Metabolites related to purine catabolism and risk of type 2 diabetes incidence; modifying efects of the TCF7L2-rs7903146 polymorphism

Studies examining associations between purine metabolites and type 2 diabetes (T2D) are limited. We prospectively examined associations between plasma levels of purine metabolites with T2D risk and the modifying effects of transcription factor-7-like-2 (TCF7L2) rs7903146 polymorphism on these associations. This is a case-cohort design study within the PREDIMED study, with 251 incident T2D cases and a random sample of 694 participants (641 non-cases and 53 overlapping cases) without T2D at baseline (median follow-up: 3.8 years). Metabolites were semi-quantitatively profiled with LC-MS/MS. Cox regression analysis revealed that high plasma allantoin levels, including allantoin-to-uric acid ratio and high xanthine-to-hypoxanthine ratio were inversely and positively associated with T2D risk, respectively, independently of classical risk factors. Elevated plasma xanthine and inosine levels were associated with a higher T2D risk in homozygous carriers of the TCF7L2-rs7903146 T-allele. The potential mechanisms linking the aforementioned purine metabolites and T2D risk must be also further investigated

Circulating citric acid cycle metabolites and risk of cardiovascular disease in the PREDIMED study

Background and aim Plasma citric acid cycle (CAC) metabolites might be likely related to cardiovascular disease (CVD). However, studies assessing the longitudinal associations between circulating CAC-related metabolites and CVD risk are lacking. The aim of this study was to evaluate the association of baseline and 1-year levels of plasma CAC-related metabolites with CVD incidence (a composite of myocardial infarction, stroke or cardiovascular death), and their interaction with Mediterranean diet interventions. Methods and results Case-cohort study from the PREDIMED trial involving participants aged 55–80 years at high cardiovascular risk, allocated to MedDiets or control diet. A subcohort of 791 participants was selected at baseline, and a total of 231 cases were identified after a median follow-up of 4.8 years. Nine plasma CAC-related metabolites (pyruvate, lactate, citrate, aconitate, isocitrate, 2-hydroxyglutarate, fumarate, malate and succinate) were measured using liquid chromatography-tandem mass spectrometry. Weighted Cox multiple regression was used to calculate hazard ratios (HRs). Baseline fasting plasma levels of 3 metabolites were associated with higher CVD risk, with HRs (for each standard deviation, 1-SD) of 1.46 (95%CI:1.20–1.78) for 2-hydroxyglutarate, 1.33 (95%CI:1.12–1.58) for fumarate and 1.47 (95%CI:1.21–1.78) for malate (p of linear trend <0.001 for all). A higher risk of CVD was also found for a 1-SD increment of a combined score of these 3 metabolites (HR = 1.60; 95%CI: 1.32–1.94, p trend <0.001). This result was replicated using plasma measurements after one-year. No interactions were detected with the nutritional intervention. Conclusion Plasma 2-hydroxyglutarate, fumarate and malate levels were prospectively associated with increased cardiovascular risk

Lysine pathway metabolites and the risk of type 2 diabetes and cardiovascular disease in the PREDIMED study: results from two case-cohort studies

Background: The pandemic of cardiovascular disease (CVD) and type 2 diabetes (T2D) requires the identifcation of new predictor biomarkers. Biomarkers potentially modifable 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 efect of the dietary intervention on 1-year changes in these metabolites, and (c) whether the Mediterranean diet (MedDiet) interventions can modify the efects of these metabolites on CVD or T2D risk. Methods: Two unstratifed 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 quantifed using liquid chromatography–tandem mass spectrometry, at baseline and after 1-year of intervention. Results: In 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 signifcant 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 signifcant efect on 1-year changes of the metabolites. Conclusions: Our 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 efects of MedDiet intervention on lysine, 2-AAA or pipecolic acid changes was found

Plasma acylcarnitine concentrations reflect the acylcarnitine profile in cardiac tissues

Funding Information: This study was supported by the Latvian National Research Program BIOMEDICINE. E. Liepinsh was supported by the FP7 project InnovaBalt [grant Nr. 316149]. We would like to thank Dr. Reinis Vilskersts and Gita Dambrova for help with the isolated skeletal muscle experiments. Publisher Copyright: © 2017 The Author(s).Increased plasma concentrations of acylcarnitines (ACs) are suggested as a marker of metabolism disorders. The aim of the present study was to clarify which tissues are responsible for changes in the AC pool in plasma. The concentrations of medium- and long-chain ACs were changing during the fed-fast cycle in rat heart, muscles and liver. After 60 min running exercise, AC content was increased in fasted mice muscles, but not in plasma or heart. After glucose bolus administration in fasted rats, the AC concentrations in plasma decreased after 30 min but then began to increase, while in the muscles and liver, the contents of medium- and long-chain ACs were unchanged or even increased. Only the heart showed a decrease in medium- and long-chain AC contents that was similar to that observed in plasma. In isolated rat heart, but not isolated-contracting mice muscles, the significant efflux of medium- and long-chain ACs was observed. The efflux was reduced by 40% after the addition of glucose and insulin to the perfusion solution. Overall, these results indicate that during fed-fast cycle shifting the heart determines the medium- and long-chain AC profile in plasma, due to a rapid response to the availability of circulating energy substrates.publishersversionPeer reviewe

Arginine catabolism metabolites and atrial fibrillation or heart failure risk: 2 case-control studies within the Prevención con Dieta Mediterránea (PREDIMED) trial

Background Arginine-derived metabolites are involved in oxidative and inflammatory processes related to endothelial functions and cardiovascular risks. Objectives We prospectively examined the associations of arginine catabolism metabolites with the risks of atrial fibrillation (AF) or heart failure (HF), and evaluated the potential modifications of these associations through Mediterranean diet (MedDiet) interventions in a large, primary-prevention trial. Methods Two nested, matched, case-control studies were designed within the Prevención con Dieta Mediterránea (PREDIMED) trial. We selected 509 incident cases and 547 matched controls for the AF case-control study and 326 cases and 402 matched controls for the HF case-control study using incidence density sampling. Fasting blood samples were collected at baseline and arginine catabolism metabolites were measured using LC-tandem MS. Multivariable conditional logistic regression models were applied to test the associations between the metabolites and incident AF or HF. Interactions between metabolites and intervention groups (MedDiet groups compared with control group) were analyzed with the likelihood ratio test. Results Inverse association with incident AF was observed for arginine (OR per 1 SD, 0.83; 95% CI: 0.73–0.94), whereas a positive association was found for N1-acetylspermidine (OR for Q4 compared with Q1 1.58; 95% CI: 1.13–2.25). For HF, inverse associations were found for arginine (OR per 1 SD, 0.82; 95% CI: 0.69–0.97) and homoarginine (OR per 1 SD, 0.81; 95% CI: 0.68–0.96), and positive associations were found for the asymmetric dimethylarginine (ADMA) and symmetric dimethlyarginine (SDMA) ratio (OR per 1 SD, 1.19; 95% CI: 1.02–1.41), N1-acetylspermidine (OR per 1 SD, 1.34; 95% CI: 1.12–1.60), and diacetylspermine (OR per 1 SD, 1.20; 95% CI: 1.02–1.41). In the stratified analysis according to the dietary intervention, the lower HF risk associated with arginine was restricted to participants in the MedDiet groups (P-interaction = 0.044). Conclusions Our results suggest that arginine catabolism metabolites could be involved in AF and HF. Interventions with the MedDiet may contribute to strengthen the inverse association between arginine and the risk of HF. This trial was registered at controlled-trials.com as ISRCTN35739639

Olive oil and prevention of chronic diseases: summary of an International conference

Abstract Olive oil is the foremost source of fat in the Mediterranean area and, among other features, sets the Mediterranean diet apart from other dietary regimens. In January 2018, the International Olive Council convened several worldwide experts at the Robert Mondavi Institute (Davis, CA), to discuss and summarize the available data on the effects of olive oil consumption on human health. In this paper, we critically provide a synthesis of the main reported findings, which underscore how and why consuming this oil as part of a balanced diet and healthful lifestyle improves prognosis and extends life- and health-spans

Cross-sectional assessment of nut consumption and obesity, metabolic syndrome and other cardiometabolic risk factors: the PREDIMED study

INTRODUCTION: Prospective studies have consistently suggested that nut consumption is inversely related to fatal and non-fatal coronary heart disease. Limited data are available on the epidemiological associations between nut intake and cardiometabolic risk factors. OBJECTIVE: To evaluate associations between frequency of nut consumption and prevalence of cardiometabolic risk factors [obesity, metabolic syndrome (MetS), type-2 diabetes, hypertension, and dyslipidemia] in a Mediterranean population at high cardiovascular risk. MATERIALS AND METHODS: Cross-sectional study of 7,210 men and women (mean age, 67 y) recruited into the PREDIMED study. MetS was defined by the harmonized ATPIII and IDF criteria. Diabetes and hypertension were assessed by clinical diagnosis and dyslipidemia (high triglycerides, low HDL-cholesterol, and hypercholesterolemia) by lipid analyses. Nut consumption was assessed using a validated food frequency questionnaire and categorized as 3 servings/wk. Control of confounding was done with multivariate logistic regression. RESULTS: Compared to participants consuming 3 servings/wk had lower adjusted odds ratios (OR) for obesity (0.61, 95% confidence interval 0.54 to 0.68; P-trend <0.001), MetS (0.74, 0.65 to 0.85; P-trend<0.001), and diabetes (0.87, 0.78 to 0.99; P-trend = 0.043). Higher nut consumption was also associated with lower risk of the abdominal obesity MetS criterion (OR 0.68, 0.60 to 0.79; P-trend<0.001). No significant associations were observed for the MetS components high blood pressure, dyslipidemia, or elevated fasting glucose. CONCLUSIONS: Nut consumption was inversely associated with the prevalence of general obesity, central obesity, MetS, and diabetes in subjects at high cardiovascular risk

Waist to height ratio and cardiovascular risk factors in elderly individuals at high cardiovascular risk

Introduction: Several anthropometric measurements have been associated with cardiovascular disease, type-2 diabetes mellitus and other cardiovascular risk conditions, such as hypertension or metabolic syndrome. Waist-to-height-ratio has been proposed as a useful tool for assessing abdominal obesity, correcting other measurements for the height of the individual. We compared the ability of several anthropometric measurements to predict the presence of type-2 diabetes, hyperglycemia, hypertension, atherogenic dyslipidemia or metabolic syndrome. Materials and Methods: In our cross-sectional analyses we included 7447 Spanish individuals at high cardiovascular risk, men aged 55–80 years and women aged 60–80 years, from the PREDIMED study. Logistic regression models were fitted to evaluate the odds ratio of presenting each cardiovascular risk factor according to various anthropometric measures. The areas under the receiver-operating characteristic curve (AUC) were used to compare the predictive ability of these measurements. Results: In this relatively homogeneous cohort with 48.6% of type-2 diabetic individuals, the great majority of the studied anthropometric parameters were significantly and positively associated with the cardiovascular risk factors. No association was found between BMI and body weight and diabetes mellitus. The AUCs for the waist-to-height ratio and waist circumference were significantly higher than the AUCs for BMI or weight for type-2 diabetes, hyperglycemia, atherogenic dyslipidemia and metabolic syndrome. Conversely, BMI was the strongest predictor of hypertension. Conclusions: We concluded that measures of abdominal obesity showed higher discriminative ability for diabetes mellitus, high fasting plasma glucose, atherogenic dyslipidemia and metabolic syndrome than BMI or weight in a large cohort of elderly Mediterranean individuals at high cardiovascular risk. No significant differences were found between the predictive abilities of waist-to-height ratio and waist circumference on the metabolic disease

Dietary a-Linolenic acid, Marine x-3 fatty acids, and mortality in a population with high fish consumption: findings from the PREevención con DIeta MEDiterránea (PREDIMED) study

Epidemiological evidence suggests a cardioprotective role of α‐linolenic acid (ALA), a plant‐derived ω‐3 fatty acid. It is unclear whether ALA is beneficial in a background of high marine x-3 fatty acids (long-chain n-3 polyunsaturated fatty acids) intake. In persons at high cardiovascular risk from Spain, a country in which fish consumption is customarily high, we investigated whether meeting the International Society for the Study of Fatty Acids and Lipids recommendation for dietary ALA (0.7% of total energy) at baseline was related to all-cause and cardiovascular disease mortality. We also examined the effect of meeting the society’s recommendation for long-chain n-3 polyunsaturated fatty acids (≥500 mg/day). Methods and Results-—We longitudinally evaluated 7202 participants in the PREvenci on con DIeta MEDiterr anea (PREDIMED) trial. Multivariable-adjusted Cox regressionmodels were fitted to estimate hazard ratios. ALA intake correlated towalnut consumption (r=0.94). During a 5.9-y follow-up, 431 deaths occurred (104 cardiovascular disease, 55 coronary heart disease, 32 sudden cardiac death, 25 stroke). The hazard ratios formeeting ALArecommendation (n=1615, 22.4%) were 0.72 (95% CI 0.56–0.92) for all-causemortality and 0.95 (95% CI 0.58–1.57) for fatal cardiovascular disease. The hazard ratios formeeting the recommendation for long-chain n-3 polyunsaturated fatty acids (n=5452, 75.7%) were 0.84 (95% CI 0.67–1.05) for all-causemortality, 0.61 (95% CI 0.39–0.96) for fatal cardiovascular disease, 0.54 (95% CI 0.29–0.99) for fatal coronary heart disease, and 0.49 (95% CI 0.22–1.01) for sudden cardiac death. The highest reduction in all-cause mortality occurred in participants meeting both recommendations (hazard ratio 0.63 [95% CI 0.45–0.87]). Conclusions-—In participants without prior cardiovascular disease and high fish consumption, dietary ALA, supplied mainly by walnuts and olive oil, relates inversely to all-cause mortality, whereas protection from cardiac mortality is limited to fish-derived long-chain n-3 polyunsaturated fatty acids

Plasma Metabolites Associated with Coffee Consumption: A Metabolomic Approach within the PREDIMED Study

Few studies have examined the association of a wide range of metabolites with total and subtypes of coffee consumption. The aim of this study was to investigate associations of plasma metabolites with total, caffeinated, and decaffeinated coffee consumption. We also assessed the ability of metabolites to discriminate between coffee consumption categories. This is a cross-sectional analysis of 1664 participants from the PREDIMED study. Metabolites were semiquantitatively profiled using a multiplatform approach. Consumption of total coffee, caffeinated coffee and decaffeinated coffee was assessed by using a validated food frequency questionnaire. We assessed associations between 387 metabolite levels with total, caffeinated, or decaffeinated coffee consumption (≥50 mL coffee/day) using elastic net regression analysis. Ten-fold cross-validation analyses were used to estimate the discriminative accuracy of metabolites for total and subtypes of coffee. We identified different sets of metabolites associated with total coffee, caffeinated and decaffeinated coffee consumption. These metabolites consisted of lipid species (e.g., sphingomyelin, phosphatidylethanolamine, and phosphatidylcholine) or were derived from glycolysis (alpha-glycerophosphate) and polyphenol metabolism (hippurate). Other metabolites included caffeine, 5-acetylamino-6-amino-3-methyluracil, cotinine, kynurenic acid, glycocholate, lactate, and allantoin. The area under the curve (AUC) was 0.60 (95% CI 0.56–0.64), 0.78 (95% CI 0.75–0.81) and 0.52 (95% CI 0.49–0.55), in the multimetabolite model, for total, caffeinated, and decaffeinated coffee consumption, respectively. Our comprehensive metabolic analysis did not result in a new, reliable potential set of metabolites for coffee consumption