Prospective Associations of Systemic and Urinary Choline Metabolites with Incident Type 2 Diabetes

Abstract

Abstract BACKGROUND Several compounds in the choline oxidation pathway are associated with insulin resistance and prevalent diabetes; however, prospective data are scarce. We explored the relationships between systemic and urinary choline-related metabolites and incident type 2 diabetes in an observational prospective study among Norwegian patients. METHODS We explored risk associations by logistic regression among 3621 nondiabetic individuals with suspected stable angina pectoris, of whom 3242 provided urine samples. Reclassification of patients was investigated according to continuous net reclassification improvement (NRI >0). RESULTS After median (25th to 75th percentile) follow-up of 7.5 (6.4–8.7) years, 233 patients (6.4%) were registered with incident type 2 diabetes. In models adjusted for age, sex, and fasting status, plasma betaine was inversely related to new-onset disease [odds ratio (OR) per 1 SD, 0.72; 95% CI, 0.62–0.83; P < 0.00001], whereas positive associations were observed for urine betaine (1.25; 1.09–1.43; P = 0.001), dimethylglycine (1.22; 1.06–1.40; P = 0.007), and sarcosine (1.30; 1.13–1.49; P < 0.001). The associations were maintained in a multivariable model adjusting for body mass index, hemoglobin A1c, urine albumin-to-creatinine ratio, estimated glomerular filtration rate, C-reactive protein, HDL cholesterol, and medications. Plasma betaine and urine sarcosine, the indices most strongly related to incident type 2 diabetes, improved reclassification [NRI >0 (95% CI) 0.33 (0.19–0.47) and 0.16 (0.01–0.31), respectively] and showed good within-person reproducibility. CONCLUSIONS Systemic and urinary concentrations of several choline metabolites were associated with risk of incident type 2 diabetes, and relevant biomarkers may improve risk prediction.