Abstract
AIMS: N-lactoyl amino acids (Lac-AA) are emerging as crucial players in metabolic research, with potential implications for disease mechanisms and therapeutic interventions. This study exploress the role of Lac-AA in insulin resistance, type 2 diabetes (T2D), and its complications. MATERIALS AND METHODS: A cross-sectional study was conducted using data from 2918 participants from Qatar Biobank. After quality control, 2907 individuals were retained and randomly divided into discovery (n = 1990) and validation (n = 917) cohorts. Untargeted metabolomics was employed to profile serum metabolites, and analysis was focused on three Lac-AA species. Participants were stratified into insulin-sensitive, insulin-resistant, T2D without complications and T2D with complications. Associations with clinical traits were assessed using linear regression and Spearman correlation. Diagnostic performance was evaluated using Receiver Operating Characteristic (ROC) analysis in an independent cohort (n = 60). One-sample Mendelian randomisation was performed to assess causality between genetic predisposition to T2D and Lac-AA levels. Network analysis explored metabolic pathways linked to Lac-AA. RESULTS: Lac-AA levels were significantly higher in individuals with insulin resistance and diabetic complications. These findings were robustly replicated in the validation cohort. These metabolites showed strong positive correlations with markers of poor glycaemic control independent of metformin use. ROC analysis demonstrated that Lac-AA could discriminate between insulin-resistant and insulin-sensitive individuals. Mendelian randomisation analysis indicated a potential causal association between genetic risk for T2D and increased Lac-AA, particularly in patients with complications, supporting their role as downstream biomarkers of metabolic disease severity. Gaussian graphical model analysis revealed Lac-AA as central nodes in metabolic networks, showing strong associations with mitochondrial dysfunction biomarkers. CONCLUSIONS: Lac-AA may serve as integrative biomarkers of metabolic dysfunction and diabetic complications. Further longitudinal and interventional studies are needed to clarify their mechanistic roles and clinical utility.