Mediterranean diet as a strategy for preserving kidney function in patients with coronary heart disease with type 2 diabetes and obesity: a secondary analysis of CORDIOPREV randomized controlled trial.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is recognized an independent risk factor for chronic kidney disease (CKD). The precise contribution and differential response to treatment strategies to reduce kidney dysfunction, depending on whether obesity is present alongside T2DM or not, remain to be fully clarified. Our objective was to improve our understanding of how obesity contributes to kidney function in patients with T2DM and coronary heart disease (CHD), who are highly predisposed to CKD, to assign the most effective dietary approach to preserve kidney function. METHODS: 1002 patients with CHD and estimated glomerular filtration rate (eGFR)≥30 ml/min/1.73m2, were randomized to consume a Mediterranean diet (35% fat, 22% MUFA, < 50% carbohydrates) or a low-fat diet (28% fat, 12% MUFA, > 55% carbohydrates). Patients were classified into four groups according to the presence of T2DM and/or obesity at baseline: Non-Obesity/Non-T2DM, Obesity/Non-T2DM, Non-Obesity/T2DM and Obesity/T2DM. We evaluated kidney function using serum creatinine-based estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (uACR) before and after 5-years of dietary intervention. RESULTS: Patients with Obesity/T2DM had the lowest baseline eGFR and the highest baseline uACR compared to non-diabetics (p < 0.05). After dietary intervention, the Mediterranean diet induced a lower eGFR decline in patients with Obesity/T2DM, compared to a low-fat diet but not in the other groups (p = 0.014). The Mediterranean diet, but not the low-fat diet, also reduced uACR only in patients with Obesity/T2DM (p = 0.024). CONCLUSIONS: Obesity provided an additive effect to T2DM resulting in a more pronounced decline in kidney function compared to T2DM alone when compared to non-diabetics. In patients with concomitant presence of T2DM and obesity, with more metabolic complications, consumption of a Mediterranean diet seemed more beneficial than a low-fat diet in terms of preserving kidney function. These findings provide valuable insights for tailoring personalized lifestyle modifications in secondary prevention of cardiovascular disease. TRIAL REGISTRATION: URL, http://www.cordioprev.es/index.php/en . CLINICALTRIALS: gov number, NCT00924937.

Telomere length as biomarker of nutritional therapy for prevention of type 2 diabetes mellitus development in patients with coronary heart disease: CORDIOPREV randomised controlled trial.

BACKGROUND: Telomere Length (TL), a marker of cellular aging, holds promise as a biomarker to elucidate the molecular mechanism of diabetes. This study aimed to investigate whether shorter telomeres are associated with a higher risk of type 2 diabetes mellitus (T2DM) incidence in patients with coronary heart disease; and to determine whether the most suitable dietary patterns, particularly a Mediterranean diet or a low-fat diet, can mitigate the development of diabetes in these patients after a follow-up period of five years. METHODS: The CORonary Diet Intervention with Olive oil and cardiovascular PREVention study (CORDIOPREV study) was a single-centre, randomised clinical trial done at the Reina Sofia University Hospital in Córdoba, Spain. Patients with established coronary heart disease (aged 20-75 years) were randomly assigned in a 1:1 ratio by the Andalusian School of Public Health to receive two healthy diets. Clinical investigators were masked to treatment assignment; participants were not. Quantitative-PCR was used to assess TL measurements. FINDINGS: 1002 patients (59.5 ± 8.7 years and 82.5% men) were enrolled into Mediterranean diet (n = 502) or a low-fat diet (n = 500) groups. In this analysis, we included all 462 patients who did not have T2DM at baseline. Among them, 107 patients developed T2DM after a median of 60 months. Cox regression analyses showed that patients at risk of short telomeres (TL < percentile 20th) are more likely to experience T2DM than those at no risk of short telomeres (HR 1.65, p-value 0.023). In terms of diet, patients at high risk of short telomeres had a higher risk of T2DM incidence after consuming a low-fat diet compared to patients at no risk of short telomeres (HR 2.43, 95CI% 1.26 to 4.69, p-value 0.008), while no differences were observed in the Mediterranean diet group. CONCLUSION: Patients with shorter TL presented a higher risk of developing T2DM. This association could be mitigated with a specific dietary pattern, in our case a Mediterranean diet, to prevent T2DM in patients with coronary heart disease. TRIAL REGISTRATION: Clinicaltrials.gov number NCT00924937.

Altered CELF4 splicing factor enhances pancreatic neuroendocrine tumors aggressiveness influencing mTOR and everolimus response.

Pancreatic neuroendocrine tumors (PanNETs) comprise a heterogeneous group of tumors with growing incidence. Recent molecular analyses provided a precise picture of their genomic and epigenomic landscape. Splicing dysregulation is increasingly regarded as a novel cancer hallmark influencing key tumor features. We have previously demonstrated that splicing machinery is markedly dysregulated in PanNETs. Here, we aimed to elucidate the molecular and functional implications of CUGBP ELAV-like family member 4 (CELF4), one of the most altered splicing factors in PanNETs. CELF4 expression was determined in 20 PanNETs, comparing tumor and non-tumoral adjacent tissue. An RNA sequencing (RNA-seq) dataset was analyzed to explore CELF4-linked interrelations among clinical features, gene expression, and splicing events. Two PanNET cell lines were employed to assess CELF4 function in vitro and in vivo. PanNETs display markedly upregulated CELF4 expression, which is closely associated with malignancy features, altered expression of key tumor players, and distinct splicing event profiles. Modulation of CELF4 influenced proliferation in vitro and reduced in vivo xenograft tumor growth. Interestingly, functional assays and RNA-seq analysis revealed that CELF4 silencing altered mTOR signaling pathway, enhancing the effect of everolimus. We demonstrate that CELF4 is dysregulated in PanNETs, where it influences tumor development and aggressiveness, likely by modulating the mTOR pathway, suggesting its potential as therapeutic target.

Telomere Maintenance Is Associated with Type 2 Diabetes Remission in Response to a Long-Term Dietary Intervention without Non-Weight Loss in Patients with Coronary Heart Disease: From the CORDIOPREV Randomized Controlled Trial.

In order to evaluate whether telomere maintenance is associated with type 2 diabetes remission, newly diagnosed type 2 diabetes patients without glucose-lowering treatment (183 out of 1002) from the CORDIOPREV study (NCT00924937) were randomized to consume a Mediterranean or low-fat diet. Patients were classified as Responders, those who reverted from type 2 diabetes during the 5 years of dietary intervention (n = 69), and Non-Responders, who did not achieve diabetes remission by the end of the follow-up period (n = 104). We found no differences in diabetes remission between the two diets, and we determined telomere length (TL) by measuring qPCR, telomerase activity using the TRAP assay, and direct redox balance based on the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSH) via colorimetric assay. Responders exhibited higher baseline TL in comparison with Non-Responders (p = 0.040), and a higher TL at baseline significantly predicted a higher probability of type 2 diabetes remission (OR 2.13; 95% CI, 1.03 to 4.41). After the dietary intervention, Non-Responders showed significant telomere shortening (-0.19, 95% CI -0.32 to 0.57; p = 0.005). Telomere shortening was significantly pronounced in type 2 diabetes patients with a worse profile of insulin resistance and/or beta-cell functionality: high hepatic insulin resistance fasting, a high disposition index (-0.35; 95% CI, -0.54 to -0.16; p < 0.001), and a low disposition index (-0.25; 95% CI, -0.47 to -0.01; p = 0.037). In addition, changes in TL were correlated to the GSH/GSSG ratio. Responders also showed increased telomerase activity compared with baseline (p = 0.048), from 0.16 (95% CI, 0.08 to 0.23) to 0.28 (95% CI, 0.15 to 0.40), with a more marked increase after the dietary intervention compared with Non-Responders (+0.07; 95% CI, -0.06-0.20; p = 0.049). To conclude, telomere maintenance may play a key role in the molecular mechanisms underlying type 2 diabetes remission in newly diagnosed patients. However, further larger-scale prospective studies are necessary to corroborate our findings.

Dietary antioxidant intake reduces carotid intima-media thickness in coronary heart disease patients: From the CORDIOPREV study.

BACKGROUND: Atherosclerosis is the leading underlying cause of coronary heart disease (CHD). In patients with CHD, intima-media thickness of common carotid arteries (IMT-CC) is a reliable, validated, and non-invasive marker of the progression of atherosclerosis. Dietary intervention may affect IMT-CC evolution through different pathways. There is a lack of clinical trials evaluating the effect of total dietary antioxidant content of diets on IMT-CC, especially in patients with CHD. OBJECTIVE: We evaluated the correlation between the diet's total antioxidant content and the changes in IMT-CC produced after 5 years of dietary intervention following two healthy diet models (Mediterranean diet and low-fat diet). We also evaluated whether the diet's total antioxidant content was related to the total redox capacity of the participants. METHODS: From the total participants of the CORDIOPREV study (clinical trial register NCT00924937), 805 participants completed the IMT-CC measurement and the dietary antioxidant evaluation at baseline and after 5 years of dietary intervention. IMT-CC was carried out by ultrasound and the dietary antioxidant evaluation was performed by the Dietary Antioxidant Index (DAI). Additionally, direct redox balance was evaluated in a subset of population by the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSH) by colorimetric assay. RESULTS: We observed an inverse correlation between evolution of DAI and IMT-CC after 5-years of dietary intervention. The mean of the DAI index augmented in the Mediterranean Diet group, whereas it decreased in the Low-fat group. DAI was correlated to the GSH/GSSG ratio, supporting DAI as an adequate estimator of diet's antioxidant content. When looking for individual components of the DAI that were associated to the changes in IMT-CC, an inverse correlation was found for carotenoids, vitamin E, vitamin C, and zinc and the IMT-CC. CONCLUSIONS: Our study indicates that, after five years of dietary intervention, changes in DAI inversely correlate with changes in IMT-CC in patients with CHD. Overall effect of Mediterranean diet resulted in an increase of DAI, conversely to low-fat. Specific elements included in the DAI index were inversely correlated with IMT-CC.

Reduction of circulating methylglyoxal levels by a Mediterranean diet is associated with preserved kidney function in patients with type 2 diabetes and coronary heart disease: From the CORDIOPREV randomized controlled trial.

AIM: Advanced glycation end products (AGEs) play a role in kidney disease in type 2 diabetes mellitus (T2DM). However, there have been no prior controlled clinical trials examining the effects of specific diets on AGE metabolism and their impact on kidney function. Our aim was to assess whether modulating AGE metabolism resulting in reduced AGEs levels, after consumption of two healthy diets, could delay kidney function decline in patients with T2DM and coronary heart disease (CHD). METHODS: T2DM patients (540 out of 1002 patients from the CORDIOPREV study), with estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73 m2, were classified based on their baseline kidney function: normal eGFR (≥ 90 ml/min/1.73 m2), mildly decreased eGFR (60- < 90 ml/min/1.73 m2) and moderately decreased eGFR (<60 ml/min/1.73 m2). Serum AGE levels, methylglyoxal (MG) and N-carboximethyllysine (CML), and gene expression related to AGE metabolism (AGER1, RAGE, and GloxI mRNA) were measured before and after 5-years of dietary intervention (a Mediterranean diet or a low-fat diet). RESULTS: Mediterranean diet produced a lower declined of eGFR compared to the low-fat diet only in patients with mildly decreased eGFR (P = 0.035). Moreover, Mediterranean diet was able to decrease MG levels and increase GloxI expression in normal and mildly decreased eGFR patients (all P < 0.05). One standard deviation increment of MG levels after dietary intervention resulted in a 6.8-fold (95 % CI 0.039;0.554) higher probability of eGFR decline. CONCLUSION: Our study showed that lowering circulating AGE levels, specifically MG, after following a Mediterranean diet, might be linked to the preservation of kidney function, evidenced by a decreased decline of eGFR in T2DM patients with CHD. Patients with mildly decreased eGFR could potentially benefit more from AGE reduction in maintaining kidney function.

Application of Compositional Data Analysis to Study the Relationship between Bacterial Diversity in Human Faeces and Sex, Age, and Weight.

This work uses Compositional Data Analysis (CoDA) to examine the typical human faecal bacterial diversity in 39 healthy volunteers from the Andalusian region (Spain). Stool samples were subjected to high-throughput sequencing of the V3 and V4 regions of the 16S ribosomal RNA gene using Illumina MiSeq. The numbers of sequences per sample and their genus-level assignment were carried out using the Phyloseq R package. The alpha diversity indices of the faecal bacterial population were not influenced by the volunteer's sex (male or female), age (19-46 years), and weight (48.6-99.0 kg). To study the relationship between these variables and the faecal bacterial population, the ALDEx2 and coda4microbiome CoDA packages were used. Applying ALDEx2, a trend suggesting a connection between sex and the genera Senegalimassilia and Negatibacillus (slightly more abundant in females) and Desulfovibrio (more abundant in males) was found. Moreover, age was tentatively associated with Streptococcus, Tizzerella, and Ruminococaceae_UCG-003, while weight was linked to Senegalimassilia. The exploratory tool of the coda4microbiome package revealed numerous bacterial log-ratios strongly related to sex and, to a lesser extent, age and weight. Moreover, the cross-sectional analysis identified bacterial signature balances able to assign sex to samples regardless of controlling for volunteers' age or weight. Desulfovibrio, Faecalitalea, and Romboutsia were relevant in the numerator, while Coprococcus, Streptococcus, and Negatibacillus were prominent in the denominator; the greater presence of these could characterise the female sex. Predictions for age included Caproiciproducens, Coprobacter, and Ruminoclostridium in the numerator and Odoribacter, Ezakiella, and Tyzzerella in the denominator. The predictions depend on the relationship between both groups, but the abundance of the first group and scarcity of the second could be related to older individuals. However, the association of the faecal bacterial population with weight did not yield a satisfactory model, indicating scarce influence. These results demonstrate the usefulness of the CoDA methodology for studying metagenomics data and, specifically, human microbiota.

Association between telomere length and intima-media thickness of both common carotid arteries in patients with coronary heart disease: From the CORDIOPREV randomized controlled trial.

BACKGROUND AND AIMS: A critical telomere length (TL) is associated with cardiovascular mortality. Dietary habits have been demonstrated to affect cardiovascular risk. However, it remains unclear how exactly TL determines the response to specific dietary approaches in the reduction of arterial injury. We aimed to evaluate whether TL was associated with the progression of arterial injury (assessed by intima-media thickness of both common carotid arteries: IMT-CC), after long-term consumption of two healthy dietary models in patients with coronary heart disease (CHD). METHODS: From the 1002 CHD patients of the CORDIOPREV study, 903 completed IMT-CC and TL evaluation at baseline and were randomized to follow a Mediterranean diet or a low-fat diet for 5 years. RESULTS: Patients at risk of short TL (TL < 20th percentile) presented an elevated IMT-CC, (0.79 ± 0.17 vs patients at non-risk 0.74 ± 0.17 p < 0.001). TL and IMT-CC showed an inverse association (ß = -0.035, p = 0.002). Patients who consumed a Mediterranean diet, regardless of the risk of short TL, showed a significant decrease in IMT-CC, with a higher reduction in those patients with risk of short TL (-0.03 ± 0.11, p = 0.036). TL (ß = 0.019, p = 0.024), age (ß = -0.001, p = 0.031), energy intake (ß = -0.000, p = 0.036), use of statins (ß = -0.027, p = 0.028) and allocation into the Mediterranean diet (vs low-fat diet) (ß = -0.024, p = 0.003) were significant contributors to changes in IMT-CC. CONCLUSIONS: Patients who had a reduced TL exhibited a greater decrease in IMT-CC after consuming a Mediterranean diet.

Dietary modulation of advanced glycation end products metabolism on carotid intima-media thickness in type 2 diabetes patients: From the CORDIOPREV study / Modulación a través de la dieta del metabolismo de los productos finales de glicación avanzada sobre el grosor de la íntima-media carotídea en pacientes con diabetes tipo 2: estudio CORDIOPREV

Background: Advanced glycation end products (AGEs) are pro-oxidant and cytotoxic compounds involved in the progression of chronic diseases as cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). The total body burden of AGEs also depend of those consume through the diet. Our aim was to analyze whether the reduction of AGE levels, after the consumption of two-healthy diets were associated with a greater decrease of intima-media thickness of both common carotid arteries (IMT-CC) in patients with T2DM and coronary heart disease (CHD). Methods: 540 CHD patients with T2DM, at baseline, from the CORDIOPREV study, were divided into two groups: (1) Responders, patients whose IMT-CC was reduced or not changed after dietary intervention and (2) Non-responders, patients whose IMT-CC was increased after dietary intervention. A total of 423 completed baseline and the 5-year follow-up carotid ultrasounds were analyzed in this study.Results: Our data showed that Responders, despite had a higher baseline IMT-CC and serum methylglyoxal (MG) levels than Non-responders, showed a reduction of serum levels of this glycotoxin after dietary intervention. Conversely, in patients whose IMT-CC was increased after dietary intervention (Non-responders), serum MG levels were increased. Moreover, an increase of circulating level of AGEs (and in particular, MG), after dietary intervention, could be considered a risk factor for the progression of atherosclerosis in patients with T2DM and CHD. Conclusion: These results support the importance of identifying underlying mechanisms in the context of secondary prevention of CVD that would provide therapeutic targets to reduce the high risk of cardiovascular events of these patients.(AU)

Antecedentes: Los productos finales de glicación avanzada (AGE) son compuestos prooxidantes y citotóxicos involucrados en la progresión de enfermedades crónicas, como las enfermedades cardiovasculares (ECV) y la diabetes mellitus tipo 2 (DMT2). La carga corporal total de AGE también depende de aquellos que se consumen a través de la dieta. Nuestro objetivo fue analizar si la reducción de los niveles de AGE, tras el consumo de dos dietas cardiosaludables, se asociaba con una mayor disminución del grosor íntima-media de ambas arterias carótidas comunes (GIM-CC) en pacientes con DMT2 y enfermedad coronaria establecida (EC). Métodos: Un total de 540 pacientes con EC y DMT2, al inicio del estudio CORDIOPREV, se dividieron en dos grupos: 1) respondedores, pacientes cuyo GIM-CC disminuyó o no se modificó tras la intervención dietética, y 2) no respondedores, pacientes cuyo GIM-CC aumentó tras la intervención dietética. En este estudio se incluyeron, finalmente, un total de 423 pacientes, aquellos que completaron el estudio de ecografía carotídea tanto en el basal como a los 5 años de intervención dietética. Resultados: Nuestros resultados mostraron que los respondedores, a pesar de tener un GIM-CC y niveles séricos de metilglioxal (MG) más elevados que los no respondedores, mostraron una reducción de los niveles séricos de esta glicotoxina tras la intervención dietética. Por el contrario, en los pacientes cuyo IMT-CC aumentó tras la intervención dietética (no respondedores), los niveles séricos de MG aumentaron. Un aumento de los niveles circulantes de AGE (y en particular de MG) tras la intervención dietética podría considerarse un factor de riesgo para la progresión de la aterosclerosis en pacientes con DMT2 y CE. Conclusión: Estos resultados apoyan la importancia de identificar los mecanismos subyacentes en el contexto de la prevención secundaria de la ECV que proporcionarían dianas y estrategias terapéuticas para reducir el alto riesgo de eventos...(AU)

Oral intake of Lactiplantibacillus pentosus LPG1 Produces a Beneficial Regulation of Gut Microbiota in Healthy Persons: A Randomised, Placebo-Controlled, Single-Blind Trial.

The search for vegetable-origin probiotic microorganisms is a recent area of interest. This study conducted a phase I clinical trial to assess the effects of oral administration of Lactiplantibacillus pentosus LPG1, a natural strain with probiotic potential isolated from table olive fermentations, on the gut microbiota. The trial was a randomised, placebo-controlled, single-blind study involving 39 healthy volunteers. Group A (n = 20) ingested one capsule/day of L. pentosus LPG1 containing 1 × 1010 UFC/capsule, while Group B (n = 19) received one capsule/day containing only dextrose (placebo). The capsules were taken during breakfast for 30 consecutive days. Human stool samples were collected from all volunteers at the beginning (baseline) and at the end of the study (post-intervention) and were subjected to 16S rRNA metataxonomic analysis using Illumina MiSeq. Sequencing data at the genus level were statistically analysed using traditional methods and compositional data analysis (CoDA). After treatment, the alpha diversity in Group B (placebo) decreased according to an increase in the Berger and Parker dominance index (p-value < 0.05); moreover, dominance D increased and Simpson 1-D index decreased (p-value < 0.10). The Lactobacillus genus in the faeces was included in the CoDA signature balances (selbal and coda4microbiome) and played a notable role in distinguishing samples from baseline and post-intervention in Group A (LPG1). Additionally, ingesting L. pentosus LPG1 modified the gut microbiota post-intervention, increasing the presence of Parabacteroides and Agathobacter, but reducing Prevotella. These findings suggest that L. pentosus LPG1 is a potentially beneficial gut microbiota modulator in healthy persons.

Changes in quantity plant-based protein intake on type 2 diabetes remission in coronary heart disease patients: from the CORDIOPREV study.

PURPOSE: Diabetes remission is a phenomenon described in the context of drastic weight loss due to bariatric surgery or low-calorie diets. Evidence suggests that increasing the intake of plant protein could reduce the risk of type 2 diabetes. We sought for association between changes in plant protein intake in the context of 2 healthy diets without weight loss nor glucose-lowering medication, and diabetes remission in coronary heart disease patients from the CORDIOPREV study. METHODS: Newly diagnosed type 2 diabetes participants without glucose-lowering treatment were randomized to consume a Mediterranean or a low-fat diet. Type 2 diabetes remission was assessed with a median follow-up of 60 months according to the ADA recommendation. Information on patient's dietary intake was collected using food-frequency questionnaires. At first year of intervention, 177 patients were classified according to changes in plant protein consumption into those who increased or decreased its intake, in order to perform an observational analysis on the association between protein intake and diabetes remission. RESULTS: Cox regression showed that patients increasing plant protein intake were more likely to remit from diabetes than those who decreased its intake (HR = 1.71(1.05-2.77)). The remission occurred mainly at first and second year of follow-up with diminished number of patients achieving remission in the third year onwards. The increase in plant protein was associated with lower intake of animal protein, cholesterol, saturated fatty acids, and fat, and with higher intake of whole grains, fibre, carbohydrates, legumes, and tree nuts. CONCLUSION: These results support the need to increase protein intake of vegetal origin as dietary therapy to reverse type 2 diabetes in the context of healthy diets without weight loss.

Adherence to a Mediterranean lifestyle improves metabolic status in coronary heart disease patients: A prospective analysis from the CORDIOPREV study.

BACKGROUND AND OBJECTIVES: A Mediterranean lifestyle may prevent and mitigate cardiometabolic disorders. We explored whether adherence to a Mediterranean lifestyle was prospectively associated with the risk of metabolic syndrome (MetS) among coronary heart disease (CHD) patients. METHODS: The Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention (CORDIOPREV) study was an interventional diet study to compare a Mediterranean diet with a low-fat diet, in 1002 CHD patients. The Mediterranean lifestyle (MEDLIFE) index was used to assess adherence to a MEDLIFE at baseline, and after 5 years, in 851 participants from the CORDIOPREV study. Subjects were classified as having high (>13 points), moderate (12-13 points), and low (<12 points) adherence to the MEDLIFE. Multivariable logistic regression models were used to determine the association between MEDLIFE adherence and the risk of MetS development or reversal. RESULTS: During the 5-year follow-up, CORDIOPREV participants with high adherence to MEDLIFE had a lower risk of MetS development (odds ratio [OR] 0.37, 95% confidence interval [CI] 0.19-0.75, p < 0.01) and a higher likelihood of reversing preexisting MetS (OR 2.08 CI 95% 1.11-3.91, p = 0.02) compared with participants in the low MEDLIFE adherence group. Each additional one-point increment in the MEDLIFE index was associated with a 24% lower risk of MetS development (OR 0.76, 95% CI 0.64-0.90, p < 0.01) and a 21% higher likelihood of reversing preexisting MetS (OR 1.21 CI 95% 1.04-1.41, p = 0.01). CONCLUSIONS: Our results showed that greater adherence to a MEDLIFE reduced the risk of subsequent MetS development and increased the likelihood of reversing preexisting MetS among patients with CHD at baseline.

Dietary modulation of advanced glycation end products metabolism on carotid intima-media thickness in type 2 diabetes patients: From the CORDIOPREV study.

BACKGROUND: Advanced glycation end products (AGEs) are pro-oxidant and cytotoxic compounds involved in the progression of chronic diseases as cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). The total body burden of AGEs also depend of those consume through the diet. Our aim was to analyze whether the reduction of AGE levels, after the consumption of two-healthy diets were associated with a greater decrease of intima-media thickness of both common carotid arteries (IMT-CC) in patients with T2DM and coronary heart disease (CHD). METHODS: 540 CHD patients with T2DM, at baseline, from the CORDIOPREV study, were divided into two groups: (1) Responders, patients whose IMT-CC was reduced or not changed after dietary intervention and (2) Non-responders, patients whose IMT-CC was increased after dietary intervention. A total of 423 completed baseline and the 5-year follow-up carotid ultrasounds were analyzed in this study. RESULTS: Our data showed that Responders, despite had a higher baseline IMT-CC and serum methylglyoxal (MG) levels than Non-responders, showed a reduction of serum levels of this glycotoxin after dietary intervention. Conversely, in patients whose IMT-CC was increased after dietary intervention (Non-responders), serum MG levels were increased. Moreover, an increase of circulating level of AGEs (and in particular, MG), after dietary intervention, could be considered a risk factor for the progression of atherosclerosis in patients with T2DM and CHD. CONCLUSION: These results support the importance of identifying underlying mechanisms in the context of secondary prevention of CVD that would provide therapeutic targets to reduce the high risk of cardiovascular events of these patients. CLINICAL TRIAL REGISTRATION-URL: https://clinicaltrials.gov/ct2/show/NCT00924937. Unique Identifier: NCT00924937.

Effect of the Mediterranean diet and probiotic supplementation in the management of mild cognitive impairment: Rationale, methods, and baseline characteristics.

Introduction: Mild cognitive impairment (MCI) can progress to Alzheimer's disease (AD). When MCI is not properly controlled, the speed of deterioration can dramatically increase. Reduction of oxidative stress/inflammation and the modulation of the gut-brain axis could be new potential therapeutic targets for the prevention and treatment of AD. Consumption of specific nutrients, diets and probiotic supplementation have been evaluated for neurodegenerative disorders. We focus on a detailed description of the study methods and baseline characteristics of a clinical trial aiming to evaluate the efficacy of a combined nutritional intervention, i.e., a Mediterranean diet with probiotics, on cognitive capacity in a population with MCI. Methods: In this randomized, latin-square crossover, double-blind, and controlled dietary intervention trial (clinicaltrials.gov NCT05029765), 47 MCI patients were randomized to consume three dietary interventions for 24-weeks each: (1) A Mediterranean diet supplemented with probiotics (109 colony-forming units of Lactobacillus rhamnosus and Bifidobacterium longum); (2) A Mediterranean diet + placebo; and (3) A Healthy diet according to the World Health Organization (WHO) recommendations. Participants will be evaluated before and after each of the three intervention periods (each 24-weeks, with a total of 72-weeks) for adherence to the assigned diet, blood tests, cognitive performance, gut microbiota analysis and functional neuroimaging studies. Results: Fifty patients, ≥60 years-old and diagnosed with MCI, underwent randomization. A total of 47 patients completed follow-up dietary interventions (57.4% males), with a good glycemic control (HbA1c 5.8 ± 0.1%, fasting glucose and insulin 99.7 ± 3.3 mg/dL and 10.4 ± 0.9 mU/L, respectively), elevated systolic blood pressure (136.9 ± 2.1 mmHg) and increased degree of inflammation (high-sensitivity C-reactive protein, 8.8 ± 0.9 mg/dL). Baseline adherence to the Mediterranean diet was medium (7.5 ± 0.3 points on the score that ranged from 0 to 14 points). Conclusion: The results of this clinical study would provide more evidence on the need for dietary therapeutic strategies, for clinical and individual practice, in the management of MCI patients to reduce the risk of AD development. Targeting lifestyle modifications in high-risk populations could prevent substantial cases of cognitive decline. Clinical trial registration: [ClinicalTrials.gov], identifier [NCT05029765].

Diet and SIRT1 Genotype Interact to Modulate Aging-Related Processes in Patients with Coronary Heart Disease: From the CORDIOPREV Study.

We investigated whether long-term consumption of two healthy diets (low-fat (LF) or Mediterranean (Med)) interacts with SIRT1 genotypes to modulate aging-related processes such as leucocyte telomere length (LTL), oxidative stress (OxS) and inflammation in patients with coronary heart disease (CHD). LTL, inflammation, OxS markers (at baseline and after 4 years of follow-up) and SIRT1-Single Nucleotide Polymorphisms (SNPs) (rs7069102 and rs1885472) were determined in patients from the CORDIOPREV study. We analyzed the genotype-marker interactions and the effect of diet on these interactions. Regardless of the diet, we observed LTL maintenance in GG-carriers for the rs7069102, in contrast to carriers of the minor C allele, where it decreased after follow-up (p = 0.001). The GG-carriers showed an increase in reduced/oxidized glutathione (GSH/GSSG) ratio (p = 0.003), lower lipid peroxidation products (LPO) levels (p < 0.001) and a greater decrease in tumor necrosis factor-alpha (TNF-α) levels (p < 0.001) after follow-up. After the LF diet intervention, the GG-carriers showed stabilization in LTL which was significant compared to the C allele subjects (p = 0.037), although the protective effects found for inflammation and OxS markers remained significant after follow-up with the two diets. Patients who are homozygous for the SIRT1-SNP rs7069102 (the most common genotype) may benefit from healthy diets, as suggested by improvements in OxS and inflammation in patients with CHD, which may indicate the slowing-down of the aging process and its related diseases.

Metformin, testosterone, or both in men with obesity and low testosterone: A double-blind, parallel-group, randomized controlled trial.

BACKGROUND: Men with obesity tend to be insulin resistant and often have low-normal testosterone concentrations. We conducted a clinical trial aimed to evaluate potential therapeutic strategies for low testosterone in men with obesity. METHODS: We did a 1-year, parallel, randomized, double-blind, placebo-controlled trial, where we evaluated the independent and combined effects of metformin and testosterone in 106 men with obesity, aged 18-50 years, who had low levels of testosterone and no diabetes mellitus. The primary outcome was change in insulin resistance, measured as Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) index. Secondary outcomes included changes in total and free serum testosterone, body composition, metabolic variables, erectile function, and health-related quality of life (HRQoL). RESULTS: In the intention-to-treat analysis, the HOMA-IR index decreased significantly in all active groups compared to placebo (metformin -2.4, 95 % CI -4.1 to -0.8, p = 0.004; testosterone -2.7, 95 % CI -4.3 to -1.1, p = 0.001; combination -3.4, 95 % CI -5.0 to -1.8, p < 0.001). Combination therapy was not superior to testosterone alone in decreasing insulin resistance (-0.7, 95 % CI -2.3 to 0.9, p = 0.383). Only the combination of metformin plus testosterone significantly increased total and free testosterone concentrations, compared to placebo. No significant changes in body composition (except for a higher decrease in fat mass in the metformin and combination group), metabolic variables, erectile function, or HRQoL were found with any treatment. CONCLUSIONS: Among men with obesity and low testosterone concentrations, the combination of metformin plus testosterone, metformin only, and testosterone only, compared to placebo, reduced insulin resistance with no evidence of additive benefit.

A Gene Variation at the ZPR1 Locus (rs964184) Interacts With the Type of Diet to Modulate Postprandial Triglycerides in Patients With Coronary Artery Disease: From the Coronary Diet Intervention With Olive Oil and Cardiovascular Prevention Study.

Background and Aims: rs964184 variant in the ZPR1 gene has been associated with blood lipids levels both in fasting and postprandial state and with the risk of myocardial infarction in high-risk cardiovascular patients. However, whether this association is modulated by diet has not been studied. Objective: To investigate whether the type of diet (low-fat or Mediterranean diets) interacts with genetic variability at this loci to modulate fasting and postprandial lipids in coronary patients. Materials and Methods: The genotype of the rs964184 polymorphism was determined in the Cordioprev Study population (NCT00924937). Fasting and Postprandial triglycerides were assessed before and after 3 years of dietary intervention with either a Mediterranean or a low-fat diet. Postprandial lipid assessment was done by a 4-h oral fat tolerance test (OFTT). Differences in triglycerides levels were identified using repeated-measures ANCOVA. Results: From 523 patients (85% males, mean age 59 years) that completed the OFTT at baseline and after 3 years of intervention and had complete genotype information, 125 of them were carriers of the risk allele G. At the start of the study, these patients showed a higher fasting and postprandial triglycerides (TG) plasma levels. After 3 years of dietary intervention, G-carriers following a Mediterranean Diet maintained higher fasting and postprandial triglycerides, while those on the low-fat diet reduced their postprandial triglycerides to similar values to the population without the G-allele. Conclusion: After 3 years of dietary intervention, the altered postprandial triglyceride response induced by genetic variability in the rs964184 polymorphism of the ZPR1 gene can be modulated by a low-fat diet, better than by a Mediterranean diet, in patients with coronary artery disease.