Context: Carnitine and its metabolites are centrally involved in fatty acid metabolism. Although elevated circulating concentrations have been observed in obesity and insulin resistance, prospective studies examining whether these metabolites are associated with incident type 2 diabetes mellitus (T2D) are sparse.
Objective: We performed a comprehensive evaluation of metabolites along the carnitine pathway relative to incident T2D.
Design: A total of 2519 patients (73.1% men) with coronary artery disease, but without T2D, were followed for median 7.7 years until the end of 2009, during which 173 (6.9%) new cases of T2D were identified. Serum levels of free carnitine, its precursors trimethyllysine (TML) and γ-butyrobetaine, and the esters acetyl-, propionyl-, (iso)valeryl-, octanoyl-, and palmitoylcarnitine were measured by liquid chromatography/tandem mass spectrometry. Risk associations were explored by logistic regression and reported per (log-transformed) standard deviation increment.
Results: Median age at inclusion was 62 years and median body mass index (BMI) 26.0 kg/m2. In models adjusted for age, sex, fasting status, BMI, estimated glomerular filtration rate, glycated hemoglobin A1c, triglyceride and high-density lipoprotein cholesterol levels, and study center, serum levels of TML and palmitoylcarnitine associated positively [odds ratio (95% confidence interval), 1.22 (1.04 to 1.43) and 1.24 (1.04 to 1.49), respectively], whereas γ-butyrobetaine associated negatively [odds ratio (95% confidence interval) 0.81 (0.66 to 0.98)] with T2D risk.
Conclusion: Serum levels of TML, γ-butyrobetaine, and the long-chained palmitoylcarnitine predict long-term risk of T2D independently of traditional risk factors, possibly reflecting dysfunctional fatty acid metabolism in patients susceptible to T2D development.
Trial registration: ClinicalTrials.gov NCT00354081.