Post-glucose Metabolite Signatures Reflect Insulin Sensitivity and Beta-cell Function in Black South African Women

Background Postprandial metabolic responses are strong predictors of type 2 diabetes (T2D) and its underlying pathophysiological traits, insulin sensitivity and β-cell function, but remain poorly characterised in African populations. We investigated glucose-stimulated metabolite profiles across the glycaemic spectrum and their associations with insulin sensitivity and β-cell function in Black South African women. Methods This cross-sectional study included 65 women (median age: 56 years) from the Middle-Aged Soweto Cohort, categorised as normal glucose tolerance (NGT, n = 29), impaired glucose tolerance (IGT, n = 24) and T2D (n = 12). Following an oral glucose tolerance test, insulin sensitivity (Matsuda index) and β-cell function were estimated from the Mari model. Changes in metabolic profiles were characterised from fasting to 30 (Δ30) and 120 (Δ120) minutes post-glucose ingestion using a multi-platform metabolomics approach. Results Insulin sensitivity and β-cell function declined progressively from NGT to IGT to T2D. From Δ30 and Δ120, carbohydrates and bile acids increased, whereas amino acids (including BCAAs), fatty acids and lysophospholipids decreased across all groups; and associated with insulin sensitivity and β-cell function. At Δ120, bile acids, cholic acid and deoxycholic acid, remained elevated in the T2D group only. Lysophospholipids decreased across groups. Carbohydrates, bile acids, and lysophospholipids correlated positively with insulin sensitivity and β-cell function, while amino acids, BCAAs, and fatty acids correlated negatively. Conclusion: Distinct post-glucose metabolite responses across the glycaemic spectrum reflect differences in insulin sensitivity and β-cell function in Black South African women, highlighting the value of dynamic metabolic profiling for understanding T2D progression in African populations.