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.

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.

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)

Evaluación cuantitativa de los cambios microvasculares capilaroscópicos en pacientes con cardiopatía isquémica establecida / Quantitative evaluation of capillaroscopic microvascular changes in patients with established coronary heart disease

Introducción y objetivos: Las alteraciones microvasculares se han asociado a la mayoría de los factores de riesgo cardiovascular, así como a múltiples enfermedades inflamatorias. Sin embargo, se desconoce si estas anomalías son más frecuentes en pacientes con enfermedades coronarias. Nuestro objetivo fue evaluar si existe una relación entre la presencia de cardiopatía isquémica y la existencia de alteraciones capilares funcionales y estructurales en la microcirculación cutánea evaluada mediante videocapilaroscopia. Material y métodos: Comparamos 2 muestras emparejadas de 30 participantes con o sin cardiopatía isquémica pero con un perfil antropométrico y clínico similar. Realizamos una videocapilaroscopia en el dorso del tercer dedo de la mano no dominante cuantificando la densidad capilar basal, así como la densidad capilar tras la oclusión arterial y venosa para evaluar su funcionalidad y la densidad capilar máxima. También calculamos el reclutamiento capilar. Resultados: La densidad microvascular fue significativamente menor en los pacientes con cardiopatía isquémica que en los controles tanto a nivel basal como tras el estudio dinámico (oclusión arterial y venosa). No encontramos diferencias en el reclutamiento capilar. Conclusiones: En nuestro estudio, los pacientes con cardiopatía isquémica presentaban cambios microvasculares tanto funcionales como estructurales. Dado que estos resultados han sido obtenidos de una pequeña muestra, se precisarán estudios que valoren la microcirculación en pacientes coronarios y si esta está relacionada con la respuesta terapéutica y/o el pronóstico de la enfermedad (AU)

Introduction and objectives: Microcirculation disturbances have been associated to most of the cardiovascular risk factors as well as to multiple inflammatory diseases. However, whether these abnormalities are specifically augmented in patients with coronary heart disease is still unknown. We aimed to evaluate if there is a relationship between the presence of coronary heart disease and the existence of functional and structural capillary abnormalities evaluated in the cutaneous microcirculation by videocapillaroscopy. Material and methods: Two matched samples of 30 participants with and without coronary heart disease but with similar clinical and anthropometric characteristics were evaluated by videocapillaroscopy at the dorsal skin of the third finger of the non-dominant hand. We calculated basal capillary density as well as capillary density after a period of arterial and venous occlusion in order to evaluate functionality and maximum capillary density. We also measured capillary recruitment. Results: capillary density at rest was significantly lower in patients suffering from coronary heart disease than in controls. This fact was also found after dynamic tests (arterial and venous occlusion), suggesting functional impairments. Capillary recruitment of the samples was not different in our sample. Conclusions: In our study, patients with coronary heart disease exhibit functional and structural microvascular disturbances. Although this is a very preliminary study, these findings open the door for further studying the microvascular functionality in coronary patients and how it relates to the response to treatment and/or the prognosis of the disease (AU)