Whole Blood-based Transcriptional Risk Score for Nonobese Type 2 Diabetes Predicts Dynamic Changes in Glucose Metabolism

Context: The performance of peripheral blood transcriptional markers in evaluating risk of type 2 diabetes (T2D) with normal body mass index (BMI) is unknown. Objective: 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. Methods: 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. Results: 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. Conclusion: 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.