miR-125b, miR-192, miR-195, miR-130b, miR-532-5p, and miR-126 in T2D patients. Multiple linear regression analyses revealed that miR-140-5p and miR-423-5p contributed independently to explain 49.5% (P < 0.0001) of fasting glucose variance after controlling for confounders. A discriminant function of four miRNAs (miR-140-5p, miR-423-5p, miR-195, and miR-126) was specific for T2D with an accuracy of 89.2% (P < 0.0001). Metformin (but not placebo) led to significant changes in circulating miR-192 (49.5%; P = 0.022), miR-140-5p (-15.8%; P = 0.004), and miR-222 (-47.2%; P = 0.03), in parallel to decreased fasting glucose and HbA1c. Furthermore, while insulin infusion during clamp decreased miR-222 (-62%; P = 0.002), the intralipid/heparin mixture increased circulating miR-222 (163%; P = 0.015) and miR-140-5p (67.5%; P = 0.05).

CONCLUSIONS

This study depicts the close association between variations in circulating miRNAs and T2D and their potential relevance in insulin sensitivity.

摘要

目的

本研究旨在鉴定 2 型糖尿病（T2D）患者循环 microRNAs（miRNAs）的特征及其对胰岛素敏感性变化的反应。

研究设计和方法

在一项 12 名男性的初步研究中评估了循环 miRNA 谱：6 名糖耐量正常（NGT）和 6 名 T2D 患者。在一个扩展的样本中，将 45 名 NGT 与 48 名 T2D 受试者（65 名非肥胖和 28 名肥胖男性）的 10 种循环 miRNA 与 T2D 的相关性进行了横断面验证，并在 35 名 T2D 患者中进行了纵向验证，这些患者在一项为期 3 个月的二甲双胍治疗的随机、双盲、安慰剂对照试验中被招募。在 7 名健康志愿者进行 6 小时高胰岛素-正常血糖钳夹和胰岛素加静脉内脂肪乳/肝素输注前后测量循环 miRNA。

结果

横断面研究显示，T2D 患者的 miR-140-5p、miR-142-3p 和 miR-222 显著增加，miR-423-5p、miR-125b、miR-192、miR-195、miR-130b、miR-532-5p 和 miR-126 减少。多元线性回归分析显示，miR-140-5p 和 miR-423-5p 独立解释了空腹血糖变异的 49.5%（P < 0.0001），在控制混杂因素后。四个 miRNA（miR-140-5p、miR-423-5p、miR-195 和 miR-126）的判别函数对 T2D 具有特异性，准确性为 89.2%（P < 0.0001）。二甲双胍（而非安慰剂）导致循环 miR-192（49.5%；P = 0.022）、miR-140-5p（-15.8%；P = 0.004）和 miR-222（-47.2%；P = 0.03）的显著变化，同时空腹血糖和 HbA1c 降低。此外，在钳夹期间胰岛素输注时，miR-222 降低（-62%；P = 0.002），而静脉内脂肪乳/肝素混合物增加了循环 miR-222（163%；P = 0.015）和 miR-140-5p（67.5%；P = 0.05）。