Targeted amino acid profiling reveals early metabolic alterations in young-onset type 2 diabetes mellitus

Early metabolic disturbances in young-onset Type 2 Diabetes Mellitus (T2DM) are frequently overlooked by conventional glycemic indices, necessitating sensitive molecular markers of early dysfunction. Amino acids, as key regulators of metabolic flux, redox homeostasis and insulin signaling represent attractive biomarker candidates. We employed a rapid, derivatization free four minutes LC-ESI-HRMS method for quantifying 20 amino acids and three amino acid related metabolites from only 10 μL of fasting plasma. The method was applied to young onset T2DM patients (<40 years; n = 28) and healthy controls (n = 22). Eight metabolites were significantly altered in young-onset T2DM, with increased methionine and tryptophan levels and a marked reduction in cysteine. Pathway analysis revealed disruptions across 14 metabolic pathways, predominantly affecting aromatic and sulfur amino acid metabolism. Integrated univariate and multivariate analysis identified a seven amino acid panel (glycine, cysteine, glutamic acid, valine, methionine, phenylalanine and tryptophan) representing 10 out of 14 perturbed pathways. This panel demonstrated strong diagnostic performance (AUC 100; sensitivity 100%; specificity 100%), confirmed by logistic regression (AUC 100%, CI 93-100%, P < 0.0001). This amino acid signature provides mechanistic insight into early metabolic dysregulation and shows promise for early young-onset T2DM risk stratification pending validation.