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Abstract Background Type 2 diabetes (T2D) has become a worldwide pandemic. While ceramides may serve as intermediary between obesity-related lipotoxicity and T2D, the relationship with simple glycosphingolipids remains uncertain. The aim of this study was to characterize the associations between blood glycosphingolipid and ceramide species with T2D and to identify a circulating sphingolipid profile that could serve as novel biomarker for T2D risk. Methods Cross-sectional relationship between sphingolipid levels, insulin resistance, and T2D prevalence were evaluated in 2,072 American adults from MIDUS cohort. Prospectively, the association between sphingolipid species and the incidence of T2D was analyzed using a case-cohort design nested within the PREDIMED trial (250 cases and a random sample of 692 participants, with 3.8 years of median follow-up). Circulating levels of sphingolipid species in both populations were measured using LC/MS. Hazard ratios were estimated with weighted Cox regression models using Barlow weights. Results In American adults, only CER18:0 and CER22:0 were linked to insulin resistance and a higher prevalence of T2D. Conversely, three lactosylceramides (LCER 14:0, 16:0, and 24:1) showed a strong inverse relationship with both insulin resistance and T2D. These findings led to development of two sphingolipid scores. In the prospective analysis, these scores consistently predicted a reduced risk of T2D incidence in PREDIMED (HR: 0.64, 95% CI 0.44 to 0.94 and 0.58, 0.40 to 0.85 respectively) between extreme quartiles, with 5-year absolute risk differences of 9.6% (95% CI: 0.3–20.5%) and 11.4% (1.0–21.6%). They were validated in the same trial with samples obtained after 1 year of follow-up. Conclusions Our findings support the potential usefulness of circulating sphingolipid profiles as novel biomarkers for T2D risk. Moreover, this study opens the door for future research on the predictive value and possible protective roles of lactosylceramides in T2D. Graphical abstract

Abstract Background Legume consumption has been linked to a reduced risk of type 2 diabetes (T2D) and cardiovascular disease (CVD), while the potential association between plasma metabolites associated with legume consumption and the risk of cardiometabolic diseases has never been explored. Therefore, we aimed to identify a metabolite signature of legume consumption, and subsequently investigate its potential association with the incidence of T2D and CVD. Methods The current cross-sectional and longitudinal analysis was conducted in 1833 PREDIMED study participants (mean age 67 years, 57.6% women) with available baseline metabolomic data. A subset of these participants with 1-year follow-up metabolomics data (n = 1522) was used for internal validation. Plasma metabolites were assessed through liquid chromatography-tandem mass spectrometry. Cross-sectional associations between 382 different known metabolites and legume consumption were performed using elastic net regression. Associations between the identified metabolite profile and incident T2D and CVD were estimated using multivariable Cox regression models. Results Specific metabolic signatures of legume consumption were identified, these included amino acids, cortisol, and various classes of lipid metabolites including diacylglycerols, triacylglycerols, plasmalogens, sphingomyelins and other metabolites. Among these identified metabolites, 22 were negatively and 18 were positively associated with legume consumption. After adjustment for recognized risk factors and legume consumption, the identified legume metabolite profile was inversely associated with T2D incidence (hazard ratio (HR) per 1 SD: 0.75, 95% CI 0.61–0.94; p = 0.017), but not with CVD incidence risk (1.01, 95% CI 0.86–1.19; p = 0.817) over the follow-up period. Conclusions This study identified a set of 40 metabolites associated with legume consumption and with a reduced risk of T2D development in a Mediterranean population at high risk of cardiovascular disease. Trial registration: ISRCTN35739639.

Abstract Background SARS-CoV-2 is the causative agent of COVID-19 identified in December 2019, an acute infectious respiratory disease that can cause persistent neurological and musculoskeletal symptoms such as headache, fatigue, myalgias difficulty concentrating, among others including acute cerebrovascular disease with a prevalence of 1–35%. The aim of this study is to evaluate the impact of COVID-19 in undergraduate students on their academic performance as an indicator of their intellectual ability and performance in a university that maintained 100% face-to-face teaching during the 2020–2021 academic year. Methods A total of 7,039 undergraduate students were analyzed in a prospective cohort study at the University of Navarra. A questionnaire including sociodemographic and behavioral questions was sent. PCRs were performed throughout the academic year for the diagnosis of SARS-CoV-2 infection and students’ academic results were provided by the academic center, adjusted descriptive and multivariate models were performed to assess the association. Results A total of 658 (9.3%) participants were diagnosed with COVID-19, almost 4.0% of them achieved outstanding academic results, while uninfected students did so in 7.3%. SARS-CoV-2 infection was associated with a significant decrease in having outstanding academic results (OR = 0.57; 95% CI: 0.38–0.86). Conclusion Having COVID-19 disease, decreased academic performance in undergraduate students. Therefore, it is necessary to prevent infection even in the youngest sections of the population.

Abstract Background Several large observational prospective studies have reported a protection by the traditional Mediterranean diet against type 2 diabetes, but none of them used yearly repeated measures of dietary intake. Repeated measurements of dietary intake are able to improve subject classification and to increase the quality of the assessed relationships in nutritional epidemiology. Beyond observational studies, randomized trials provide stronger causal evidence. In the context of a randomized trial of primary cardiovascular prevention, we assessed type 2 diabetes incidence according to yearly repeated measures of compliance with a nutritional intervention based on the traditional Mediterranean diet. Methods PREDIMED (‘‘PREvención con DIeta MEDiterránea’’) was a Spanish trial including 7447 men and women at high cardiovascular risk. We assessed 3541 participants initially free of diabetes and originally randomized to 1 of 3 diets: low-fat diet (n = 1147, control group), Mediterranean diet supplemented with extra virgin olive (n = 1154) or Mediterranean diet supplemented with mixed nuts (n = 1240). As exposure we used actual adherence to Mediterranean diet (cumulative average), yearly assessed with the Mediterranean Diet Adherence Screener (scoring 0 to 14 points), and repeated up to 8 times (baseline and 7 consecutive follow-up years). This score was categorized into four groups:

Abstract Background Consumption of certain foods is associated with long-term weight gains and abdominal fat accumulation in healthy, middle-aged and young, non-obese participants. Whether the same foods might be associated with changes in adiposity in elderly population at high cardiovascular risk is less known. Objective Using yearly repeated measurements of both food habits and adiposity parameters, we aimed to investigate how changes in the consumption of specific foods were associated with concurrent changes in weight or waist circumference (WC) in the PREDIMED trial. Design We followed-up 7009 participants aged 55–70 years at high cardiovascular risk for a median time of 4.8 years. A validated 137-item semi-quantitative Food Frequency Questionnaire was used for dietary assessment with yearly repeated measurements. We longitudinally assessed associations between yearly changes in food consumption (serving/d) and concurrent changes in weight (kg) or WC (cm). Results Yearly increments in weight were observed with increased consumption (kg per each additional increase in 1 serving/d) for refined grains (0.32 kg/serving/d), red meat (0.24), potatoes (0.23), alcoholic beverages (0.18), processed meat (0.15), white bread (0.07) and sweets (0.04); whereas inverse associations were detected for increased consumption of low-fat yogurt (− 0.18), and low-fat milk (− 0.06). Annual WC gain (cm per each additional increase in 1 serving/d) occurred with increased consumption of snacks, fast-foods and pre-prepared dishes (0.28), processed meat (0.18), alcoholic beverages (0.13), and sweets (0.08); whereas increased consumption of vegetables (− 0.23), and nuts (− 0.17), were associated with reductions in WC. Conclusions In this assessment conducted in high-risk subjects using yearly repeated measurements of food habits and adiposity, some ultra-processed foods, refined carbohydrates (including white bread), potatoes, red meats and alcohol were associated with higher weight and WC gain, whereas increases in consumption of low-fat dairy products and plant foods were associated with less gain in weight and WC. Trial registration This study was registered at controlled-trials.com with International Standard Randomized Controlled Trial Number (ISRCTN): 35739639. Registration date: 5 October 2005.

Abstract Background The pandemic of cardiovascular disease (CVD) and type 2 diabetes (T2D) requires the identification of new predictor biomarkers. Biomarkers potentially modifiable with lifestyle changes deserve a special interest. Our aims were to analyze: (a) The associations of lysine, 2-aminoadipic acid (2-AAA) or pipecolic acid with the risk of T2D or CVD in the PREDIMED trial; (b) the effect of the dietary intervention on 1-year changes in these metabolites, and (c) whether the Mediterranean diet (MedDiet) interventions can modify the effects of these metabolites on CVD or T2D risk. Methods Two unstratified case-cohort studies nested within the PREDIMED trial were used. For CVD analyses, we selected 696 non-cases and 221 incident CVD cases; for T2D, we included 610 non-cases and 243 type 2 diabetes incident cases. Metabolites were quantified using liquid chromatography–tandem mass spectrometry, at baseline and after 1-year of intervention. 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 significant interaction (p = 0.032) between baseline lysine and T2D on the risk of CVD was observed: subjects with prevalent T2D and high levels of lysine exhibited the highest risk of CVD. The intervention with MedDiet did not have a significant effect on 1-year changes of the metabolites. 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 effects of MedDiet intervention on lysine, 2-AAA or pipecolic acid changes was found. Trial registration ISRCTN35739639; registration date: 05/10/2005; recruitment start date 01/10/2003

Abstract Background Primary prevention trials have demonstrated that the traditional Mediterranean diet is associated with a reduction in cardiovascular mortality and morbidity. However, this benefit has not been proven for secondary prevention after an acute coronary syndrome (ACS). We hypothesized that a high-intensity Mediterranean diet intervention after an ACS decreases the vulnerability of atherosclerotic plaques by complex interactions between anti-inflammatory effects, microbiota changes and modulation of gene expression. Methods The MEDIMACS project is an academically funded, prospective, randomized, controlled and mechanistic clinical trial designed to address the effects of an active randomized intervention with the Mediterranean diet on atherosclerotic plaque vulnerability, coronary endothelial dysfunction and other mechanistic endpoints. One hundred patients with ACS are randomized 1:1 to a monitored high-intensity Mediterranean diet intervention or to a standard-of-care arm. Adherence to diet is assessed in both arms using food frequency questionnaires and biomarkers of compliance. The primary endpoint is the change (from baseline to 12 months) in the thickness of the fibrous cap of a non-significant atherosclerotic plaque in a non-culprit vessel, as assessed by repeated optical coherence tomography intracoronary imaging. Indices of coronary vascular physiology and changes in gastrointestinal microbiota, immunological status and protein and metabolite profiles will be evaluated as secondary endpoints. Discussion The results of this trial will address the key effects of dietary habits on atherosclerotic risk and will provide initial data on the complex interplay of immunological, microbiome-, proteome- and metabolome-related mechanisms by which non-pharmacological factors may impact the progression of coronary atherosclerosis after an ACS. Trial registration ClinicalTrials.gov NCT03842319 . Registered on 13 May 2019