Obesity-associated metabolites in relation to type 2 diabetes risk: A prospective nested case-control study of the CARRS cohort

Aims: To determine whether obesity-associated metabolites are associated with type 2 diabetes (T2DM) risk among South Asians. Materials and Methods: Serum-based nuclear magnetic resonance imaging metabolomics data were generated from two South Asian population-based prospective cohorts from Karachi, Pakistan: CARRS1 (N = 4017) and CARRS2 (N = 4802). Participants in both cohorts were followed up for 5 years and incident T2DM was ascertained. A nested case-control study approach was developed to select participants from CARRS1 (N_cases = 197 and N_controls = 195) and CARRS2 (N_cases = 194 and N_controls = 200), respectively. First, we investigated the association of 224 metabolites with general obesity based on body mass index and with central obesity based on waist-hip ratio, and then the top obesity-associated metabolites were studied in relation to incident T2DM. Results: In a combined sample of the CARRS1 and CARRS2 cohorts, out of 224 metabolites, 12 were associated with general obesity and, of these, one was associated with incident T2DM. Fifteen out of 224 metabolites were associated with central obesity and, of these, 10 were associated with incident T2DM. The higher level of total cholesterol in high-density lipoprotein (HDL) was associated with reduced T2DM risk (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.53, 0.86; P = 1.2 × 10⁻³), while higher cholesterol esters in large very-low-density lipoprotein (VLDL) particles were associated with increased T2DM risk (OR 1.90, 95% CI 1.40, 2.58; P = 3.5 × 10⁻⁵). Conclusion: Total cholesterol in HDL and cholesterol esters in large VLDL particles may be an important biomarker in the identification of early development of obesity-associated T2DM risk among South Asian adults.