Blood Metabolomic Signatures of One-Hour Glucose Predict Cardiometabolic Risk

Abstract

Background: Elevated 1-hour glucose levels during an oral glucose tolerance test (OGTT) strongly predict type 2 diabetes (T2D) and cardiovascular disease. We investigated whether fasting blood metabolome predicting 1-hour glucose could be a target for improving β-cell function, long-term glycemic trajectories, and reducing the risks of T2D and coronary heart disease (CHD). We also investigated whether plasma microRNAs derived from key metabolic organs regulate changes in a metabolomic risk score (MRS) for predicting 1-hour glucose. Methods: Untargeted blood metabolomics and a frequently sampled 75g OGTT were performed in participants from the OmniCarb trial (n=162). In an independent weight-loss dietary intervention trial (POUNDS Lost), temporal changes in MRS and plasma microRNAs measured by genome-wide sequencing were analyzed. In addition, associations of MRS at baseline and its 10-year changes with long-term risk of incident T2D and CHD were prospectively investigated in the Nurses’ Health Study (NHS). Results: We created a fasting blood MRS for predicting 1-hour glucose (Pearson r = 0.8) and found significant associations with half-day (diurnal) postprandial glucose excursions and insulin secretion after 5-week controlled feeding interventions varying in carbohydrate amount and glycemic index. In the POUNDS Lost trial, diet-induced changes in MRSs were related to 2-year trajectories of glucose metabolism; circulating microRNAs regulating cardiometabolic abnormalities were pivotal factors influencing these changes. In the NHS, women in the top 20% of MRS had a multivariate-adjusted relative risk of 3.80 (95% CI: 2.22, 6.51) for T2D and 1.48 (1.04, 2.12) for CHD compared to those in the lowest 20%. Additionally, 10-year increases in plasma metabolites related to 1-hour glucose were linearly associated with a higher risk of T2D. Conclusions: Our findings indicate that fasting blood metabolomic signatures predicting elevated 1-hour glucose reflect disease pathophysiology and are a target for preventing T2D and CHD.