Abstract
BackgroundThe pandemic of cardiovascular disease (CVD) and type 2 diabetes (T2D) requires the identification of new predictor biomarkers. Biomarkers potentially modifiable with lifestyle changes deserve a special interest. Our aims were to analyze: (a) The associations of lysine, 2-aminoadipic acid (2-AAA) or pipecolic acid with the risk of T2D or CVD in the PREDIMED trial; (b) the effect of the dietary intervention on 1-year changes in these metabolites, and (c) whether the Mediterranean diet (MedDiet) interventions can modify the effects of these metabolites on CVD or T2D risk.MethodsTwo unstratified case-cohort studies nested within the PREDIMED trial were used. For CVD analyses, we selected 696 non-cases and 221 incident CVD cases; for T2D, we included 610 non-cases and 243 type 2 diabetes incident cases. Metabolites were quantified using liquid chromatography–tandem mass spectrometry, at baseline and after 1-year of intervention.ResultsIn weighted Cox regression models, we found that baseline lysine (HR+1 SD increase = 1.26; 95% CI 1.06–1.51) and 2-AAA (HR+1 SD increase = 1.28; 95% CI 1.05–1.55) were both associated with a higher risk of T2D, but not with CVD. A significant interaction (p = 0.032) between baseline lysine and T2D on the risk of CVD was observed: subjects with prevalent T2D and high levels of lysine exhibited the highest risk of CVD. The intervention with MedDiet did not have a significant effect on 1-year changes of the metabolites.ConclusionsOur results provide an independent prospective replication of the association of 2-AAA with future risk of T2D. We show an association of lysine with subsequent CVD risk, which is apparently diabetes-dependent. No evidence of effects of MedDiet intervention on lysine, 2-AAA or pipecolic acid changes was found.Trial registration ISRCTN35739639; registration date: 05/10/2005; recruitment start date 01/10/2003
Highlights
The pandemic of cardiovascular disease (CVD) and type 2 diabetes (T2D) requires the identification of new predictor biomarkers
In the baseline comparison of characteristics between incident T2D cases and non-cases, we found that baseline glucose levels among future diabetes cases pointed to a pre-diabetic baseline stage
We found that higher levels of lysine, 2-aminoadipic acid (2-AAA) and pipecolic acid were associated with T2D but the strongest association was found for 2-AAA, which was significantly associated with an increased risk of T2D in the basic model adjusted for sex, age and intervention group (hazard ratios (HR)+1 standard deviation (SD) increase = 1.29; 95% confidence intervals (95% CI) 1.10–1.52 Table 3), in the multivariable model (HR+1 SD increase = 1.27; 95% CI 1.07–1.50, data not shown) and even in the plasma glucose-adjusted model (HR+1 SD increase = 1.28; 95% CI 1.05–1.55; Table 3)
Summary
The pandemic of cardiovascular disease (CVD) and type 2 diabetes (T2D) requires the identification of new predictor biomarkers. Due to unhealthy diet and lifestyles in the context of ageing populations, the global epidemic of cardiovascular disease (CVD) and type 2 diabetes (T2D) has reached unexpected dimensions. Previous studies have shown that circulating 2-aminoadipic acid (2-AAA) levels were associated with obesity and metabolic syndrome [3, 4] and had the ability to predict the risk of future T2D [5]. The metabolite 2-AAA results from the degradation pathway of lysine (Additional file 1: Fig. S1), an essential amino acid. In the pathway of lysine degradation (Additional file 1: Fig. S1) there is another metabolite, pipecolic acid, that may be implicated in other diseases such as human diabetic corneal stroma [6]. It seemed important to further explore lysine degradation pathway in relation to T2D to find potential biomarkers and/or underlying biological mechanisms
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