LC-MS/MS Profiling of Blood Serum Reveals Disease-Enriched Peptides in Metabolic Syndrome

Background: Metabolic syndrome (MetS) is a heterogeneous cardiometabolic group of conditions in which early disturbances of glucose homeostasis are not always adequately captured by routine clinical tests. Methods: In this pilot study, liquid chromatography–tandem mass spectrometry (LC-MS/MS)-based blood serum peptidomics was applied to identify circulating peptide signatures associated with MetS and progressive glycemic impairment. Serum samples from healthy donors and patients with MetS, including subgroups with normoglycemia, prediabetes, and diabetes mellitus, were subjected to peptide enrichment by ultrafiltration and solid-phase extraction prior to LC-MS/MS analysis. Results: Overall, 6754 unique peptides derived from 1820 precursor proteins were identified, and 32 peptides were significantly overrepresented in patients with MetS relative to healthy donors. Eight precursor proteins and five identified peptides showed significant positive correlations with glycemic stage, likely indicating progressive remodeling of the circulating serum peptidome during disease progression. A separate analysis of patients with prediabetes revealed additional candidate markers associated with early metabolic alterations. Moreover, multivariate logistic regression identified a four-peptide panel with good discriminatory performance for differentiating healthy donors from patients with MetS, yielding a leave-one-out cross-validated area under the curve of 0.91. Conclusions: Collectively, these findings indicate that serum peptidome profiling can reveal biologically and clinically relevant possible candidate biomarkers associated with MetS and early dysglycemia.