Metabolomic approaches to dissect dysregulated metabolism in the progression of pre-diabetes to T2DM

Most of pre-diabetes were eventually progress to diabetes, thereby profiling of prediabetic metabolic disorders may be an effective targeted preventive measure. We aimed to elucidate internal motivation of the progression of pre-diabetes to type 2 diabetes mellitus (T2DM) from a metabolic perspective. Four sets of serum samples (20 subjects per group) according to fasting blood glucose (FBG) concentration were collected for metabolomic analysis. An integrative approach of metabolome and WGCNA was employed to explore candidate metabolites. Compared with healthy group (FBG < 5.6 mmol/L), 113 metabolites were differentially expressed in the early stage of pre-diabetes (5.6 mmol/L ≤ FBG < 6.1 mmol/L), 237 in the late stage of pre-diabetes (6.1 mmol/L ≤ FBG < 7.0 mmol/L) and 245 in T2DM group (FBG ≥ 7.0 mmol/L). A total of 27 DEMs were identified shared in all comparisons. Among them, L-norleucine was down-regulated whereas ethionamide, glutathione oxidized, 5-Methylcytosine and alpha-D-Glucopyranoside beta-D-fructofuranosyl were increased with the rising of FBG. Surprisingly, 15 (11 LPCs, L-norleucine, glutathione oxidized, arachidonic acid and 5-Oxoproline) of the 27 DEMs were ferroptosis-associated metabolites. WGCNA clustered all metabolites into 8 modules and pathway enrichment analysis of DEMs showed a significant annotation to insulin resistance-related pathway. Integrated analysis of DEMs, ROC and WGCNA modules determined 12 potential biomarkers for pre-diabetes and T2DM, including L-norleucine, 8 of which were L-arginine or its metabolites. L-norleucine and L-arginine could be served as biomarkers for pre-diabetes. The inventory of metabolites provides by our serum metabolome offer insights into T2DM physiology metabolism.