Metabolomic Signature of Coronary Artery Disease in Type 2 Diabetes Mellitus

Abstract

Coronary artery disease (CAD) is a common complication of type 2 diabetes mellitus (T2D). This case-control study was done to identify metabolites with different concentrations between T2D patients with and without CAD and to characterise implicated metabolic mechanisms relating to CAD. Fasting serum samples of 57 T2D subjects, 26 with (cases) and 31 without CAD (controls), were targeted for metabolite profiling of 163 metabolites. To assess the association between metabolite levels and CAD, partial least squares (PLS) analysis and multivariate logistic regression analysis with adjustment for CAD risk factors and medications were performed. We observed a separation of cases and controls with two classes of metabolites being significantly associated with CAD, including phosphatidylcholines, and serine. Four metabolites being independent from the common CAD risk factors displaying best separation between cases and controls were further selected. Addition of the metabolite concentrations to risk factor analysis raised the area under the receiver-operating-characteristic curve from 0.72 to 0.88 (p = 0.020), providing improved sensitivity and specificity for CAD classification. Serum phospholipid and serine levels independently discriminate T2D patients with and without CAD. Oxidative stress and reduced antioxidative capacity lead to lower metabolite concentrations probably due to changes in membrane composition and accelerated phospholipid degradation.

Figure 1

CAD patients separated from non-CAD subjects. PLS-DA (partial least squares discriminant analysis) results are shown. Subjects with CAD are depicted in yellow and subjects without CAD in blue; medication intake is displayed as insulin therapy (circle) or oral antidiabetic agent intake (triangle); sex differences are highlighted in the size of the symbols: females (larger) and males (smaller).

Figure 2

Boxplots of the four identified CAD-specific metabolites. The continuous horizontal line is the median. The lower boundary of the box represents the 25th percentile, and the other boundary represents the 75th percentile. Whiskers above and below the box represent the 95th and 5th percentile.

Figure 3

Comparison of sensitivity and specificity with and without the four metabolites. ROC curves and measures of model fit (AUC) are presented for (1) model with clinical parameters (sex, age, BMI, HbA1c, diabetes duration, SBP, DBP, antihypertensives, TG, LDL : HDL ratio, lipid-lowering agents, albumin, and eGFR; dashed line) and (2) model combining the four selected metabolites and the clinical model (solid line).