Insulin-resistance (IR) is one of the most important precursors of type 2 diabetes (T2D). Recent evidence suggests an association of depression with the onset of T2D. Accumulating evidence shows that depression and T2D share common biological origins, and DNA methylation examination might reveal the link between lifestyle, disease risk, and potential therapeutic targets for T2D. Here we hypothesize that integrative mining of IR and depression cohort data will facilitate predictive biomarkers identification for T2D. We utilized a newly proposed method to extract gene-level information from probe level data on genome-wide DNA methylation array. We identified a set of genes associated with IR and depression in clinical cohorts. By overlapping the IR-related nutraceutical-gene network with depression networks, we identified a common subnetwork centered with Vitamin D Receptor (VDR) gene. Preliminary clinical validation of gene methylation set in a small cohort of T2D patients and controls was established using the Sequenome matrix-assisted laser desorption ionization-time flight mass spectrometry. A set of sites in the promoter regions of VDR showed a significant difference between T2D patients and controls. Using a logistic regression model, the optimal prediction performance of these sites was AUC = 0.902，and an odds ratio = 19.76. Thus, monitoring the methylation status of specific VDR promoter region might help stratify the high-risk individuals who could potentially benefit from vitamin D dietary supplementation. Our results highlight the link between IR and depression, and the DNA methylation analysis might facilitate the search for their shared mechanisms in the etiology of T2D.

胰岛素抵抗 (IR) 是 2 型糖尿病 (T2D) 最重要的前兆之一。最近的证据表明抑郁症与 T2D 的发生有关。越来越多的证据表明，抑郁症和 T2D 具有共同的生物学起源，DNA 甲基化检查可能揭示生活方式、疾病风险和 T2D 潜在治疗目标之间的联系。在这里，我们假设综合挖掘 IR 和抑郁队列数据将有助于 T2D 的预测性生物标志物识别。我们利用新提出的方法从全基因组 DNA 甲基化阵列的探针水平数据中提取基因水平信息。我们在临床队列中确定了一组与 IR 和抑郁症相关的基因。通过将 IR 相关的营养药物基因网络与抑郁症网络重叠，我们确定了一个以维生素 D 受体 (VDR) 基因为中心的常见子网络。使用 Sequenome 基质辅助激光解吸电离时间飞行质谱法对一小群 T2D 患者和对照组中的基因甲基化进行了初步临床验证。VDR 启动子区域中的一组位点在 T2D 患者和对照之间显示出显着差异。使用逻辑回归模型，这些站点的最佳预测性能为 AUC = 0.902，优势比 = 19.76。因此，监测特定 VDR 启动子区域的甲基化状态可能有助于对可能从维生素 D 膳食补充剂中受益的高风险个体进行分层。我们的结果强调了 IR 和抑郁症之间的联系，