Estrategias dietéticas en el manejo de la diabetes mellitus tipo 2 en pacientes con enfermedad coronaria establecida: estudio CORDIOPREV

Type 2 diabetes mellitus (T2DM) has currently become a global pandemic and its prevalence has increased over the past few decades, with no signs of receding in the near future, imposing a socioeconomic burden on health services, economy and society. In addition, patients with concomitant presence of coronary heart disease (CHD) and T2DM have a significantly increased risk of developing a new cardiovascular event than those without T2DM. This risk of cardiovascular recurrence seems to be increased by the duration of the T2DM, evidencing the relevance of early identification and efficiently control of the disease to reduce associated morbidities and mortalities. T2DM is considered a metabolic disease mainly characterized by impaired insulin secretion and action that is strongly related with nutrition and other lifestyle habits. In fact, dietary intervention studies have shown that changes in dietary habits and increased physical activity can reduce T2DM incidence establishing an association between specific dietary patterns and diabetes risk. More specifically, low-carbohydrate, low-fat calorie-restricted or Mediterranean-style diets are associated with cardiovascular benefits, improved glucose homeostasis and insulin sensitivity. However, these dietary approaches appear to be disease status-dependent, as metabolic flexibility decreases over time reducing the potential benefits of lifestyle changes or pharmacological treatments. Newly diagnosed T2DM has recently been proved to be reversible by different strategies, such as intense weight loss (either bariatric surgery or very low caloric diet). We have recently found that the consumption of a healthy dietary pattern (a low-fat diet or a Mediterranean diet) determined an improvement of hepatic insulin sensitivity, a reduction in hemoglobin A1c (HbA1c) and a recovery of β-cell functionality in newly diagnosed T2DM patients with CHD. However, consumption of these healthy diets did not promote T2DM remission in every patient, highlighting the lack of comprehension about the mechanisms underlying T2DM remission promoted by dietary changes. Advanced glycation end products (AGEs) are a group of pro-oxidant and cytotoxic compounds, generated from the Maillard reaction, which contribute to the onset and progression of certain chronic diseases, such as T2DM and cardiovascular disease. While a small amount of AGEs is generated endogenously as normal metabolism consequence, especially in T2DM patients because of chronic hyperglycemia, the main exogenous sources of AGEs is through diet, which depends both on the composition and the food processing. In this context, we have recently showed that the Mediterranean diet could be considered a good dietary model for reducing the content of dietary and circulating AGE levels, as the degree of oxidative stress and inflammation. It has been evidenced that AGEs play an important role in the progression of T2DM and its complications. However, there is no evidence of the participation of AGEs in T2DM remission. Previous results also support the fact that elevated plasmatic levels of branched-chain amino acids (BCAAs) have been related with T2DM incidence and metabolic abnormalities such as insulin resistance, obesity, cardiovascular risk and glucose intolerance. In this sense, BCAA are considered as potential biomarkers for T2DM and cardiovascular disease. Recent studies have shown that the Mediterranean diet is able to reduce fasting plasma BCAA levels (valine, leucine, and isoleucine). Although, to date, the molecular mechanisms are not well understood, the multiple roles of BCAAs in the development of insulin resistance could lead to the development of more effective therapies for T2DM. In this context, several studies support the relation between Mediterranean diet consumption and a reduction in dietary and circulating AGEs and plasma BCAAs, as a reduction in inflammation and oxidative stress. Mediterranean diet is characterized by its richness in monounsaturated fat (mainly from virgin olive oil), vegetables, fruit, nuts, legumes and whole grain cereals, which provide fiber, antioxidants, vitamins, minerals and polyphenols with a low consumption of processed foods. The healthy properties of the Mediterranean diet are mostly due to its anti-inflammatory and anti-oxidative effects and the way of cooking boost these beneficial effects. Multiple studies relate this dietary pattern to the reduction and prevention of multiple diseases such as T2DM or CVD. However, more studies are needed to determine the effects of this diet on the pathophysiology of the disease and its relation to T2DM remission. This research can reduce T2DM incidence worldwide but also reduce its prevalence through the possibility of T2DM remission, which becomes even more relevant when it can be mediated by lifestyle changes and healthy dietary patterns, that have high adherence ratio, such as the Mediterranean diet.En las últimas décadas la prevalencia de diabetes mellitus tipo 2 (T2DM) ha incrementado drásticamente, suponiendo un grave problema de salud a nivel mundial. Sin signos de recesión en un futuro cercano, la T2DM supone una gran carga al sistema de salud, la economía y la sociedad. Este hecho es especialmente relevante para pacientes con enfermedad coronaria establecida (CHD) y T2DM concomitante, pues la presencia simultánea de ambas enfermedades aumenta significativamente el riesgo de desarrollar un nuevo evento cardiovascular y, por tanto, un incremento en la mortalidad. La duración de la T2DM y el bajo control de la misma aumenta el riesgo de recurrencia cardiovascular, lo que evidencia la relevancia de la identificación precoz y el control eficaz de la enfermedad para reducir la morbimortalidad asociada, así como identificar aquellos subgrupos a los que se pueden aplicar con éxito recomendaciones dietéticas u otro tipo de tratamiento para prevenir o remitir la T2DM. La T2DM se considera una enfermedad metabólica caracterizada principalmente por una alteración en la secreción y acción de la insulina que está fuertemente relacionada con la nutrición y otros hábitos de vida. De hecho, los estudios de intervención dietética han demostrado que los cambios en los hábitos dietéticos y el aumento de la actividad física pueden reducir la incidencia de T2DM, estableciendo una asociación entre patrones dietéticos y el riesgo de la misma. Más concretamente, las dietas bajas en carbohidratos, bajas en grasa, con restricción calórica o una dieta Mediterránea están asociadas con beneficios cardiovasculares, una mejor homeostasis de la glucosa y sensibilidad a la insulina. Sin embargo, la adaptación de estos enfoques dietéticos o el tratamiento a seguir podría variar en función de la situación basal y metabólica del paciente y del estado de la enfermedad en sí, ya que la flexibilidad metabólica podría afectar a los potenciales beneficios de los cambios en el estilo de vida o los tratamientos farmacológicos. Recientemente se ha demostrado que la T2DM de reciente diagnostico puede revertirse a través de una pérdida intensiva de peso que puede ser conseguida mediante cirugía bariátrica o el seguimiento de una dieta hipocalórica. Sin embargo, últimos estudios sobre el tema han evidenciado la remisión de la T2DM a través de dietas saludables sin pérdida de peso asociada (una dieta baja en grasa o una dieta Mediterránea), provocando en estos pacientes una mejora de la sensibilidad a la insulina hepática, una reducción de la hemoglobina A1c (HbA1c) y una recuperación de la funcionalidad de las células β en pacientes con T2DM de reciente diagnóstico y CHD. Sin embargo, el consumo de estas dietas saludables no consiguió la remisión de la T2DM en el total de los pacientes del estudio, lo que destaca la falta de comprensión sobre los mecanismos que subyacen a la remisión de la T2DM promovida por cambios dietéticos. Los productos finales de glicación avanzada (AGEs) son un grupo de compuestos prooxidantes y citotóxicos, generados a partir de la reacción de Maillard, que contribuyen a la aparición y progresión de ciertas enfermedades crónicas, como la T2DM y las enfermedades cardiovasculares. Los AGEs proceden principalmente de fuentes exógenas, pero una pequeña parte se genera de forma endógena como consecuencia del metabolismo normal, especialmente en pacientes con T2DM debido a la hiperglucemia crónica. La principal fuente exógena de AGEs procede de la dieta, que depende tanto de la composición como del procesado de los alimentos. Existen evidencias del papel que juegan los AGEs en la progresión de la T2DM y sus complicaciones. Sin embargo, no hay evidencia de la participación de los AGEs en la remisión de la T2DM. 6 Por otra parte, la incidencia de T2DM, así como con otras anomalías metabólicas como la resistencia a la insulina, la obesidad o el riesgo cardiovascular se relacionan con niveles plasmáticos elevados de aminoácidos de cadena ramificada (BCAA). En este sentido, los BCAA se consideran biomarcadores potenciales para la T2DM y la enfermedad cardiovascular. Aunque, hasta la fecha, los mecanismos moleculares no se comprenden bien, las múltiples funciones de los BCAA en el desarrollo de la resistencia a la insulina podrían conducir al desarrollo de terapias más efectivas para la T2DM. En este contexto, diversos estudios han demostrado que existe relación entre la dieta Mediterránea y la reducción de los niveles dietéticos y circulantes de AGEs y los niveles plasmáticos de BCAA, así como el grado de estrés oxidativo y la inflamación en los que la siguieron. La dieta Mediterránea se caracteriza por su riqueza en grasas monoinsaturadas (principalmente del aceite de oliva virgen), verduras, frutas, frutos secos, legumbres y cereales integrales, que aportan fibra, antioxidantes, vitaminas, minerales y polifenoles con un bajo consumo de alimentos procesados. Las propiedades saludables de la dieta Mediterránea se deben en su mayoría al poder sinérgico de sus componentes provocando efectos antiinflamatorios y antioxidantes, que se potencia con la forma de cocinar de esta región. Múltiples estudios relacionan este patrón dietético con la reducción y prevención de múltiples enfermedades como la T2DM o la enfermedad cardiovascular. Sin embargo, son necesarios más estudios para desentrañar los efectos de esta dieta en la fisiopatología de la enfermedad y su relación la remisión de la T2DM. Ya que esto podría no solo reducir la incidencia de esta enfermedad a nivel mundial sino también la prevalencia a través de la posibilidad de remisión de la T2DM, que adquiere aún más relevancia cuando puede estar mediada por cambios en el estilo de vida y patrones dietéticos saludables y de relativamente fácil adherencia, como la dieta Mediterránea

Olive oil and postprandial hyperlipidemia: implications for atherosclerosis and metabolic syndrome

42 Páginas; 4 Tablas; 6 FigurasOlive oil is the primary source of fat in the Mediterranean diet, which is associated with a significant improvement in health status, as measured by reduced mortality from several chronic diseases. The current pandemic of obesity, metabolic syndrome, and type 2 diabetes is intimately associated with an atherogenic dyslipidemic phenotype. The core components of the dyslipidemia of the metabolic syndrome, which most likely initiate atherosclerosis, are the “lipid triad” consisting of high plasma triglycerides, low levels of high-density lipoproteins, and a preponderance of small, dense low-density lipoproteins at fasting. However, postprandial (non-fasting) TGs (postprandial hyperlipidemia) are also recognized as an important component for atherosclerosis. Herein, the purpose of this review was to provide an update on the effects and mechanisms related to olive oil on postprandial hyperlipidemia and its implications for the onset and progression of atherosclerosis and metabolic syndrome.This study was supported by research Grant AGL2011-29008 (Spanish Ministry of Science and Innovation, MICINN). S. M. has the benefit of a FPI fellowship (BES-2012-056104) of MICINN. B. B. and S. L. acknowledge financial support from “V Own Research Plan” (University of Seville) and the Spanish Research Council (CSIC)/Juan de la Cierva, respectively.Peer reviewe

The effects of exogenous fatty acids and niacin on human monocyte-macrophage plasticity

Scope: Macrophage plasticity allows adapting to different environments, having a dual activity in inflammatory-related diseases. Our hypothesis is that the type of dietary fatty acids into human postprandial triglyceride-rich lipoproteins (TRLs), alone or in combination with niacin (vitamin B3), could modulate the plasticity of monocytes-macrophages. Methods and results: We isolated TRLs at the postprandial peak from blood samples of healthy volunteers after the ingestion of a meal rich in saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs) or MUFAs plus omega-3 long-chain polyunsaturated fatty acids (LCPUFAs). Autologous monocytes isolated at fasting were first induced to differentiate into naïve macrophages. We observed that postprandial TRL-MUFAs, particularly in combination with niacin, enhance competence to monocytes to differentiate and polarise into M2 macrophages. Postprandial TRL-SFAs made polarised macrophages prone to an M1 phenotype. In contrast to dietary SFAs, dietary MUFAs in the meals plus immediate-release niacin primed circulating monocytes for a reduced postprandial pro-inflammatory profile. Conclusion: Our study underlines a role of postprandial TRLs as a metabolic entity in regulating the plasticity of the monocyte-macrophage lineage and also brings an understanding of the mechanisms by which dietary fatty acids are environmental factors fostering the innate immune responsiveness in humans.Ministerio de Ciencia e Innovación AGL2011- 2900

Endothelial Dysfunction and Advanced Glycation End Products in Patients with Newly Diagnosed Versus Established Diabetes: From the CORDIOPREV Study

Endothelial dysfunction and intima-media thickness of common carotid arteries (IMT-CC) are considered subclinical markers of atherosclerotic cardiovascular disease (ASCVD). Advanced glycation end products (AGEs) are increased in type 2 diabetes mellitus (T2DM) patients, compared with non-diabetics, being implicated in micro- and macrovascular complications. Our aim was to compare serum AGEs levels and subclinical atherosclerotic markers between patients with established and newly diagnosed T2DM. Among 540 patients with T2DM and coronary heart disease from the CORDIOPREV study, 350 patients had established T2DM and 190 patients had newly diagnosed T2DM. Serum levels of AGEs (methylglyoxal (MG) and N-carboxymethyl lysine (CML)) and subclinical atherosclerotic markers (brachial flow-mediated vasodilation (FMD) and IMT-CC) were measured. AGEs levels (all p < 0.001) and IMT-CC (p = 0.025) were higher in patients with established vs. newly diagnosed T2DM, whereas FMD did not differ between the two groups. Patients with established T2DM and severe endothelial dysfunction (i.e., FMD < 2%) had higher serum MG levels, IMT-CC, HOMA-IR and fasting insulin levels than those with newly diagnosed T2DM and non-severe endothelial dysfunction (i.e., FMD ≥ 2%) (all p < 0.05). Serum CML levels were greater in patients with established vs. newly diagnosed T2DM, regardless of endothelial dysfunction severity. Serum AGEs levels and IMT-CC were significantly higher in patients with established vs. newly diagnosed T2DM, highlighting the progressively increased risk of ASCVD in the course of T2DM. Establishing therapeutic strategies to reduce AGEs production and delay the onset of cardiovascular complications in newly diagnosed T2DM patients or minimize ASCVD risk in established T2DM patients is needed

A plasma fatty acid profile associated to type 2 diabetes development: from the CORDIOPREV study

Purpose: The prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide. For this reason, it is essential to identify biomarkers for the early detection of T2DM risk and/or for a better prognosis of T2DM. We aimed to identify a plasma fatty acid (FA) profile associated with T2DM development. Methods: We included 462 coronary heart disease patients from the CORDIOPREV study without T2DM at baseline. Of these, 107 patients developed T2DM according to the American Diabetes Association (ADA) diagnosis criteria after a median follow-up of 60 months. We performed a random classification of patients in a training set, used to build a FA Score, and a Validation set, in which we tested the FA Score. Results: FA selection with the highest prediction power was performed by random survival forest in the Training set, which yielded 4 out of the 24 FA: myristic, petroselinic, α-linolenic and arachidonic acids. We built a FA Score with the selected FA and observed that patients with a higher score presented a greater risk of T2DM development, with an HR of 3.15 (95% CI 2.04–3.37) in the Training set, and an HR of 2.14 (95% CI 1.50–2.84) in the Validation set, per standard deviation (SD) increase. Moreover, patients with a higher FA Score presented lower insulin sensitivity and higher hepatic insulin resistance (p < 0.05). Conclusión: Our results suggest that a detrimental FA plasma profile precedes the development of T2DM in patients with coronary heart disease, and that this FA profile can, therefore, be used as a predictive biomarker

Quality and Quantity of Protein Intake Influence Incidence of Type 2 Diabetes Mellitus in Coronary Heart Disease Patients: From the CORDIOPREV Study

Evidence suggests that enriching a diet with plant-based proteins could reduce the risk of developing type 2 diabetes mellitus. In the present work, we evaluated the association between the change in plant protein intake (adjusted by energy) and incidence of type 2 diabetes mellitus in patients with coronary heart disease from the CORDIOPREV (coronary diet intervention with olive oil and cardiovascular prevention) study. At baseline and during the follow-up, patients underwent medical examination and blood and oral glucose tolerance tests. Information on patient’s dietary intake was gathered by registered dietitians using a validated food frequency questionnaire. A total of 106 out of 436 nondiabetic patients at baseline developed type 2 diabetes mellitus after a median follow-up of 60 months. Cox regression analyses showed that patients who belonged to the group that increased plant protein intake exhibited a lower risk of developing the disease (HR = 0.64, (0.43–0.96)). Changes in plant protein intake were positively correlated with changes in carbohydrates, fibre, and legumes intake and negatively correlated with changes in saturated fatty acids intake. Results of the present study support the need of improving diet with plant-based proteins to prevent the onset of type 2 diabetes mellitus

Acute effects of dietary fatty acids on osteclastogenesis via RANKL/RANK/OPG system

3 Figuras.-- 2 TablasScope: Postprandial state is directly linked with chronic diseases. We hypothesized that dietary fats may have acute effects on health status by modulating osteoclast differentiation and activation in a fatty acid-dependent manner. Methods and results: In healthy subjects, a fat-enriched meal increased plasma levels of the RANKL (receptor activator of nuclear factor κB ligand)/OPG (osteoprotegerin) ratio (SFAs > MUFAs = PUFAs) in the postprandial state. Postprandial TRL-SFAs enhanced tartrate-resistant acid phosphatase (TRAP) activity and the expression of osteoclast marker genes (TRAP, OSCAR, RANK, and CATHK) while downregulated the expression of OPG gene in human monocyte-derived osteoclasts. These effects were not observed with monounsaturated fatty acid (MUFA)-enriched postprandial triglyceride-rich lipoproteins (TRLs). Moreover, postprandial TRL-SFAs increased the release of osteoclastogenic cytokines (TNF-α, IL-1β, and IL-6) meanwhile TRL-MUFAs and TRL-PUFAs increased the release of anti-osteoclastogenic cytokines (IL-4 and IL-10) in the medium of human monocyte-derived osteoclasts. Conclusion: For the first time, we show that postprandial TRLs are metabolic entities with osteoclastogenic activity and that this property is related to the type of dietary fatty acid in the meal. The osteoclastogenic potency was as follows: SFAs >>> MUFAs = PUFAs. These exciting findings open opportunities for developing nutritional strategies with olive oil as the principal dietary source of MUFAs, notably oleic acid, to prevent development and progression of osteoclast-related diseases.This study was supported by the research Grant AGL2011‐29008 (Spanish Ministry of Science and Innovation, MICINN). S.M. has the benefit of a FPI fellowship (BES‐2012‐056104) of MICINN. B.B. and S.L. acknowledges financial support from “V Own Research Plan” (University of Seville) and the Spanish Research Council (CSIC)/Juan de la Cierva, respectively. We thank the students (Pablo de Olavide University) who participated in this study. We are also grateful to Arturo Navarro for his technical expertise

Dietary fatty acids on aortic root calcification in mice with metabolic syndrome

21 Páginas, 3 Figuras, 3 TablasMetabolic syndrome (MetS) is associated with obesity, dyslipidemia, type 2 diabetes, and chronic low-grade inflammation. The aim of this study was to determine the role of high-fat low-cholesterol diets (HFLCDs) rich in SFAs (HFLCD-SFAs), MUFAs (HFLCD-MUFAs) or MUFAs plus omega-3 long-chain PUFAs (HFLCD-PUFAs) on vascular calcification by the modulation of the RANKL/RANK/OPG system in the aortic roots of Lepob/obLDLR−/− mice. Animals fed with HFLCD-SFAs had increased weight and a greater atheroma plaque size, calcification, and RANKL/CATHK expression in the aortic root than mice on MUFA-enriched diets, with an increasing OPG expression in the aortic roots of the latter. Our study demonstrates that compared to dietary SFAs, MUFAs from olive oil protect against atherosclerosis by interfering with vascular calcification via the RANKL/RANK/OPG system in the setting of MetS. These findings open opportunities for developing novel nutritional strategies with olive oil as the most important dietary source of MUFAs (notably oleic acid) to prevent cardiovascular complications in MetS.This study was supported by the research Grant AGL2011-29008 (Spanish Ministry of Science and Innovation, MICINN). S. M. has the benefit of a FPI fellowship (BES-2012-056104) of MICINN. B. B. and S. L. acknowledge financial support from “V Own Research Plan” (The University of Seville) and the Spanish Research Council (CSIC)/Juan de la Cierva, respectively.Peer reviewe

Owning a Pet Is Associated with Changes in the Composition of Gut Microbiota and Could Influence the Risk of Metabolic Disorders in Humans

Pet ownership positively influences clinical outcomes in cardiovascular prevention. Additionally, cardiovascular disease (CVD) has been previously linked to microbiota dysbiosis. We evaluated the influence of owning a pet and its relationship with the intestinal microbiota. We analyzed the gut microbiota from 162 coronary patients from the CORDIOPREV study (NCT00924937) according to whether they owned pets (n = 83) or not (n = 79). The pet-owner group was further divided according to whether they owned dogs only (n = 28) or not (n = 55). A 7-item pet-owners test score was used. Patients who owned pets had less risk of metabolic syndrome (MetS) (OR = 0.462) and obesity (OR = 0.519) and were younger (p < 0.001) than patients who did not own pets. Additionally, patients who owned dogs had less risk of MetS (OR = 0.378) and obesity (OR = 0.418) and were younger (p < 0.001) than patients who did not own pets. A preponderance of the genera Serratia and Coprococcus was found in the group of owners, while the genera Ruminococcus, an unknown genus of Enterobacteriaceae and Anaerotruncus were preponderant in the group of non-owners. In patients who owned dogs, Methanobrevibacter and two more genera, Coprococcus and Oscillospira, were more common. Our study suggests that the prevalence of MetS and obesity in CVD patients is lower in pet owners, and that pet ownership could be a protective factor against MetS through the shaping of the gut microbiota. Thus, owning a pet could be considered as a protective factor against cardiometabolic diseases

High density lipoprotein subfractions and extent of coronary atherosclerotic lesions: From the cordioprev study.

The extent of atherosclerotic coronary heart disease (CHD) is associated with its prognosis, thus discovering potential biomarkers related to worse outcomes could prove valuable. The present work aims to investigate whether lipoprotein subfractions are associated with angiographic CHD severity. Patients from the CORDIOPREV study exhibiting coronary lesions in angiography were classified into two groups (single-vessel coronary disease (SVD) or multivessel coronary disease (MVD)). High-throughput nuclear magnetic resonance (NMR) spectroscopy determined lipoprotein subfractions concentration and composition. SVD patients showed a higher concentration of medium and small HDL particles compared with MVD patients. For medium HDL, total lipids, phospholipids, total cholesterol, cholesteryl esters and free cholesterol reflected HDL particle concentration, whereas, for small HDL, total lipids, phospholipids, and free cholesterol mirrored lipoprotein particle concentration. Among traditional cardiovascular risk factors, age, hypertension and T2D were independently associated with angiography severity. In multivariate logistic regression models, medium and small HDL particles remained inversely associated with angiography severity (OR 0.77 (95% CI: 0.64-0.91); OR 0.78 (95% CI: 0.67-0.91), respectively) after adjusting with covariates. In CHD patients mostly on statin treatment, angiography severity is inversely related to small and medium HDL subclasses concentration measured by NMR. These particles are also independent predictors of the presence of MVD, and its use increased the prediction of this entity over traditional risk factors