Nunez Lopez Yury O, Garufi Gabriella, Seyhan Attila A
Translational Research Institute for Metabolism and Diabetes, Florida Hospital, 301 East Princeton St., Orlando, FL 32804, USA.
Mol Biosyst. 2016 Dec 20;13(1):106-121. doi: 10.1039/c6mb00596a.
Today obesity and type 2 diabetes (T2D) have both reached epidemic proportions. However, our current understanding of the primary mechanisms leading to these diseases is still limited due to the complex multifactorial nature of the underlying phenomena. We hypothesize that the levels of specific cytokines and miRNAs vary across the diabetes spectrum and unique signatures associated with them may serve as early biomarkers of the disease and provide insights into respective pathogenetic mechanisms. In this study, we measured the circulating levels of cytokines and microRNAs (miRNAs) in lean and obese humans with prediabetes (n = 21), T2D (n = 17), and healthy controls (n = 20) (ORIGINS trial, NCT02226640). Data were analyzed by fitting linear models adjusted for confounding variables (BMI, age, and gender in the diabetes context and age, gender, and diabetes status in the obesity context) and implementing nonparametric randomization-based tests for statistical inference. Group differences and correlations (r > 0.3) between variables with P < 0.05 were considered significant. False discovery rates (FDR) correcting for multiple testing were calculated using the Benjamini-Hochberg correction. We found a number of circulating cytokines and miRNAs deregulated in subjects with obesity, prediabetes, and T2D. Specifically, cytokines IL-6, IL-8, IL-10, IL-12, and SFRP4, as well as miRNAs miR-21, miR-24.1, miR-27a, miR-28-3p, miR-29b, miR-30d, miR-34a, miR-93, miR-126, miR-146a, miR-148, miR-150, miR-155, and miR-223, significantly changed across the diabetes spectrum, and were associated with measures of pancreatic islet β cell function and glycemic control, among others. Notably, SFRP4 was the only studied cytokine that was significantly associated with obesity, prediabetes, and T2D, which underscores the important role of this molecule during disease development and progression. Our data suggest that changes in circulating miRNAs and cytokines may have clinical utility as biomarkers of prediabetes.
如今，肥胖症和2型糖尿病（T2D）均已达到流行程度。然而，由于潜在现象具有复杂的多因素性质，我们目前对导致这些疾病的主要机制的理解仍然有限。我们假设特定细胞因子和微小RNA（miRNA）的水平在糖尿病谱系中各不相同，与之相关的独特特征可能作为该疾病的早期生物标志物，并为各自的发病机制提供见解。在本研究中，我们测量了患有糖尿病前期（n = 21）、T2D（n = 17）的肥胖和消瘦人群以及健康对照者（n = 20）（ORIGINS试验，NCT02226640）体内细胞因子和微小RNA（miRNA）的循环水平。通过拟合针对混杂变量（糖尿病情况下的BMI、年龄和性别以及肥胖情况下的年龄、性别和糖尿病状态）进行调整的线性模型并实施基于非参数随机化的统计推断检验来分析数据。P < 0.05的变量之间的组间差异和相关性（r > 0.3）被视为具有统计学意义。使用Benjamini-Hochberg校正计算用于多重检验校正的错误发现率（FDR）。我们发现许多循环细胞因子和miRNA在肥胖、糖尿病前期和T2D患者中失调。具体而言，细胞因子白细胞介素-6（IL-6）、白细胞介素-8（IL-8）、白细胞介素-10（IL-10）、白细胞介素-12（IL-12）和分泌型卷曲相关蛋白4（SFRP4），以及miRNA miR-21、miR-24.1、miR-27a、miR-28-3p、miR-29b、miR-30d、miR-34a、miR-93、miR-126、miR-146a、miR-148、miR-150、miR-155和miR-223在整个糖尿病谱系中发生了显著变化，并与胰岛β细胞功能和血糖控制等指标相关。值得注意的是，SFRP4是唯一一项研究中与肥胖、糖尿病前期和T2D均显著相关的细胞因子，这突出了该分子在疾病发生和发展过程中的重要作用。我们的数据表明，循环miRNA和细胞因子的变化可能作为糖尿病前期的生物标志物具有临床应用价值。
