Serum metabolomic dysregulation reveals systemic pathophysiology of type 2 diabetes mellitus in black South African ancestry

Abstract

Background Type 2 diabetes (T2DM) poses a significant global health challenge, and its prevalence is rising rapidly in South Africa. There is evidence that suggests individuals of African ancestry exhibit distinct pathophysiological features, including hyperinsulinemia, reduced hepatic insulin clearance, and unique adipose tissue distribution. However, data on Black South Africans are limited. Thus, the aim of the study is to characterize metabolites associated with metabolic dysregulation in Black South Africans with T2DM using NMR-based metabolomics. Methods This was a cross-sectional study conducted at the Dr George Mukhari Academic Hospital, including 55 Black South African participants: 23 non-diabetic and 32 with T2DM. NMR metabolomics was performed. A random forest classifier was employed to discriminate between diabetic and non-diabetic individuals. Results T2DM participants were significantly older and had higher HbA1c, LDL-C, and ApoB-100 levels, while triglycerides were lower than in non-diabetic controls. Multivariate analysis presented a clear separation, with 95% confidence intervals for each group. The key metabolic differences included elevated glucose, mannose, glycerol, 1-methylnicotinamide, histidine, and several short-chain fatty acids, while glutamine was reduced in T2DM. Pathway enrichment revealed significant perturbations in amino acid, carbohydrate, and energy metabolism, as well as in microbial-derived metabolites. ROC analysis confirmed several metabolites (AUC ≥ 0.8) as potential biomarkers. Conclusion Black South African individuals with T2DM exhibit noticeable metabolic signatures characterised by dysregulated pathways for amino acids, lipids, energy, and the gut microbiota, reflecting mechanisms of insulin resistance and glycaemic control. These findings highlight the potential of metabolomics to enable precision medicine approaches to improve T2DM management and outcomes.