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Objective: Evaluate the ability of a newly developed diabetes risk score, the Diabetes Risk Index (DRI), to predict incident type 2 diabetes mellitus (T2D) in a large adult population. Methods: The DRI was developed by combining the Lipoprotein Insulin Resistance Index (LP-IR), calculated from 6 lipoprotein subspecies and size parameters, and the branched chain amino acids, valine and leucine, all of which have been shown previously to be associated with future T2D. DRI scores were calculated in a total of 6134 nondiabetic men and women in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) Study. Cox proportional hazards regression was used to evaluate the association of DRI scores with incident T2D. Results: During a median follow-up of 8.5 years, 306 new T2D cases were ascertained. In analyses adjusted for age and sex, there was a significant association between DRI scores and incident T2D with the hazard ratio (HR) for the highest versus lowest quartile being 12.07 (95% confidence interval: 6.97&ndash, 20.89, p &lt, 0.001). After additional adjustment for body mass index (BMI), family history of T2D, alcohol consumption, diastolic blood pressure, total cholesterol, triglycerides, HDL cholesterol and HOMA-IR, the HR was attenuated but remained significant (HR 3.20 (1.73&ndash, 5.95), p = 0.001). Similar results were obtained when DRI was analyzed as HR per 1 SD increase (HR 1.37 (1.14&ndash, 1.65), p &lt, 0.001). The Kaplan&ndash, Meier plot demonstrated that patients in the highest quartile of DRI scores presented at higher risk (p-value for log-rank test &lt, 0.001). Conclusions: Higher DRI scores are associated with an increased risk of T2D. The association is independent of clinical risk factors for T2D including HOMA-IR, BMI and conventional lipids.

Background: Gut microbiota-related metabolites, trimethylamine-N-oxide (TMAO), choline, and betaine, have been shown to be associated with cardiovascular disease (CVD) risk. Moreover, lower plasma betaine concentrations have been reported in subjects with type 2 diabetes mellitus (T2DM). However, few studies have explored the association of betaine with incident T2DM, especially in the general population. The goals of this study were to evaluate the performance of a newly developed betaine assay and to prospectively explore the potential clinical associations of betaine and future risk of T2DM in a large population-based cohort. Methods: We developed a high-throughput, nuclear magnetic resonance (NMR) spectroscopy procedure for acquiring spectra that allow for the accurate quantification of plasma/serum betaine and TMAO. Assay performance for betaine quantification was assessed and Cox proportional hazards regression was employed to evaluate the association of betaine with incident T2DM in 4336 participants in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Results: Betaine assay results were linear (y = 1.02X − 3.75) over a wide range of concentrations (26.0−1135 µM). The limit of blank (LOB), limit of detection (LOD) and limit of quantitation (LOQ) were 6.4, 8.9, and 13.2 µM, respectively. Coefficients of variation for intra- and inter-assay precision ranged from 1.5−4.3% and 2.5−5.5%, respectively. Deming regression analysis of results produced by NMR and liquid chromatography coupled to tandem mass spectrometry(LC-MS/MS) revealed an R2 value of 0.94 (Y = 1.08x − 1.89) and a small bias for higher values by NMR. The reference interval, in a cohort of apparently healthy adult participants (n = 501), was determined to be 23.8 to 74.7 µM (mean of 42.9 ± 12.6 µM). In the PREVEND study (n = 4336, excluding subjects with T2DM at baseline), higher betaine was associated with older age and lower body mass index, total cholesterol, triglycerides, and hsCRP. During a median follow-up of 7.3 (interquartile range (IQR), 5.9−7.7) years, 224 new T2DM cases were ascertained. Cox proportional hazards regression models revealed that the highest tertile of betaine was associated with a lower incidence of T2DM. Hazard ratio (HR) for the crude model was 0.61 (95% CI: 0.44−0.85, p = 0.004). The association remained significant even after adjusting for multiple clinical covariates and T2DM risk factors, including fasting glucose. HR for the fully-adjusted model was 0.50 (95% CI: 0.32−0.80, p = 0.003). Conclusions: The newly developed NMR-based betaine assay exhibits performance characteristics that are consistent with usage in the clinical laboratory. Betaine levels may be useful for assessing the risk of future T2DM.

Background: Low circulating magnesium (Mg) is associated with an increased risk of developing type 2 diabetes mellitus (T2DM). We aimed to study the performance of a nuclear magnetic resonance (NMR)-based assay that quantifies ionized Mg in EDTA plasma samples and prospectively investigate the association of Mg with the risk of T2DM. Methods: The analytic performance of an NMR-based assay for measuring plasma Mg was evaluated. We studied 5747 subjects free of T2DM at baseline in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study. Results: Passing&ndash, Bablok regression analysis, comparing NMR-measured ionized Mg with total Mg measured by the Roche colorimetric assay, produced a correlation of r = 0.90, with a slope of 1.08 (95% CI: 1.00&ndash, 1.13) and an intercept of 0.02 (95% CI: &minus, 0.02&ndash, 0.08). During a median follow-up period of 11.2 (IQR: 7.7&ndash, 12.0) years, 289 (5.0%) participants developed T2DM. The association of NMR-measured ionized Mg with T2DM risk was modified by sex (Pinteraction = 0.007). In women, we found an inverse association between Mg and the risk of developing T2DM, independent of adjustment for potential confounders (HR: 1.80, 95% CI: 1.20&ndash, 2.70). In men, we found no association between Mg and the risk of developing T2DM (HR: 0.90, 95%: 0.67&ndash, 1.21). Conclusion: Lower NMR-measured plasma ionized Mg was independently associated with a higher risk of developing T2DM in women, but not in men.