Identification of Plasma Inositol and Indoxyl Sulfate as Novel Biomarker Candidates for Atherosclerosis in Patients with Type 2 Diabetes. -Findings from Metabolome Analysis Using GC/MS.

An identification of the high-risk group of atherosclerotic cardiovascular disease (CVD) is important in the management of patients with diabetes. Metabolomics is a potential tool for the discovery of new biomarkers. With this background, we aimed to identify metabolites associated with atherosclerosis in patients with type 2 diabetes mellitus (T2DM). A total of 176 patients with T2DM who have never had a CVD event and 40 who were survivors of coronary artery disease (CAD) events were enrolled. Non-targeted metabolome analysis of fasting plasma samples was performed using gas chromatography coupled with mass spectrometry (GC/MS) highly optimized for multiple measurement of blood samples. First, metabolites were screened by analyzing the association with the established markers of subclinical atherosclerosis (i.e., carotid maximal intima-media thickness (max-IMT) and flow-mediated vasodilation (FMD)) in the non-CVD subjects. Then, the associations between the metabolites detected and the history of CAD were investigated. A total of 65 annotated metabolites were detected. Non-parametric univariate analysis identified inositol and indoxyl sulfate as significantly (p＜0.05) associated with both max-IMT and FMD. These metabolites were also significantly associated with CAD. Moreover, inositol remained to be associated with CAD even after adjustments for traditional coronary risk factors. We identified novel biomarker candidates for atherosclerosis in Japanese patients with T2DM using GC/MS-based non-targeted metabolomics.