Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
J Clin Endocrinol Metab. 2023 Dec 21;109(1):114-124. doi: 10.1210/clinem/dgad466.
The performance of peripheral blood transcriptional markers in evaluating risk of type 2 diabetes (T2D) with normal body mass index (BMI) is unknown.
We developed a whole blood-based transcriptional risk score (wb-TRS) for nonobese T2D and assessed its contributions on disease risk and dynamic changes in glucose metabolism.
Using a community-based cohort with blood transcriptome data, we developed the wb-TRS in 1105 participants aged ≥40 years who maintained a normal BMI for up to 10 years, and we validated the wb-TRS in an external dataset. Potential biological significance was explored.
The wb-TRS included 144 gene transcripts. Compared to the lowest tertile, wb-TRS in tertile 3 was associated with 8.91-fold (95% CI, 3.53-22.5) higher risk and each 1-unit increment was associated with 2.63-fold (95% CI, 1.87-3.68) higher risk of nonobese T2D. Furthermore, baseline wb-TRS significantly associated with dynamic changes in average, daytime, nighttime, and 24-hour glucose, HbA1c values, and area under the curve of glucose measured by continuous glucose monitoring over 6 months of intervention. The wb-TRS improved the prediction performance for nonobese T2D, combined with fasting glucose, triglycerides, and demographic and anthropometric parameters. Multi-contrast gene set enrichment (Mitch) analysis implicated oxidative phosphorylation, mTORC1 signaling, and cholesterol metabolism involved in nonobese T2D pathogenesis.
A whole blood-based nonobese T2D-associated transcriptional risk score was validated to predict dynamic changes in glucose metabolism. These findings suggested several biological pathways involved in the pathogenesis of nonobese T2D.
外周血转录标志物在评估正常体重指数（BMI）的 2 型糖尿病（T2D）风险方面的表现尚不清楚。
我们开发了一种基于全血的非肥胖 2 型糖尿病转录风险评分（wb-TRS），并评估了其对疾病风险和葡萄糖代谢动态变化的贡献。
使用具有血液转录组数据的社区为基础的队列，我们在 1105 名年龄≥40 岁且在长达 10 年内保持正常 BMI 的参与者中开发了 wb-TRS，并在外部数据集进行了验证。探索了潜在的生物学意义。
wb-TRS 包含 144 个基因转录本。与最低三分位相比，三分位 3 的 wb-TRS 与 8.91 倍（95%CI，3.53-22.5）的更高风险相关，每个 1 单位的增加与 2.63 倍（95%CI，1.87-3.68）的非肥胖 2 型糖尿病更高风险相关。此外，基线 wb-TRS 与 6 个月干预期间平均、白天、夜间和 24 小时葡萄糖、HbA1c 值和连续血糖监测的曲线下面积的动态变化显著相关。与空腹血糖、甘油三酯以及人口统计学和人体测量学参数相结合，wb-TRS 改善了对非肥胖 2 型糖尿病的预测性能。多对比度基因集富集（Mitch）分析表明，氧化磷酸化、mTORC1 信号和胆固醇代谢参与了非肥胖 2 型糖尿病的发病机制。
验证了一种基于全血的非肥胖 2 型糖尿病相关转录风险评分，以预测葡萄糖代谢的动态变化。这些发现表明了几种参与非肥胖 2 型糖尿病发病机制的生物学途径。
