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The potential role of the lipidome in atrial fibrillation (AF) development is still widely unknown. We aimed to assess the association between lipidome profiles of the Prevención con Dieta Mediterránea (PREDIMED) trial participants and incidence of AF. We conducted a nested case–control study (512 incident centrally adjudicated AF cases and 735 controls matched by age, sex, and center). Baseline plasma lipids were profiled using a Nexera X2 U-HPLC system coupled to an Exactive Plus orbitrap mass spectrometer. We estimated the association between 216 individual lipids and AF using multivariable conditional logistic regression and adjusted the p values for multiple testing. We also examined the joint association of lipid clusters with AF incidence. Hitherto, we estimated the lipidomics network, used machine learning to select important network-clusters and AF-predictive lipid patterns, and summarized the joint association of these lipid patterns weighted scores. Finally, we addressed the possible interaction by the randomized dietary intervention.Forty-one individual lipids were associated with AF at the nominal level (p per+1SD of 1.32 (95% confidence interval: 1.16–1.51; p Current Controlled Trials number, ISRCTN35739639.

We evaluated whether the intake of dietary vitamin D is associated with the incidence of both colorectal cancer (CRC) and colon cancer in the framework of the PREDIMED cohort of older adults at high cardiovascular risk. We analyzed data from 7216 men and women (55–80 years) without CRC at baseline from the PREvencion con DIeta MEDiterranea study. Baseline consumption of vitamin D was assessed using a validated 137-item food frequency questionnaire. Cox proportional hazards ratios (HRs) of CRC and colon cancer incidence were estimated for quartiles and per 1-SD of baseline vitamin D intake. During a median follow-up of 6 years, we documented 97 incident CRC cases after the exclusion of subjects with no baseline dietary data and/or outliers of energy intake. A non-significant HRs and 95% confidence intervals (CIs) of CRC for the comparison of extreme quartiles (4th vs 1st) of vitamin D intake were observed [0.55 (0.30–1.00), P for trend = 0.072], whereas it was significant for colon cancer incidence alone [0.44 (0.22–0.90), P for trend = 0.032]. However, this association became significant in CRC and colon cancer incidence, after excluding 391 subjects consuming baseline vitamin D and/or calcium medication or prescribed supplements [0.52 (0.28–0.96) and 0.41 (0.12–0.85), respectively]. A higher dietary intake of vitamin D was significantly associated with a reduced CRC risk in individuals at high cardiovascular risk.

[Background & aims]: The Portfolio and Dietary Approaches to Stop Hypertension (DASH) diets have been shown to lower cardiometabolic risk factors in randomized controlled trials (RCTs). However, the Portfolio diet has only been assessed in RCTs of hyperlipidemic patients. Therefore, to assess the Portfolio diet in a population with metabolic syndrome (MetS), we conducted a longitudinal analysis of one-year data of changes in the Portfolio and DASH diet scores and their association with cardiometabolic risk factors in Prevención con Dieta Mediterránea (PREDIMED)-Plus trial. [Methods]: PREDIMED-Plus is an ongoing clinical trial (Trial registration: ISRCTN89898) conducted in Spain that includes 6874 older participants (mean age 65 y, 48% women) with overweight/obesity fulfilling at least three criteria for MetS. Data for this analysis were collected at baseline, six months and one year. Adherence to the Portfolio and DASH diet scores were derived from a validated 143-item food frequency questionnaire. We used linear mixed models to examine the associations of 1-SD increase and quartile changes in the diet scores with concomitant changes in cardiometabolic risk factors. [Results]: After adjusting for several potential confounders, a 1-SD increase in the Portfolio diet score was significantly associated with lower HbA1c (β [95% CI]: −0.02% [−0.02, −0.01], P < 0.001), fasting glucose (−0.47 mg/dL [−0.83, −0.11], P = 0.01), triglycerides (−1.29 mg/dL [−2.31, −0.28], P = 0.01), waist circumference (WC) (−0.51 cm [−0.59, −0.43], P < 0.001), and body mass index (BMI) (−0.17 kg/m2 [−0.19, −0.15], P < 0.001). A 1-SD increase in the DASH diet score was significantly associated with lower HbA1c (−0.03% [−0.04, −0.02], P < 0.001), glucose (−0.84 mg/dL [−1.18, −0.51], P < 0.001), triglycerides (−3.38 mg/dL [−4.37, −2.38], P < 0.001), non-HDL-cholesterol (−0.47 mg/dL [−0.91, −0.04], P = 0.03), WC (−0.69 cm [−0.76, −0.60 cm], P < 0.001), BMI (−0.25 kg/m2 [−0.28, −0.26 kg/m2], P < 0.001), systolic blood pressure (−0.57 mmHg [−0.81, −0.32 mmHg], P < 0.001), diastolic blood pressure (−0.15 mmHg [−0.29, −0.01 mmHg], P = 0.03), and with higher HDL-cholesterol (0.21 mg/dL [0.09, 0.34 mg/dL, P = 0.001]). Similar associations were seen when both diet scores were assessed as quartiles, comparing extreme categories of adherence. [Conclusions]: Among older adults at high cardiovascular risk with MetS, greater adherence to the Portfolio and DASH diets showed significant favourable prospective associations with several clinically relevant cardiometabolic risk factors. Both diets are likely beneficial for cardiometabolic risk reduction., The PREDIMED-Plus trial was supported by the Spanish government's official funding agency for biomedical research, ISCIII, through the Fondo de Investigación para la Salud (FIS) and co-funded by European Union ERDF/ESF, “A way to make Europe”/“Investing in your future” (five coordinated FIS projects led by JS-S and JVid, including the following projects: PI13/00673, PI13/00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728, PI13/01090, PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI14/00972, PI14/00728, PI14/01471, PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183,PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441, PI17/00508, PI17/01732, PI17/00926, PI19/00957, PI19/00386, PI19/00309, PI19/01032, PI19/00576, PI19/00017, PI19/01226, PI19/00781, PI19/01560, and PI19/01332), the Special Action Project entitled: Implementación y evaluación de una intervención intensiva sobre la actividad física Cohorte PREDIMED-Plus grant to JS-S, the European Research Council (Advanced Research Grant 2014–2019, 340918) to MÁM-G, the Recercaixa Grant to JS-S (2013ACUP00194), grants from the Consejería de Salud de la Junta de Andalucía (PI0458/2013, PS0358/2016, and PI0137/2018), a grant from the Generalitat Valenciana (PROMETEO/2017/017), a SEMERGEN grant, and funds from the European Regional Development Fund (CB06/03). This research was also partially funded by EU-H2020 Grant (EAT2BENICE/H2020-SFS-2016-2; Ref 728018). Study resulting from the SLT006/17/00246 grant, funded by the Department of Health of the Generalitat de Catalunya by the call “Acció instrumental de programes de recerca orientats en l'àmbit de la recerca i la innovació en salut”. We thank CERCA Programme/Generalitat de Catalunya for institutional support. This work is partially supported by ICREA under the ICREA Academia programme. IP-G receives a grant from the Spanish Ministry of Education, Culture and Sports (FPU 17/01925). MRBL was supported by “Miguel Servet Type I” program (CP15/00028) from the ISCIII-Madrid (Spain), cofinanced by the Fondo Europeo de Desarrollo Regional-FEDER. AJG was supported by the Nora Martin Fellowship in Nutritional Sciences, the Banting & Best Diabetes Centre Tamarack Graduate Award in Diabetes Research, the Peterborough K.M. Hunter Charitable Foundation Graduate Award and an Ontario Graduate Scholarship. PH-A was supported by a postdoctoral fellowship (Juan de la Cierva-Formación), FJCI-2017–32205, funded by the Ministry of Science and Innovation. RE group has been supported by the ‘Ajut 2017-2021 SGR 1717 from the Generalitat de Catalunya. DJAJ was funded by the Government of Canada through the Canada Research Chair Endowment. JK was supported by the ‘FOLIUM’ programme within the FUTURMed project from the Fundación Instituto de Investigación Sanitaria Illes Balears (financed by 2017 annual plan of the sustainable tourism tax and at 50% with charge to the ESF Operational Program 2014–2020 of the Balearic Islands). JLS was funded by a Diabetes Canada Clinician Scientist Award.

Background Previous meta-analyses, with some methodological controversies, have assessed the relation between nut consumption and type 2 diabetes (T2D) risk and pointed to contradictory results, making desirable the performance of an updated meta-analysis. Objectives We aimed to systematically review and meta-analyze all the published studies investigating the relations of total nuts and different types of nuts-i.e., walnuts, peanuts, peanut butter, and total tree nuts-with the prevalence and incidence of T2D. Methods A systematic search was conducted in the PubMed and Cochrane databases through 12 August, 2020. The inverse variance method with fixed-effect models was used to pool data across studies, expressed as risk ratios (RRs) or ORs and 95% CIs for prospective cohort and cross-sectional studies, respectively. The Cochran Q test and I2 statistics were used to test and quantify heterogeneity, respectively. Dose-response meta-analysis was also conducted. Results Eight studies (5 prospective and 3 cross-sectional) were included in the quantitative synthesis. Meta-analyses of cross-sectional studies and prospective cohort studies, comparing the highest with the lowest categories, revealed a nonsignificant association between total nut consumption and T2D. Meta-analyses of prospective cohort studies showed an inverse association between peanut butter consumption and T2D incidence (RR: 0.87; 95% CI: 0.77, 0.98; I2 = 50.6%; Pheterogeneity = 0.16), whereas no association was observed between peanuts or tree nuts and T2D. There was no evidence of a linear dose-response or nonlinear dose-response gradient for total nut and peanut consumption in prospective cohort studies. The certainty of the evidence using NutriGrade was very low for all the exposures. Conclusions Current results do not demonstrate an association of total nut, peanut, or tree nut consumption with T2D. Peanut butter consumption may be inversely associated with this disease.This review protocol was registered at www.crd.york.ac.uk/prospero/ as CRD42020149756.

BACKGROUND: Walnut consumption is associated with lower risk of type 2 diabetes (T2D) and cardiovascular disease (CVD). However, it is unknown whether plasma metabolites related to walnut consumption are also associated with lower risk of cardiometabolic diseases. OBJECTIVES: The study aimed to identify plasma metabolites associated with walnut consumption and evaluate the prospective associations between the identified profile and risk of T2D and CVD. METHODS: The discovery population included 1833 participants at high cardiovascular risk from the PREvención con DIeta MEDiterránea (PREDIMED) study with available metabolomics data at baseline. The study population included 57% women (baseline mean BMI (in kg/m(2)): 29.9; mean age: 67 y). A total of 1522 participants also had available metabolomics data at year 1 and were used as the internal validation population. Plasma metabolomics analyses were performed using LC-MS. Cross-sectional associations between 385 known metabolites and walnut consumption were assessed using elastic net continuous regression analysis. A 10-cross-validation (CV) procedure was used, and Pearson correlation coefficients were assessed between metabolite weighted models and self-reported walnut consumption in each pair of training–validation data sets within the discovery population. We further estimated the prospective associations between the identified metabolite profile and incident T2D and CVD using multivariable Cox regression models. RESULTS: A total of 19 metabolites were significantly associated with walnut consumption, including lipids, purines, acylcarnitines, and amino acids. Ten-CV Pearson correlation coefficients between self-reported walnut consumption and the plasma metabolite profile were 0.16 (95% CI: 0.11, 0.20) in the discovery population and 0.15 (95% CI: 0.10, 0.20) in the validation population. The metabolite profile was inversely associated with T2D incidence (HR per 1 SD: 0.83; 95% CI: 0.71, 0.97; P = 0.02). For CVD incidence, the HR per 1-SD was 0.71 (95% CI: 0.60, 0.85; P

Evidence has shown that the nutritional quality of gluten-free products (GFPs) is lower than that of non-GFPs. Our main objective was to compare the nutritional quality through nutritional profiles of foods underlying the Nutri-Score front-of-pack and the price of GFPs with respect to non-GFPs, and to evaluate whether there is a correlation between both parameters. Nutritional information of all products was obtained from the CELIACBASE database and the price through Spanish supermarkets websites. Global quality using the Nutri-Score algorithm and the price were compared between both types of products. GFPs do not always have poorer quality than their counterparts. A better quality of gluten-free pasta was correlated with the higher price but also a worse quality of gluten-free muesli was correlated with the higher price. The price of GFPs compared to non-GFPs was higher up to 391.5%. However, for ham and cheese pizza, ham pizza, Marie biscuits, and baby biscuits, the difference was not statistically significant. Generally, the price of GFPs did not correlate with better nutritional quality. Nutri-Score would ease the nutritional quality identification, empowering consumers and could also influence manufacturers to improve the nutritional quality of GFPs. Nowadays, given that many GFPs have poor nutritional quality, they should be included only occasionally in a balanced gluten-free diet.

Telomere length (TL) has been associated with aging and is determined by lifestyle. However, the mechanisms by which a dietary pattern such as the Mediterranean diet (MedDiet) affects TL homeostasis are still unknown. Our aim was to analyse the effect of an energy-restricted MedDiet with physical activity promotion (intervention group) versus an unrestricted-caloric MedDiet with no weight-loss advice (control group) on TL and 8-hydroxydeoxyguanosine (8-OHdG) plasma levels. In total, 80 non-diabetic participants with metabolic syndrome were randomly selected from the PREDIMED (PREvención con DIeta MEDiterránea)-Plus-Reus study. TL was measured by a hybridisation method and 8-OHdG levels by ELISA at baseline and after one year of intervention. Linear mixed models (LMM)—raw and after adjusting for potential confounders—were used to examine the associations between TL or 8-OHdG plasma levels by intervention group and/or time. A total of 69 subjects with available DNA samples were included in the analyses. A significant β-coefficient was found for time towards increasing values through the year of follow-up for TL (unadjusted β of 0.740 (95% CI: 0.529 to 0.951), and multivariable model β of 0.700 (95% CI: 0.477 to 0.922)). No significant βs were found, neither for the intervention group nor for the interaction between the intervention group and time. Regarding 8-OHdG plasma levels, no significant βs were found for the intervention group, time, and its interaction. Our results suggest that MedDiet could have an important role in preventing telomere shortening, but calorie restriction and exercise promotion did not provide an additional advantage concerning telomere length after one year of MedDiet intervention.

The associations between circulating vitamin D concentrations and total and site-specific colorectal cancer (CRC) incidence have been examined in several epidemiological studies with overall inconclusive findings. The aim of this systematic review and meta-analysis of both case-control and prospective cohort studies was to evaluate the association between CRC and circulating levels of vitamin D. The main exposure and outcome were circulating total 25(OH)D and CRC, respectively, in the overall population (i.e., all subjects). Two reviewers, working independently, screened all the literature available to identify studies that met the inclusion criteria (e.g., case-control or prospective cohort studies, published in English, and excluding non-original papers). Data were pooled by the generic inverse variance method using a random or fixed effect model, as approriate. Heterogeneity was identified using the Cochran's Q-test and quantified by the I2 statistic. Results were stratified by study design, sex, and metabolite of vitamin D. Sensitivity and subgroup analyses were also performed. A total of 28 original studies were included for the quantitative meta-analysis. Meta-analyses comparing the highest vs lowest categories, showed a 39% lower risk between levels of total 25(OH)D and CRC risk (OR (95% CI): 0.61 (0.52; 0.71); 11 studies) in case-control studies; whereas a 20% reduced CRC risk in prospective cohort studies (HR (95% CI): 0.80 (0.66; 0.97); 6 studies). Results in women mirrored main results, whereas results in men were non-significant in both analyses. Our findings support an inverse association between circulating vitamin D levels and CRC risk.

Fatty acid metabolic dysregulation in mitochondria is a common mechanism involved in the development of heart failure (HF) and atrial fibrillation (AF). We evaluated the association between plasma acylcarnitine levels and the incidence of HF or AF, and whether the mediterranean diet (MedDiet) may attenuate the association between acylcarnitines and HF or AF risk.Two case-control studies nested within the Prevención con dieta mediterránea (PREDIMED) trial. High cardiovascular risk participants were recruited in Spain: 326 incident HF and 509 AF cases individually matched to 1 to 3 controls. Plasma acylcarnitines were measured with high-throughput liquid chromatography-tandem mass spectrometry. Conditional logistic regression models were fitted to estimate multivariable OR and 95%CI. Additive and multiplicative interactions were assessed by intervention group, obesity (body mass index ≥ 30 kg/mElevated levels of medium- and long-chain acylcarnitines were associated with increased HF risk (adjusted ORAmong individuals at high cardiovascular risk, elevated long-chain acylcarnitines were associated with a higher risk of incident HF and AF. An intervention with MedDiet+extra-virgin olive oil may reduce AF risk associated with long-chain acylcarnitines. This trial was registered at controlled-trials.com (Identifier: ISRCTN35739639).

Background Telomere attrition may play an important role in the pathogenesis and severity of type 2 diabetes (T2D), increasing the probability of β cell senescence and leading to reduced cell mass and decreased insulin secretion. Nutrition and lifestyle are known factors modulating the aging process and insulin resistance/secretion, determining the risk of T2D. Objectives The aim of this study was to evaluate the effects of pistachio intake on telomere length and other cellular aging-related parameters of glucose and insulin metabolism. Methods Forty-nine prediabetic subjects were included in a randomized crossover clinical trial. Subjects consumed a pistachio-supplemented diet (PD, 50 E% [energy percentage] carbohydrates and 33 E% fat, including 57 g pistachios/d) and an isocaloric control diet (CD, 55 E% carbohydrates and 30 E% fat) for 4 mo each, separated by a 2-wk washout period. DNA oxidation was evaluated by DNA damage (via 8-hydroxydeoxyguanosine). Leucocyte telomere length and gene expression related to either oxidation, telomere maintenance or glucose, and insulin metabolism were analyzed by multiplexed quantitative reverse transcriptase-polymerase chain reaction after the dietary intervention. Results Compared with the CD, the PD reduced oxidative damage to DNA (mean: −3.5%; 95% CI: −8.07%, 1.05%; P = 0.009). Gene expression of 2 telomere-related genes (TERT and WRAP53) was significantly upregulated (164% and 53%) after the PD compared with the CD (P = 0.043 and P = 0.001, respectively). Interestingly, changes in TERT expression were negatively correlated to changes in fasting plasma glucose concentrations and in the homeostatic model assessment of insulin resistance. Conclusions Chronic pistachio consumption reduces oxidative damage to DNA and increases the gene expression of some telomere-associated genes. Lessening oxidative damage to DNA and telomerase expression through diet may represent an intriguing way to promote healthspan in humans, reversing certain deleterious metabolic consequences of prediabetes. This study was registered at clinicaltrials.gov as NCT01441921.

Simple Summary Colorectal cancer (CRC) is the third most diagnosed cancer in men and the second in women worldwide, being the second most deadly cancer worldwide. The evidence coming from experimental studies suggest a protective effect of vitamin D intake on the risk of CRC. Different studies have shown that vitamin D may play a chemopreventive role in colorectal adenoma incidence, malignant transformation and progression. Our objective was to conduct an updated systematic review and meta-analysis of both case-control and prospective cohort studies on vitamin D intake and CRC. This manuscript provides a complete and updated state-of-the-art about vitamin D intake and CRC risk. Abstract Obesity, a sedentary lifestyle, high red meat consumption and alcohol, and tobacco are considered the driving factors behind colorectal cancer (CRC) worldwide. Both diet and lifestyle are recognized to play an important role in the prevention of CRC. Forty years later, the vitamin D–cancer hypothesis is considered consistent. However, the relationship between low vitamin D intake and CRC is still controversial. The aim of this meta-analysis is to determine the associations between Vitamin D intake and CRC. MEDLINE-PubMed and Cochrane databases were searched up to May 2020 for studies evaluating the association between vitamin D intake (from foods and supplements) and CRC. Two reviewers, working independently, screened all titles and abstracts to identify the studies that met the inclusion criteria (case-control or prospective cohort (PC) studies published in English). Data were pooled by the generic inverse variance method using a random or fixed effect model. Heterogeneity was identified using the Cochran Q-test and quantified by the I2 statistic. A total of 31 original studies were included for the quantitative meta-analysis, comprising a total 47.540 cases and 70.567 controls in case-control studies, and a total of 14.676 CRC-incident cases (out of 808.130 subjects in PC studies) from 17 countries. A significant 25% lower risk was reported comparing the highest vs. the lowest dietary vitamin D consumption and CRC risk (odds ratio (95% confidence interval): 0.75 (0.67; 0.85)) in case-control studies, whereas a non-significant association was reported in case of prospective studies (hazard ratio (95% confidence interval): 0.94 (0.79; 1.11). The present meta-analysis demonstrates that high dietary vitamin D is associated to CRC prevention. However, larger and high-quality prospective studies and clinical trials are warranted to confirm this association.

BACKGROUND: The tryptophan–kynurenine pathway is linked to inflammation. We hypothesize that metabolites implicated in this pathway may be associated with the risk of heart failure (HF) or atrial fibrillation (AF) in a population at high risk of cardiovascular disease. OBJECTIVES: We aimed to prospectively analyze the associations of kynurenine-related metabolites with the risk of HF and AF and to analyze a potential effect modification by the randomized interventions of the PREDIMED (Prevención con Dieta Mediterránea) trial with Mediterranean diet (MedDiet). METHODS: Two case–control studies nested within the PREDIMED trial were designed. We selected 324 incident HF cases and 502 incident AF cases individually matched with ≤3 controls. Conditional logistic regression models were fitted. Interactions with the intervention were tested for each of the baseline plasma metabolites measured by LC–tandem MS. RESULTS: Higher baseline kynurenine:tryptophan ratio (OR for 1 SD: 1.20; 95% CI: 1.01, 1.43) and higher levels of kynurenic acid (OR: 1.19; 95% CI: 1.01, 1.40) were associated with HF. Quinolinic acid was associated with AF (OR: 1.15; 95% CI: 1.01, 1.32) and HF (OR: 1.25; 95% CI: 1.04, 1.49). The MedDiet intervention modified the positive associations of kynurenine (P(interaction) = 0.006), kynurenic acid (P(interaction) = 0.008), and quinolinic acid (P(interaction) = 0.033) with HF and the association between kynurenic acid and AF (P(interaction) = 0.02). CONCLUSIONS: We found that tryptophan–kynurenine pathway metabolites were prospectively associated with higher HF risk and to a lesser extent with AF risk. Moreover, an effect modification by MedDiet was observed for the association between plasma baseline kynurenine-related metabolites and the risk of HF, showing that the positive association of increased levels of these metabolites and HF was restricted to the control group.

Background and aims: Modifiable lifestyle factors, such as physical activity (PA) and Mediterranean diet (MD), decrease metabolic syndrome (MetS). The aim was to assess 1-year changes of leisure-time physical activity (LTPA), sedentary behavior, and diet quality according to MetS severity in older population at high cardiovascular risk. Methods and results: Prospective analysis of 55-75-year-old 4359 overweight/obese participants with MetS (PREDIMED-Plus trial) categorized in tertiles according to 1-year changes of a validated MetS severity score (MetSSS). Anthropometrics, visceral adiposity index, triglycerides and glucose index, dietary nutrient intake, biochemical marker levels, dietary inflammatory index, and depression symptoms were measured. Diet quality was assessed by 17-item MD questionnaire. PAs were self-reported using the Minnesota-REGICOR Short Physical Activity Questionnaire and 30-s chair stand test. Sedentary behaviors were measured using the Spanish version of the Nurses' Health Study questionnaire. After 1-year follow-up, decreasing MetSSS was associated with an anti-inflammatory dietary pattern, high intake of vegetables, fruits, legumes, nuts, whole grain cereals, white fish, and bluefish and low intake of refined cereals, red and processed meat, cookies/sweets, and snacks/ready-to-eat-meals. It resulted in high intake of polyunsaturated fatty acids, omega-3 fatty acids, protein, fiber, vitamins B1, B6, B9, C, D, potassium, magnesium, and phosphorus and low glycemic index and saturated fatty acid, trans fatty acid, and carbohydrates intake. Regarding PA and sedentary behavior, decreasing MetSSS was associated with increased moderate-to-vigorous LTPA, chair stand test, and decreased sedentary and TV-viewing time. Conclusion: Decreasing MetSSS was associated with an anti-inflammatory dietary pattern, high LTPA, high MD adherence, low sedentary time, and low depression risk. 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Background Epidemiologic studies have reported a modest inverse association between dairy consumption and the risk of type 2 diabetes (T2D). Whether plasma metabolite profiles associated with dairy consumption reflect this relationship remains unknown. Objectives We aimed to identify the plasma metabolites associated with total and specific dairy consumption, and to evaluate the association between the identified multi-metabolite profiles and T2D. Methods The discovery population included 1833 participants from the Prevencion con Dieta Mediterranea (PREDIMED) trial. The confirmatory cohorts included 1522 PREDIMED participants at year 1 of the trial and 4932 participants from the Nurses' Health Studies (NHS), Nurses' Health Study II (NHSII), and Health Professionals Follow-Up Study US-based cohorts. Dairy consumption was assessed using validated FFQs. Plasma metabolites (n = 385) were profiled using LC-MS. We identified the dairy-related metabolite profiles using elastic net regularized regressions with a 10-fold cross-validation procedure. We evaluated the associations between the metabolite profiles and incident T2D in the discovery and the confirmatory cohorts. Results Total dairy intake was associated with 38 metabolites. C14:0 sphingomyelin (positive coefficient), C34:0 phosphatidylethanolamine (positive coefficient), and γ-butyrobetaine (negative coefficient) were associated in a directionally similar fashion with total and specific (milk, yogurt, cheese) dairy consumption. The Pearson correlation coefficients between self-reported total dairy intake and predicted total dairy intake based on the corresponding multi-metabolite profile were 0.37 (95% CI, 0.33-0.40) in the discovery cohort and 0.16 (95% CI, 0.13-0.19) in the US confirmatory cohort. After adjusting for T2D risk factors, a higher total dairy intake-related metabolite profile score was associated with a lower T2D risk [HR per 1 SD; discovery cohort: 0.76 (95% CI, 0.63-0.90); US confirmatory cohort: 0.88 (95% CI, 0.78-0.99)]. Conclusions Total dairy intake was associated with 38 metabolites, including 3 consistently associated with dairy subtypes (C14:0 sphingomyelin, C34:0 phosphatidylethanolamine, γ-butyrobetaine). A score based on the 38 identified metabolites showed an inverse association with T2D risk in Spanish and US populations.

The increased prevalence of atrial fibrillation (AF) and heart failure (HF) highlights the need to better understand the mechanisms underlying these cardiovascular diseases (CVDs). In the present study, we aimed to evaluate the association between glycolysis-related metabolites and the risk of AF and HF in a Mediterranean population at high risk of CVD. We used two case-control studies nested within the PREDIMED trial. A total of 512 incident AF cases matched to 734 controls, and 334 incident HF cases matched to 508 controls, were included. Plasma metabolites were quantified by using hydrophilic interaction liquid chromatography coupled with high-resolution negative ion mode MS detection. Conditional logistic regression analyses were performed. The results showed no association between baseline plasma glycolysis intermediates and other related metabolites with AF. Only phosphoglycerate was associated with a higher risk of HF (OR for 1 SD increase: 1.28; 95% CI: 1.06, 1.53). The present findings do not support a role of the glycolysis pathway in the pathogenesis of AF. However, the increased risk of HF associated with phosphoglycerate requires further studies. This research was funded by The National Institutes of Health (R01HL118264), the Spanish Ministry of Health (Instituto de Salud Carlos III), and the Ministerio de Economía y Competitividad-Fondo Europeo de Desarrollo Regional (Projects CNIC-06/2007, RTIC G03/140, CIBER 06/03, PI06-1326, PI07-0954, PI11/02505, SAF2016-80532, SAF2009-12304 and AGL2010-22319-C03-03), and by the Generalitat Valenciana (PROMETEO 17/2017, ACOMP2010-181, AP111/10, AP-042/11, ACOM2011/145, ACOMP/2012/190, ACOMP/2013/159 and ACOMP/213/165), and CIBER Obesidad y Nutrición, Madrid, Spain, Fondo de Investigación Sanitaria, Madrid, Spain. THEMATIC NETWORK “PREDIMED”, RD 06/0045, coordinated by MAM-G, funded by ISCIII 2006-2013. N. Becerra-Tomás, a postdoctoral fellowship (Juan de la Cierva Formación, FJC2018-036016-I); P. Hernández-Alonso, a postdoctoral fellowship (Juan de la Cierva Formación, FJCI-2017-32205); M. Guasch-Ferré, American Diabetes Association grant #1-18-PMF-029; E. Ros, grants for research through his institution from the California Walnut Commission (CWC); J. Salas-Salvadó (senior author of this work), partially supported by ICREA under the ICREA Academia programme, grants/research support from the American Pistachio Growers and International Nut and Dried Fruit Foundation through his Institution.

Background The quality of carbohydrate consumed, assessed by the glycemic index (GI), glycemic load (GL), or carbohydrate quality index (CQI), affects the postprandial glycemic and insulinemic responses, which have been implicated in the etiology of several chronic diseases. However, it is unclear whether plasma metabolites involved in different biological pathways could provide functional insights into the role of carbohydrate quality indices in health. Objectives We aimed to identify plasma metabolomic profiles associated with dietary GI, GL, and CQI. Methods The present study is a cross-sectional analysis of 1833 participants with overweight/obesity (mean age = 67 y) from 2 case-cohort studies nested within the PREDIMED (Prevencion con Dieta Mediterranea) trial. Data extracted from validated FFQs were used to estimate the GI, GL, and CQI. Plasma concentrations of 385 metabolites were profiled with LC coupled to MS and associations of these metabolites with those indices were assessed with elastic net regression analyses. Results A total of 58, 18, and 57 metabolites were selected for GI, GL, and CQI, respectively. Choline, cotinine, γ-butyrobetaine, and 36:3 phosphatidylserine plasmalogen were positively associated with GI and GL, whereas they were negatively associated with CQI. Fructose-glucose-galactose was negatively and positively associated with GI/GL and CQI, respectively. Consistent associations of 21 metabolites with both GI and CQI were found but in opposite directions. Negative associations of kynurenic acid, 22:1 sphingomyelin, and 38:6 phosphatidylethanolamine, as well as positive associations of 32:1 phosphatidylcholine with GI and GL were also observed. Pearson correlation coefficients between GI, GL, and CQI and the metabolomic profiles were 0.30, 0.22, and 0.27, respectively. Conclusions The GI, GL, and CQI were associated with specific metabolomic profiles in a Mediterranean population at high cardiovascular disease risk. Our findings may help in understanding the role of dietary carbohydrate indices in the development of cardiometabolic disorders. This trial was registered at isrctn.com as ISRCTN35739639.

Vitamin B12 has been widely related to methionine metabolism, which is an essential component for biological methylation reactions, including DNA methylation. However, the relationship between vitamin B12 and DNA methylation is still controversial. In addition, there is increasing evidence for the association between vitamin B12 and the risk of colorectal cancer (CRC), although results of this association need to be assessed with caution. For this purpose, we hypothesized that serum vitamin B12 could be associated with global DNA methylation in the CRC context. To test this hypothesis, we studied the association between global DNA methylation through long interspersed nuclear element-1 (LINE1) in CRC patients under the 25th percentile of serum vitamin B12. We found that the high vitamin B12 group had low LINE1 methylation in both tumor area and peripheral blood mononuclear cells (PBMCs) than the low serum vitamin B12 group. LINE1 methylation levels were significantly lower in tumor area compared to the adjacent tumor-free area, only in the high vitamin B12 group. LINE1 methylation in visceral adipose tissue (VAT) and PBMCs were correlated with tumoral, inflammatory, and insulin metabolism markers. However, the interaction between LINE1 methylation and vitamin B12 levels was associated with neoadjuvant therapy in the regression analysis only in men, suggesting a beneficial relationship. In conclusion, our results reported an inverse association between DNA methylation and vitamin B12 in the CRC context, which suggests that vitamin B12 may be implicated in an epigenetic state or mediation in CRC.

[Background] Although the association between glutamate and glutamine in relation to cardiometabolic disorders has been evaluated, the role of these metabolites in the development of atrial fibrillation (AF) and heart failure (HF) remains unknown., [Objectives] We examined associations of glutamate, glutamine, and the glutamine-to-glutamate ratio with AF and HF incidence in a Mediterranean population at high cardiovascular disease (CVD) risk., [Methods] The present study used 2 nested case-control studies within the PREDIMED (Prevención con Dieta Mediterránea) study. During ∼10 y of follow‐up, there were 509 AF incident cases matched to 618 controls and 326 HF incident cases matched to 426 controls. Plasma concentrations of glutamate and glutamine were semiquantitatively profiled with LC–tandem MS. ORs were estimated with multivariable conditional logistic regression models. [Results] In fully adjusted models, per 1-SD increment, glutamate was associated with a 29% (95% CI: 1.08, 1.54) increased risk of HF and glutamine‐to‐glutamate ratio with a 20% (95% CI: 0.67, 0.94) decreased risk. Glutamine-to-glutamate ratio was also inversely associated with HF risk (OR per 1-SD increment: 0.80; 95% CI: 0.67, 0.94) when comparing extreme quartiles. Higher glutamate concentrations were associated with a worse cardiometabolic risk profile, whereas a higher glutamine-to-glutamate ratio was associated with a better cardiometabolic risk profile. No associations between the concentrations of these metabolites and AF were observed., [Conclusions] Our findings suggest that high plasma glutamate concentrations possibly resulting from alterations in the glutamate-glutamine cycle may contribute to the development of HF in Mediterranean individuals at high CVD risk., Supported by NIH grant R01HL118264 (to FBH); Spanish Ministry of Health (Instituto de Salud Carlos III) and Ministerio de Economía y Competitividad-Fondo Europeo de Desarrollo Regional projects CNIC-06/2007, RTIC G03/140, CIBER 06/03, PI06-1326, PI07-0954, PI11/02505, SAF2016-80532, SAF2009-12304, and AGL2010-22319-C03-03; and Generalitat Valenciana PROMETEO 17/2017, ACOMP2010-181, AP111/10, AP-042/11, ACOM2011/145, ACOMP/2012/190, ACOMP/2013/159, and ACOMP/213/165. CP was the recipient of Instituto de Salud Carlos III Miguel Servet fellowship grant CP 19/00189. PH-A was supported by Juan de la Cierva-Formación postdoctoral fellowship FJCI-2017-32205. MG-F was supported by American Diabetes Association grant #1-18-PMF-029.

[Background and aims]: The aim of this study was to ascertain the association between the consumption of different categories of edible olive oils (virgin olive oils and olive oil) and olive pomace oil and ankle-brachial pressure index (ABI) in participants in the PREDIMED-Plus study, a trial of lifestyle modification for weight and cardiovascular event reduction in individuals with overweight/obesity harboring the metabolic syndrome., [Methods]: We performed a cross-sectional analysis of the PREDIMED-Plus trial. Consumption of any category of olive oil and olive pomace oil was assessed through a validated food-frequency questionnaire. Multivariable linear regression models were fitted to assess associations between olive oil consumption and ABI. Additionally, ABI ≤1 was considered as the outcome in logistic models with different categories of olive oil and olive pomace oil as exposure., [Results]: Among 4330 participants, the highest quintile of total olive oil consumption (sum of all categories of olive oil and olive pomace oil) was associated with higher mean values of ABI (beta coefficient: 0.014, 95% confidence interval [CI]: 0.002, 0.027) (p for trend = 0.010). Logistic models comparing the consumption of different categories of olive oils, olive pomace oil and ABI ≤1 values revealed an inverse association between virgin olive oils consumption and the likelihood of a low ABI (odds ratio [OR] 0.73, 95% CI [0.56, 0.97]), while consumption of olive pomace oil was positively associated with a low ABI (OR 1.22 95% CI [1.00, 1.48])., [Conclusions]: In a Mediterranean population at high cardiovascular risk, total olive oil consumption was associated with a higher mean ABI. These results suggest that olive oil consumption may be beneficial for peripheral artery disease prevention, but longitudinal studies are needed., The authors especially thank the PREDIMED-Plus participants for their enthusiastic collaboration, the PREDIMED-Plus personnel for outstanding support, and the personnel of all associated primary care centres for their exceptional effort. CIBEROBN, CIBERESP and CIBERDEM are initiatives of Instituto de Salud Carlos III, Spain.

Backgrounds Colorectal cancer (CRC) results from the accumulation of epigenetic and genetic changes in colon cells during neoplasic transformation, which the activation of Wingless (Wnt) signaling pathway is a common mechanism for CRC initiation. The Wnt pathway is mainly regulated by Wnt antagonists, as secreted frizzled-related protein (SFRP) family. Indeed, SFRP2 is proposed as a noninvasive biomarker for CRC diagnosis. Vitamin D also antagonizes Wnt signaling in colon cancers cells. Several studies showed that vitamin D was able to alter DNA methylation, although this mechanism is not yet clear. Therefore, the aim of this study was to find an association between circulating 25-OH vitamin D (30th percentile of vitamin D) and the SFRP2 methylation. Methods A total of 67 CRC patients were included in the study. These patients were subdivided into two groups based on their 30th percentile vitamin D (20 patients were below, and 47 participants were above the 30th percentile of vitamin D). We investigated the SFRP2 methylation in peripheral blood mononuclear cells (PBMCs), visceral adipose tissue (VAT), CRC tumor tissue, and adjacent tumor-free area. We also determined the relationship between SFRP2 methylation and methylation of carcinogenic and adipogenic genes. Finally, we tested the effect of vitamin D on the SFRP2 methylation in human colorectal carcinoma cell lines 116 (HCT116) and studied the association of neoadjuvant therapy under the 30th percentile vitamin D with SFRP2 promoter methylation. Results SFRP2 methylation in tumor area was decreased in patients who had higher levels of vitamin D. SFRP2 promoter methylation was positively correlated in tumor area with insulin and homeostasis model assessment of insulin resistance (HOMA-IR) but negatively correlated with HDL-c. SFRP2 methylation was also correlated with T cell lymphoma invasion and metastasis 1 (TIAM1) methylation in tumor area and CCAAT/enhancer-binding protein alpha (C/EBPα) in VAT. Treatment with vitamin D did not affect SFRP2 methylation in HCT116 cell line. Finally, neoadjuvant treatment was correlated with higher circulating 25-OH vitamin D and SFRP2 methylation under linear regression model. Conclusion Our results showed that higher circulating vitamin D is associated with low SFRP2 promoter methylation. Therefore, our results could suggest that vitamin D may have an epigenetic effect on DNA methylation. Finally, higher vitamin D could contribute to an improvement response to neoadjuvant treatment.

Dietary polyphenol intake is associated with improvement of metabolic disturbances. The aims of the present study are to describe dietary polyphenol intake in a population with metabolic syndrome (MetS) and to examine the association between polyphenol intake and the components of MetS. This cross-sectional analysis involved 6633 men and women included in the PREDIMED (PREvenci&oacute, n con DIeta MEDiterranea-Plus) study. The polyphenol content of foods was estimated from the Phenol-Explorer 3.6 database. The mean of total polyphenol intake was 846 &plusmn, 318 mg/day. Except for stilbenes, women had higher polyphenol intake than men. Total polyphenol intake was higher in older participants (&gt, 70 years of age) compared to their younger counterparts. Participants with body mass index (BMI) &gt, 35 kg/m2 reported lower total polyphenol, flavonoid, and stilbene intake than those with lower BMI. Total polyphenol intake was not associated with a better profile concerning MetS components, except for high-density lipoprotein cholesterol (HDL-c), although stilbenes, lignans, and other polyphenols showed an inverse association with blood pressure, fasting plasma glucose, and triglycerides. A direct association with HDL-c was found for all subclasses except lignans and phenolic acids. To conclude, in participants with MetS, higher intake of several polyphenol subclasses was associated with a better profile of MetS components, especially HDL-c.

Background: The interaction between obesity and genetic traits on high density lipoprotein (HDL) levels has been extensively studied. The variance of serum HDL has a strong genetic heritability, although the studied variant only explains a small part of this variation. The goal of this study was to investigate the associations between the apolipoprotein type 2 (APOA2) rs3813627 single nucleotide polymorphism (SNP) and anthropometric and biochemical variables, though body mass index (BMI). Methods: This study included 153 subjects (91 overweight/obese (BMI&sup3, 25 kg/m2) and 62 non-obese individuals (BMI &lt, 25 kg/m2)). The APOA2 rs3813627 SNP was selected and genotyped. Genotype analysis was performed to analyze the associations between APOA2 SNPs and anthropometric and biochemical variables through BMI. Results: The APOA2 rs3813627 TT genotype was associated with low HDL levels in comparison with the APOA2 rs3813627 GG and GT genotype in overweight/obese individuals, but not in the non-obese subjects (p &lt, 0.05). The same trend was observed in the apolipoprotein type 1 (APOA1) protein levels (p &lt, 0.05). Correlation analysis revealed a negative correlation between HDL and APOA1 levels and APOA2 rs3813627 SNP under recessive model (p &lt, 0.05). The odds ratio for low HDL levels was 3.76 and 3.94 for low APOA1 levels. The mediation analysis of APOA2 rs3813627 SNP through BMI showed a full mediation on HDL and partial mediation on APOA1 levels (p &lt, 0.05). Bioinformatic analysis showed that rs3813627 lies in the APOA2 promoter and overlaps motifs for several bound transcription factors. Conclusion: On the basis of these data, the APOA2 rs3813627 SNP is associated with low HDL and APOA1 levels susceptibility, and this effect was mediated by an increased BMI.

SCOPE: The plasma metabolomics profiles of protein intake has been rarely investigated. We aimed to identify the distinct plasma metabolomics profiles associated with overall intakes of protein as well as with intakes from animal and plant protein sources. METHODS AND RESULTS: Cross-sectional analysis using data from 1,833 participants at high risk of cardiovascular disease. Plasma metabolomics analysis was performed using LC-MS. Associations between 385 identified metabolites and the intake of total, animal protein (AP) and plant protein (PP), and plant-to-animal ratio (PR) were assessed using elastic net continuous regression analyses. A double 10-cross-validation (CV) procedure was used and Pearson correlations coefficients between multi-metabolite weighted models and reported protein intake in each pair of training-validation datasets were calculated. A wide set of metabolites was consistently associated with each protein source evaluated. These metabolites mainly consisted of amino acids and their derivatives, acylcarnitines, different organic acids and lipid species. Few metabolites overlapped among protein sources (i.e. C14:0 SM, C20:4 carnitine, GABA and allantoin) but none of them towards the same direction. Regarding AP and PP approaches, C20:4 carnitine and dimethylglycine were positively associated with PP but negatively associated with AP. However, allantoin, C14:0 SM, C38:7 PE plasmalogen, GABA, metronidazole and trigonelline (N-methylnicotinate) behaved contrary. Ten-CV Pearson correlations coefficients between self-reported protein intake and plasma metabolomics profiles ranged from 0.21 for PR to 0.32 for total protein. CONCLUSIONS: Different sets of metabolites were associated with total, animal and plant protein intake. Further studies are needed to assess the contribution of these metabolites in protein biomarkers’ discovery and prediction of cardiometabolic alterations.

Accelerated telomere shortening has been associated with several age-related diseases and/or decreased lifespan in humans. The Mediterranean diet (MedDiet) is considered to be 1 of the most recognized diets for disease prevention and healthy aging, partially due to its demonstrated anti-inflammatory and antioxidative properties which may impact on telomere length (TL). The aim of this meta-analysis was to determine the associations between MedDiet adherence and TL maintenance. MEDLINE-PubMed and Cochrane databases were searched up to December 2018 for studies evaluating the association between MedDiet adherence and TL in blood cells. Two reviewers, working independently, screened all titles and abstracts to identify studies that met the inclusion criteria [cross-sectional, case-control, and prospective cohort studies and randomized clinical trials (RCTs) published in English and excluded nonoriginal articles]. Data were pooled by the generic inverse variance method using the random effects model and expressed as standardized mean difference (SMD). Heterogeneity was identified using the Cochran Q test and quantified by the I(2) statistic. A total of 8 original cross-sectional studies were included for the quantitative meta-analysis, comprising a total of 13,733 participants from 5 countries. A positive association between adherence to the MedDiet and TL was observed in all meta-analyses, with the exception of those conducted only in men: SMD (95% CI) of 0.130 (0.029; 0.231) for all subjects, 0.078 (0.005; 0.152) for women, and 0.095 (–0.005; 0.195) for men. Only 1 prospective cohort study and 1 RCT were identified, therefore, we could not undertake a meta-analysis for these study designs. The present meta-analysis of cross-sectional studies demonstrates that higher MedDiet adherence is associated with longer TL. At the same time, larger and high-quality prospective studies and clinical trials are warranted to confirm this association.

PREDIMED-PLUS investigators: et al., [Background]: High nut consumption has been previously associated with decreased prevalence of metabolic syndrome (MetS) regardless of race and dietary patterns., [Objectives]: The aim of this study was to assess whether changes in nut consumption over a 1-y follow-up are associated with changes in features of MetS in a middle-aged and older Spanish population at high cardiovascular disease risk., [Methods]: This prospective 1-y follow-up cohort study, conducted in the framework of the PREvención con DIeta MEDiterránea (PREDIMED)-Plus randomized trial, included 5800 men and women (55–75 y old) with overweight/obesity [BMI (in kg/m2) ≥27 and, [Results]: As nut consumption increased, between each tertile there was a significant decrease in WC, TG, systolic blood pressure, weight, and BMI (P < 0.05), and a significant increase in HDL cholesterol (only in women, P = 0.044). The interaction effect between time and group was significant for total energy intake (P < 0.001), adherence to the Mediterranean diet (MedDiet) (P < 0.001), and nut consumption (P < 0.001). Across tertiles of increasing nut consumption there was a significant increase in extra virgin olive oil intake and adherence to the MedDiet; change in energy intake, on the other hand, was inversely related to consumption of nuts., [Conclusions]: Features of MetS and excess weight were inversely associated with nut consumption after a 1-y follow-up in the PREDIMED-Plus study cohort. This trial was registered at isrctn.com as ISRCTN89898870., The PREDIMED-Plus trial was supported by the official funding agency for biomedical research of the Spanish government, Instituto de Salud Carlos III (ISCIII), through the Fondo de Investigación para la Salud (FIS), which is cofunded by the European Regional Development Fund (5 coordinated FIS projects led by JS-S and J Vidal, including projects PI13/00673, PI13/00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728, PI13/01090, PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI14/00972, PI14/00728, PI14/01471, PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183, PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441, PI17/00508, PI17/01732, PI17/00926, PI19/00957, PI19/00386, PI19/00309, PI19/01032, PI19/00576, PI19/00017, PI19/01226, PI19/00781, PI19/01560, and PI19/01332); the Special Action Project entitled Implementación y evaluación de una intervención intensive sobre la actividad física Cohorte PREDIMED-Plus grant (to JS-S); European Research Council Advanced Research Grant 2013–2018, 340918 (to MÁM-G); Recercaixa Grant 2013ACUP00194 (to JS-S); Consejería de Salud de la Junta de Andalucía grants PI0458/2013, PS0358/2016, and PI0137/2018; Generalitat Valenciana grant PROMETEO/2017/017; a SEMERGEN grant; EU-COST Action CA16112; Balearic Islands Government grant of support to research groups 35/2011; Balearic Islands Health Research Institute (IdISBa) grants; European Regional Development Fund funds CIBEROBN CB06/03 and CB12/03; and European Commission fund EAT2BENICE_H2020_SFS2016. PH-A is supported by Juan de la Cierva-Formación postdoctoral fellowship FJCI-2017-32205. AC is supported by IdISBa “TECH” fellowship TECH18/03, funded by the 2018 Sustainable Tourism Tax annual plan. LG-A is supported by a FPU PhD program from the Spanish Ministry of Education.

One-year dietary quality change according to the preceding maximum weight in a lifestyle intervention program (PREDIMED-Plus trial, 55–75-year-old overweight or obese adults; n = 5695) was assessed. A validated food frequency questionnaire was used to assess dietary intake. A total of 3 groups were made according to the difference between baseline measured weight and lifetime maximum reported weight: (a) participants entering the study at their maximum weight, (b) moderate weight loss maintainers (WLM), and (c) large WLM. Data were analyzed by General Linear Model. All participants improved average lifestyle. Participants entering the study at their maximum weight were the most susceptible to improve significantly their dietary quality, assessed by adherence to Mediterranean diet, DII and both healthful and unhealthful provegetarian patterns. People at maximum weight are the most benefitted in the short term by a weight management program. Long term weight loss efforts may also reduce the effect of a weight management program., European Research Council (ERC) 340918, Official funding agency for biomedical research of the Spanish government, ISCIII, through the Fondo de Investigacion para la Salud (FIS), Junta de Andalucia PI0458/2013 PS0358/2016 PI0137/2018, Especial Action Project entitled: Implementacion y evaluacion de una intervencion intensive sobre la actividad fisica Cohorte PREDIMED-Plus grant, Recercaixa Grant 2013ACUP00194, Generalitat Valenciana PROMETEO/2017/017, SEMERGEN Grant, European Union (EU) European Cooperation in Science and Technology (COST) CA16112, Balearic Islands Government 35/2011, Balearic Islands Health Research Institute (IDISBA), European Union (EU) CIBEROBN CB06/03 CB12/03 PI13/00673 PI13/00492 PI13/00272 PI13/01123 PI13/00462 PI13/00233 PI13/02184 PI13/00728 PI13/01090 PI13/01056 PI14/01722 PI14/00636 PI14/00618 PI14/00696 PI14/01206 PI14/01919 PI14/00853 PI14/01374 PI14/00972 PI14/00728, European Commission European Commission Joint Research Centre EAT2BENICE_H2020_SFS2016, Fernando Tarongi Bauza Grant, PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183, PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441, PI17/00508, PI14/01471, PI17/01732, PI17/00926, PI19/00957, PI19/00386, PI19/00309, PI19/01032, PI19/00576, PI19/00017, PI19/01226, PI19/00781, PI19/01560, PI19/01332

espanolIntroduccion: hasta la fecha, una dieta sin gluten (SG) es el unico tratamiento para las personas con enfermedad celiaca. Tanto las evaluaciones de ingesta de alimentos individuales como las colectivas son un desafio debido a la falta de una base de datos de composicion de productos SG (PSG). Objetivos: describir el proceso de desarrollo de una base de datos de composicion de PSG y comparar el perfil nutricional y el precio de algunos PSG y productos con gluten. Metodos: inicialmente, se registraron un total de 216 marcas de PSG comercializadas en Espana. La informacion nutricional se recopilo de las etiquetas nutricionales y hojas informativas de los productos, que habian sido proporcionadas por las companias de alimentos o recopiladas de primera mano por los investigadores. Luego, se compararon el perfil nutricional y el precio de los grupos de cereales y subproductos alimenticios, incluidos 19 tipos de productos. Los analisis estadisticos se realizaron utilizando el programa estadistico SPSS (edicion 22.0; SPSS, Chicago, IL, EUA). Resultados: se incluyeron un total de 2247 PSG de 126 marcas de alimentos diferentes en la base de datos de composicion de PSG (CELIAC-BASE). Clasificamos estos productos en 14 grupos de alimentos. El contenido de proteinas de los PSG estudiados fue significativamente menor, y el precio de los mismos fue mas alto, que el de sus homologos con gluten. Algunos PSG, pero no todos, presentaron un mayor contenido de grasa y azucar, y un menor contenido de fibra dietetica, que sus homologos con gluten. Algunos PSG eran hasta 6 veces mas caros que sus homologos con gluten. Conclusiones: CELIAC-BASE es una herramienta pionera para dietistas-nutricionistas. Muchos PSG tienen perfiles nutricionales no saludables y deben consumirse solo ocasionalmente en una dieta equilibrada libre de gluten. EnglishBackground: to date, gluten-free (GF) diet is the only treatment available for individuals with celiac disease. Both individual and collective food intake assessments are a challenge because a food composition database of GF products (GFPs) is lacking. Objectives: to describe the process of developing a food composition database of GFPs, and to compare the nutritional profile and price of some GFPs and non-GFPs. Methods: initially, a total of 216 brands of GFPs marketed in Spain were recorded. Nutritional information was collected from nutritional labels and product fact sheets that had been provided by food companies or collected first-hand by researchers. Then, the nutritional profile and price of the cereal and cereal byproducts foodstuff groups, including 19 types of products, were compared. Statistical analyses were performed using the SPSS statistical program (22.0 edition; SPSS, Chicago, IL, USA). Results: a total of 2,247 GFPs from 126 different foodstuff brands were included in the food composition database of GFPs (CELIAC-BASE). We classified these products into 14 foodstuff groups. The protein content of the GFPs studied was significantly lower, and the price was higher, than that of their non-GFP counterparts. Some, but not all, GFPs had a higher content of fat and sugar, and a lower content of dietary fiber as compared to their non-GFP counterparts. Some GFPs were up to 6 times more expensive than the corresponding non-GFPs. Conclusions: CELIAC-BASE is a pioneering tool for dietitians. Many GFPs have poor nutritional profiles and should be consumed only occasionally in a balanced GF diet.

Background High glucose and insulin concentrations seem to have a negative impact on bone health. However, the relation between the dietary glycemic index (DGI) and the dietary glycemic load (DGL), which has proved to be effective at modulating blood glucose concentrations after carbohydrate consumption, has yet to be explored in relation to bone health. Objective The aim of the study was to examine the associations between the DGI or DGL and the risk of osteoporotic-related fractures in an elderly Mediterranean population. Design The study was conducted in 870 subjects aged 55-80 y at high cardiovascular disease risk participating in the PREvencion con DIeta MEDiterranea (PREDIMED)-Reus study. The DGI and DGL were estimated from validated food-frequency questionnaires with the use of the international glycemic index and glycemic load values, with glucose as reference. Data on osteoporotic fractures were acquired from a systematic review of medical records. We used Cox proportional hazard models to assess the risk of osteoporotic fracture according to tertiles of average DGI and DGL. Results A total of 114 new cases of osteoporotic-related fractures were documented after a mean follow-up of 8.9 y. Participants in the highest tertile of DGI and DGL had a significantly higher risk of osteoporotic fractures than those in the lowest tertile after adjusting for potential confounders (HR: 1.80; 95% CI: 1.03, 3.15 and HR: 3.20; 95% CI: 1.25, 8.18, respectively). Conclusions A high DGI and DGL are associated with a higher risk of osteoporosis-related fractures in an elderly Mediterranean population at high cardiovascular disease risk. This trial was registered at isrctn.com as ISRCTN35739639.

INTRODUCTION Vitamin D has been widely associated with colorectal cancer (CRC) through different insights. This study aims to explore the association between serum 25-hydroxyvitamin D (25(OH)D) and the global DNA methylation in tumor from CRC patients. METHODS AND RESULTS A genome-wide DNA methylation analysis is conducted in 20 CRC patients under categorical (10 patients have 25(OH)D

OBJECTIVES: To prospectively analyze the associations between urea cycle metabolites and incident atrial fibrillation (AF) or heart failure (HF), and to evaluate the effect of a Mediterranean diet (MD) intervention on such associations. METHODS: We designed two nested case-control studies within the PREDIMED trial, a randomized controlled trial aimed to evaluate the effect of two MD interventions, supplemented with either extra virgin olive oil (EVOO) or nuts, on cardiovascular disease (CVD). Fasting blood samples were collected at baseline and urea cycle metabolites (arginine, citrulline, and ornithine) and methylarginines (asymmetric dimethylarginine/symmetric dimethylarginine ratio (ADMA/SDMA ratio)) were determined using liquid chromatography tandem mass spectrometry. We used conditional logistic regression models, adjusted for potential confounders, to analyze the associations between the metabolites and incident AF or HF. Potential interactions between metabolites and intervention (MD groups vs control group) were tested with the likelihood ratio test. RESULTS: The study population comprised a total of 1241 participants (509 cases) for AF case-control and 824 participants (326 cases) for HF case-control. Arginine was inversely associated with incident AF (OR per SD 0.83, 95% CI 0.73; 0.94) and HF (OR per SD 0.82, 95% CI 0.69; 0.97). Whereas ADMA/SDMA ratio was positively associated with AF (OR per SD 1.19, 95% CI 1.02; 1.41) but not with HF risk. A statistically significant interaction (P = 0.044) was found between arginine and intervention on HF risk. The lower risk of HF associated with arginine was only observed in participants of the MD groups (EVOO + nuts). CONCLUSIONS: The results of the present study suggest that urea cycle metabolites, arginine and ADMA/SDMA ratio specifically, could be involved in AF and HF pathophysiology. Moreover, the dietary intervention may modify the association between arginine and HF. FUNDING SOURCES: National Institutes of Health (NIH), Spanish Government Official Agency for funding biomedical research-Instituto de Salud Carlos III (ISCIII) and CIBEROBN

The specific nutritional composition of nuts could affect different metabolic pathways involved in a broad range of metabolic diseases. We therefore investigated whether chronic consumption of pistachio nuts modifies the urine metabolome in prediabetic subjects. We designed a randomized crossover clinical trial in 39 prediabetic subjects. They consumed a pistachio-supplemented diet (PD, 50% carbohydrates, 33% fat, including 57 g/d of pistachios daily) and a control diet (CD, 55% carbohydrates, 30% fat) for 4 months each, separated by a 2-week wash-out. Nuclear magnetic resonance (NRM) was performed to determine changes in 24-h urine metabolites. Significant changes in urine metabolites according to the different intervention periods were found in uni- and multivariate analysis. Score plot of the first two components of the multilevel partial least squares discriminant analysis (ML-PLS-DA) showed a clear separation of the intervention periods. Three metabolites related with gut microbiota metabolism (i.e., hippurate, p-cresol sulfate and dimethylamine) were found decreased in PD compared with CD (P

Different plasma metabolites have been related to insulin resistance (IR). However, there is a lack of metabolite models predicting IR with external validation. The aim of this study is to identify a multi-metabolite model associated to the homeostatic model assessment (HOMA)-IR values. We performed a cross-sectional metabolomics analysis of samples collected from overweight and obese subjects from two independent studies. The training step was performed in 236 subjects from the SATIN study and validated in 102 subjects from the GLYNDIET study. Plasma metabolomics profile was analyzed using three different approaches: GC/quadrupole-TOF, LC/quadrupole-TOF, and nuclear magnetic resonance (NMR). Associations between metabolites and HOMA-IR were assessed using elastic net regression analysis with a leave-one-out cross validation (CV) and 100 CV runs. HOMA-IR was analyzed both as linear and categorical (median or lower versus higher than the median). Receiver operating characteristic curves were constructed based on metabolites’ weighted models. A set of 30 metabolites discriminating extremes of HOMA-IR were consistently selected. These metabolites comprised some amino acids, lipid species and different organic acids. The area under the curve (AUC) for the discrimination between HOMA-IR extreme categories was 0.82 (95% CI: 0.74–0.90), based on the multi-metabolite model weighted with the regression coefficients of metabolites in the validation dataset. We identified a set of metabolites discriminating between extremes of HOMA-IR and able to predict HOMA-IR with high accuracy.

Obesity is well accepted as crucial risk factor that plays a critical role in the initiation and progression of colorectal cancer (CRC). More specifically, visceral adipose tissue (VAT) in people with obesity could produce chronic inflammation and an altered profile expression of key transcription factors that promote a favorable microenvironment to colorectal carcinogenesis. For this, the aim of this study was to explore the relationship between adipogenic and inflammatory transcription factors in VAT from nonobese, obese, and/or CRC patients. To test this idea, we studied the expression and methylation of CCAAT-enhancer binding protein type alpha (C/EBP-&alpha, ), peroxisome proliferator-activated receptor gamma (PPAR-&gamma, ), peroxisome proliferator-activated receptor gamma coactivator 1-&alpha, (PGC-1&alpha, ) and nuclear factor &kappa, light-chain-enhancer of activated B cells (NF-&kappa, B) in VAT from non-obese control, non-obese CRC subjects, overweight/obese control, and overweight/obese CRC patients and their correlation with anthropometric and biochemical variables. We found decreased expression of C/EBP-&alpha, in overweight/obese CRC patients in comparison with overweight/obese control subjects. PGC-1&alpha, and NF-&kappa, B were overexpressed in CRC patients independently of the BMI. NF-&kappa, B promoter was hypomethylated in overweight/obese CRC patients when compared to overweight/obese control individuals. In addition, multiple significant correlations between expression, methylation, and biochemical parameters were found. Finally, linear regression analysis showed that the expression of C/EBP-&alpha, B and that NF-&kappa, B methylation were associated with CRC and able to explain up to 55% of CRC variability. Our results suggest that visceral adipose tissue may be a key factor in tumor development and inflammatory state. We propose C/EBP-&alpha, PGC-1&alpha, B to be interesting candidates as potential biomarkers in adipose tissue for CRC patients.

Background Insulin resistance is a complex metabolic disorder and is often associated with type 2 diabetes (T2D). Objectives The aim of this study was to test whether baseline metabolites can additionally improve the prediction of insulin resistance beyond classical risk factors. Furthermore, we examined whether a multimetabolite model predicting insulin resistance in nondiabetics can also predict incident T2D. Methods We used a case-cohort study nested within the Prevencion con Dieta Mediterranea (PREDIMED) trial in subsets of 700, 500, and 256 participants without T2D at baseline and 1 and 3 y. Fasting plasma metabolites were semiquantitatively profiled with liquid chromatography-tandem mass spectrometry. We assessed associations between metabolite concentrations and the homeostasis model of insulin resistance (HOMA-IR) through the use of elastic net regression analysis. We subsequently examined associations between the baseline HOMA-IR-related multimetabolite model and T2D incidence through the use of weighted Cox proportional hazard models. Results We identified a set of baseline metabolites associated with HOMA-IR. One-year changes in metabolites were also significantly associated with HOMA-IR. The area under the curve was significantly greater for the model containing the classical risk factors and metabolites together compared with classical risk factors alone at baseline [0.81 (95% CI: 0.79, 0.84) compared with 0.69 (95% CI: 0.66, 0.73)] and during a 1-y period [0.69 (95% CI: 0.66, 0.72) compared with 0.57 (95% CI: 0.53, 0.62)]. The variance in HOMA-IR explained by the combination of metabolites and classical risk factors was also higher in all time periods. The estimated HRs for incident T2D in the multimetabolite score (model 3) predicting high HOMA-IR (median value or higher) or HOMA-IR (continuous) at baseline were 2.00 (95% CI: 1.58, 2.55) and 2.24 (95% CI: 1.72, 2.90), respectively, after adjustment for T2D risk factors. Conclusions The multimetabolite model identified in our study notably improved the predictive ability for HOMA-IR beyond classical risk factors and significantly predicted the risk of T2D.

OBJECTIVE The long-term impact of intentional weight loss on cardiovascular events remains unknown. We describe 12-month changes in body weight and cardiovascular risk factors in PREvención con DIeta MEDiterránea (PREDIMED)-Plus, a trial designed to evaluate the long-term effectiveness of an intensive weight loss lifestyle intervention on primary cardiovascular prevention. RESEARCH DESIGN AND METHODS Overweight/obese adults with metabolic syndrome aged 55–75 years (n = 626) were randomized to an intensive weight loss lifestyle intervention based on an energy-restricted Mediterranean diet, physical activity promotion, and behavioral support (IG) or a control group (CG). The primary and secondary outcomes were changes in weight and cardiovascular risk markers, respectively. RESULTS Diet and physical activity changes were in the expected direction, with significant improvements in IG versus CG. After 12 months, IG participants lost an average of 3.2 kg vs. 0.7 kg in the CG (P < 0.001), a mean difference of −2.5 kg (95% CI −3.1 to −1.9). Weight loss ≥5% occurred in 33.7% of IG participants compared with 11.9% in the CG (P < 0.001). Compared with the CG, cardiovascular risk factors, including waist circumference, fasting glucose, triglycerides, and HDL cholesterol, significantly improved in IG participants (P < 0.002). Reductions in insulin resistance, HbA1c, and circulating levels of leptin, interleukin-18, and MCP-1 were greater in IG than CG participants (P < 0.05). IG participants with prediabetes/diabetes significantly improved glycemic control and insulin sensitivity, along with triglycerides and HDL cholesterol levels compared with their CG counterparts. CONCLUSIONS PREDIMED-Plus intensive lifestyle intervention for 12 months was effective in decreasing adiposity and improving cardiovascular risk factors in overweight/obese older adults with metabolic syndrome, as well as in individuals with or at risk for diabetes.

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 (&ge, 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&ndash, 0.64), 0.78 (95% CI 0.75&ndash, 0.81) and 0.52 (95% CI 0.49&ndash, 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.