One-year longitudinal association between changes in dietary choline or betaine intake and cardiometabolic variables in the PREvención con DIeta MEDiterránea-Plus (PREDIMED-Plus) trial.

BACKGROUND: Choline and betaine intakes have been related to cardiovascular health. OBJECTIVES: We aimed to explore the relation between 1-y changes in dietary intake of choline or betaine and 1-y changes in cardiometabolic and renal function traits within the frame of the PREDIMED (PREvención con DIeta MEDiterránea)-Plus trial. METHODS: We used baseline and 1-y follow-up data from 5613 participants (48.2% female and 51.8% male; mean ± SD age: 65.01 ± 4.91 y) to assess cardiometabolic traits, and 3367 participants to assess renal function, of the Spanish PREDIMED-Plus trial. Participants met ≥3 criteria of metabolic syndrome and had overweight or obesity [BMI (in kg/m2) ≥27 and ≤40]. These criteria were similar to those of the PREDIMED parent study. Dietary intakes of choline and betaine were estimated from the FFQ. RESULTS: The greatest 1-y increase in dietary choline or betaine intake (quartile 4) was associated with improved serum glucose concentrations (-3.39 and -2.72 mg/dL for choline and betaine, respectively) and HbA1c levels (-0.10% for quartile 4 of either choline or betaine intake increase). Other significant changes associated with the greatest increase in choline or betaine intake were reduced body weight (-2.93 and -2.78 kg, respectively), BMI (-1.05 and -0.99, respectively), waist circumference (-3.37 and -3.26 cm, respectively), total cholesterol (-4.74 and -4.52 mg/dL, respectively), and LDL cholesterol (-4.30 and -4.16 mg/dL, respectively). Urine creatinine was reduced in quartile 4 of 1-y increase in choline or betaine intake (-5.42 and -5.74 mg/dL, respectively). CONCLUSIONS: Increases in dietary choline or betaine intakes were longitudinally related to improvements in cardiometabolic parameters. Markers of renal function were also slightly improved, and they require further investigation.This trial was registered at https://www.isrctn.com/ as ISRCTN89898870.

The Effect of Sex and Obesity on the Gene Expression of Lipid Flippases in Adipose Tissue.

Molecular mechanisms behind obesity and sex-related effects in adipose tissue remain elusive. During adipocyte expansion, adipocytes undergo drastic remodelling of lipid membrane compositions. Lipid flippases catalyse phospholipid translocation from exoplasmic to the cytoplasmic leaflet of membranes. The present study aimed to analyse the effect of sex, obesity, and their interactions on the gene expression of two lipid flippases-ATP8A1 and ATP8B1-and their possible microRNA (miR) modulators in visceral adipose tissue (VAT). In total, 12 normal-weight subjects (5 premenopausal women and 7 men) and 13 morbidly obese patients (7 premenopausal women and 6 men) were submitted to surgery, and VAT samples were obtained. Gene expression levels of ATP8A1, ATP8B1, miR-548b-5p, and miR-4643 were measured in VAT. Our results showed a marked influence of obesity on VAT ATP8A1 and ATP8B1, although the effects of obesity were stronger in men for ATP8A1. Both genes positively correlated with obesity and metabolic markers. Furthermore, ATP8B1 was positively associated with miR-548b-5p and negatively associated with miR-4643. Both miRs were also affected by sex. Thus, lipid flippases are altered by obesity in VAT in a sex-specific manner. Our study provides a better understanding of the sex-specific molecular mechanisms underlying obesity, which may contribute to the development of sex-based precision medicine.

Factors associated with successful dietary changes in an energy-reduced Mediterranean diet intervention: a longitudinal analysis in the PREDIMED-Plus trial.

PURPOSE: Long-term nutrition trials may fail to respond to their original hypotheses if participants do not comply with the intended dietary intervention. We aimed to identify baseline factors associated with successful dietary changes towards an energy-reduced Mediterranean diet (MedDiet) in the PREDIMED-Plus randomized trial. METHODS: Longitudinal analysis of 2985 participants (Spanish overweight/obese older adults with metabolic syndrome) randomized to the active intervention arm of the PREDIMED-Plus trial. Dietary changes were assessed with a 17-item energy-reduced MedDiet questionnaire after 6 and 12 months of follow-up. Successful compliance was defined as dietary changes from baseline of ≥ 5 points for participants with baseline scores < 13 points or any increase if baseline score was ≥ 13 points. We conducted crude and adjusted multivariable logistic regression models to identify baseline factors related to compliance. RESULTS: Consistent factors independently associated with successful dietary change at both 6 and 12 months were high baseline perceived self-efficacy in modifying diet (OR6-month: 1.51, 95% CI 1.25-1.83; OR12-month: 1.66, 95% CI 1.37-2.01), higher baseline fiber intake (OR6-month: 1.62, 95% CI 1.07-2.46; OR12-month: 1.62, 95% CI 1.07-2.45), having > 3 chronic conditions (OR6-month: 0.65, 95% CI 0.53-0.79; OR12-month: 0.76, 95% CI 0.62-0.93), and suffering depression (OR6-month: 0.80, 95% CI 0.64-0.99; OR12-month: 0.71, 95% CI 0.57-0.88). CONCLUSION: Our results suggested that recruitment of individuals with high perceived self-efficacy to dietary change, and those who initially follow diets relatively richer in fiber may lead to greater changes in nutritional recommendations. Participants with multiple chronic conditions, specifically depression, should receive specific tailored interventions. TRIAL REGISTRATION: ISRCTN registry 89898870, 24th July 2014 retrospectively registered http://www.isrctn.com/ISRCTN89898870 .

Pro-vegetarian food patterns and cardiometabolic risk in the PREDIMED-Plus study: a cross-sectional baseline analysis.

PURPOSE: We explored the cross-sectional association between the adherence to three different provegetarian (PVG) food patterns defined as general (gPVG), healthful (hPVG) and unhealthful (uPVG), and the cardiometabolic risk in adults with metabolic syndrome (MetS) of the PREDIMED-Plus randomized intervention study. METHODS: We performed a cross-sectional analysis of baseline data from 6439 participants of the PREDIMED-Plus randomized intervention study. The gPVG food pattern was built by positively scoring plant foods (vegetables/fruits/legumes/grains/potatoes/nuts/olive oil) and negatively scoring, animal foods (meat and meat products/animal fats/eggs/fish and seafood/dairy products). The hPVG and uPVG were generated from the gPVG by adding four new food groups (tea and coffee/fruit juices/sugar-sweetened beverages/sweets and desserts), splitting grains and potatoes and scoring them differently. Multivariable-adjusted robust linear regression using MM-type estimator was used to assess the association between PVG food patterns and the standardized Metabolic Syndrome score (MetS z-score), a composed index that has been previously used to ascertain the cardiometabolic risk, adjusting for potential confounders. RESULTS: A higher adherence to the gPVG and hPVG was associated with lower cardiometabolic risk in multivariable models. The regression coefficients for 5th vs. 1st quintile were - 0.16 (95% CI: - 0.33 to 0.01) for gPVG (p trend: 0.015), and - 0.23 (95% CI: - 0.41 to - 0.05) for hPVG (p trend: 0.016). In contrast, a higher adherence to the uPVG was associated with higher cardiometabolic risk, 0.21 (95% CI: 0.04 to 0.38) (p trend: 0.019). CONCLUSION: Higher adherence to gPVG and hPVG food patterns was generally associated with lower cardiovascular risk, whereas higher adherence to uPVG was associated to higher cardiovascular risk.

Effect of a Nutritional and Behavioral Intervention on Energy-Reduced Mediterranean Diet Adherence Among Patients With Metabolic Syndrome: Interim Analysis of the PREDIMED-Plus Randomized Clinical Trial.

Importance: High-quality dietary patterns may help prevent chronic disease, but limited data exist from randomized trials about the effects of nutritional and behavioral interventions on dietary changes. Objective: To assess the effect of a nutritional and physical activity education program on dietary quality. Design, Setting, and Participants: Preliminary exploratory interim analysis of an ongoing randomized trial. In 23 research centers in Spain, 6874 men and women aged 55 to 75 years with metabolic syndrome and no cardiovascular disease were enrolled in the trial between September 2013 and December 2016, with final data collection in March 2019. Interventions: Participants were randomized to an intervention group that encouraged an energy-reduced Mediterranean diet, promoted physical activity, and provided behavioral support (n = 3406) or to a control group that encouraged an energy-unrestricted Mediterranean diet (n = 3468). All participants received allotments of extra-virgin olive oil (1 L/mo) and nuts (125 g/mo) for free. Main Outcomes and Measures: The primary outcome was 12-month change in adherence based on the energy-reduced Mediterranean diet (er-MedDiet) score (range, 0-17; higher scores indicate greater adherence; minimal clinically important difference, 1 point). Results: Among 6874 randomized participants (mean [SD] age, 65.0 [4.9] years; 3406 [52%] men), 6583 (96%) completed the 12-month follow-up and were included in the main analysis. The mean (SD) er-MedDiet score was 8.5 (2.6) at baseline and 13.2 (2.7) at 12 months in the intervention group (increase, 4.7 [95% CI, 4.6-4.8]) and 8.6 (2.7) at baseline and 11.1 (2.8) at 12 months in the control group (increase, 2.5 [95% CI, 2.3-2.6]) (between-group difference, 2.2 [95% CI, 2.1-2.4]; P < .001). Conclusions and Relevance: In this preliminary analysis of an ongoing trial, an intervention that encouraged an energy-reduced Mediterranean diet and physical activity, compared with advice to follow an energy-unrestricted Mediterranean diet, resulted in a significantly greater increase in diet adherence after 12 months. Further evaluation of long-term cardiovascular effects is needed. Trial Registration: isrctn.com Identifier: ISRCTN89898870.

Metabolomics-guided insights on bariatric surgery versus behavioral interventions for weight loss.

OBJECTIVE: To review the metabolomic studies carried out so far to identify metabolic markers associated with surgical and dietary treatments for weight loss in subjects with obesity. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. RESULTS: Thirty-two studies successfully met the eligibility criteria. The metabolic adaptations shared by surgical and dietary interventions mirrored a state of starvation ketoacidosis (increase of circulating ketone bodies), an increase of acylcarnitines and fatty acid ß-oxidation, a decrease of specific amino acids including branched-chain amino acids (BCAA) and (lyso)glycerophospholipids previously associated with obesity, and adipose tissue expansion. The metabolic footprint of bariatric procedures was specifically characterized by an increase of bile acid circulating pools and a decrease of ceramide levels, a greater perioperative decline in BCAA, and the rise of circulating serine and glycine, mirroring glycemic control and inflammation improvement. In one study, 3-hydroxybutyrate was particularly identified as an early metabolic marker of long-term prognosis after surgery and proposed to increase current prognostic modalities and contribute to personalized treatment. CONCLUSIONS: Metabolomics helped in deciphering the metabolic response to weight loss treatments. Moving from association to causation is the next challenge to move to a further level of clinical application.

Effects of glucagon-like peptide-1 on the differentiation and metabolism of human adipocytes.

BACKGROUND AND PURPOSE: Glucagon-like peptide-1 (GLP-1) analogues improve glycaemic control in type 2 diabetic (T2D) patients and cause weight loss in obese subjects by as yet unknown mechanisms. We recently demonstrated that the GLP-1 receptor, which is present in adipocytes and the stromal vascular fraction of human adipose tissue (AT), is up-regulated in AT of insulin-resistant morbidly obese subjects compared with healthy lean subjects. The aim of this study was to explore the effects of in vitro and in vivo administration of GLP-1 and its analogues on AT and adipocyte functions from T2D morbidly obese subjects. EXPERIMENTAL APPROACH: We analysed the effects of GLP-1 on human AT and isolated adipocytes in vitro and the effects of GLP-1 mimetics on AT of morbidly obese T2D subjects in vivo. KEY RESULTS: GLP-1 down-regulated the expression of lipogenic genes when administered during in vitro differentiation of human adipocytes from morbidly obese patients. GLP-1 also decreased the expression of adipogenic/lipogenic genes in AT explants and mature adipocytes, while increasing that of lipolytic markers and adiponectin. In 3T3-L1 adipocytes, GLP-1 decreased free cytosolic Ca2+ concentration ([Ca2+]i). GLP-1-induced responses were only partially blocked by GLP-1 receptor antagonist exendin (9­39). Moreover, administration of exenatide or liraglutide reduced adipogenic and inflammatory marker mRNA in AT of T2D obese subjects. CONCLUSIONS AND IMPLICATIONS: Our data suggest that the beneficial effects of GLP-1 are associated with changes in the adipogenic potential and ability of AT to expand, via activation of the canonical GLP-1 receptor and an additional, as yet unknown, receptor.

The frequency and impact of hypoglycemia among hospitalized patients with diabetes: A population-based study.

We aimed to evaluate the frequency of hypoglycemia and its impact on the length of stay and all-cause in-hospital mortality in hospitalized patients with diabetes. We used data from the Basic Minimum Data Set of the Spanish National Health System. Hypoglycemia was defined as having an ICD-9-CM code 250.8, 251.0, 251.1, and 251.2, and categorized as primary if it was the main cause of admission and secondary if it occurred during the hospital stay. The association between hypoglycemia and the study outcomes was evaluated in two cohorts - with and without secondary hypoglycemia - matched by propensity scores and using multivariate models. Among the 5,447,725 discharges with a diagnosis of diabetes recorded from January 1997 to December 2010, there were 92,591 (1.7%) discharges with primary hypoglycemia and 154,510 (2.8%) with secondary hypoglycemia. The prevalence of secondary hypoglycemia increased from 1.1% in 1997 to a peak of 3.8% in 2007, while the prevalence of primary hypoglycemia remained fairly stable. Primary hypoglycemia was associated with reduced in-hospital mortality (Odds ratio [OR] 0.06; 95% Confidence interval [CI], 0.03-0.10) and a significant decrease in time to discharge (Hazard ratio [HR] 2.53; 95% CI, 2.30-2.76), while secondary hypoglycemia was associated with an increased likelihood of in-hospital mortality (OR 1.12; 95% CI, 1.09-1.15) and a significant increase in time to discharge (HR 0.80; 95% CI, 0.79-0.80). In conclusion, the prevalence of secondary hypoglycemia is increasing in patients with diabetes and is associated with an increased likelihood of in-hospital mortality and a longer hospital stay.

Educational inequalities and cardiovascular risk factors. A cross-sectional population-based study in southern Spain.

OBJECTIVES: To determine the prevalence and distribution of modifiable cardiovascular risk factors focused on educational level differences, in an adult population in Southern Spain. DESIGN AND SAMPLE: Cross-sectional population-based study. Random sample from the adult population assigned to a Primary Health Care Centre in Málaga (Southern Spain), which attends 38,625 inhabitants. MEASURES: Level of education, physical activity, blood pressure, waist perimeter, body mass index, lipid profile, fasting plasma glucose, among others, were assessed. RESULTS: Final sample included 2,270 subjects with a mean age of 43.65 (SD: 16.65), 49.74% male and 50.26% female. 57.6% had none or only primary studies. Overweight was present in 55.8%, smokers were 27.6% and sedentary people 51.9%. Once adjusted by sex and age, all modifiable factors were lower in people with higher education. The highest risks were sedentarism (OR 1.95; 95% CI: 1.16-3.29) and hypertension (OR: 2.07 95% CI: 1.49-2.80) for those with lower education. CONCLUSIONS: There is a clear inverse gradient of cardiovascular risk factors and educational level in the study population. Public health and community nurses should develop strong interventions for this challenge and extend their influence to public policies focused on educational inequalities and health.

Modulation of human monocyte CD36 by type 2 diabetes mellitus and other atherosclerotic risk factors.

BACKGROUND: The pathophysiological role of CD36 in atherosclerosis seems to be largely dependent on its pro-inflammatory function and ability to take up oxidized low-density lipoprotein. Controversy exists concerning the potential beneficial/harmful effects of vascular CD36 inhibition in atherosclerosis. However, as atherosclerosis in murine models does not result in clinical end points such as plaque rupture and thrombotic ischaemia, typical of human disease, clinical studies are required to understand the functional role of CD36 in human atherosclerosis. MATERIALS AND METHODS: Our aim was to investigate whether CD36 expression in monocytes is modulated by the presence of an increasing number of atherosclerotic risk factors, and specifically by hyperglycaemia because of diabetes mellitus. The study included 33 patients with advanced atherosclerosis and eight healthy blood donors, as controls. The patients were classified according to the presence of atherosclerotic risk factors. Diabetes mellitus was classified as either well-controlled or poorly controlled. Monocytes were exposed in vitro to low (5·5mM) or high glucose (26mM) concentrations for increasing times. RESULTS: Our results demonstrated that protein levels of glycated CD36 were significantly higher in patients with 3-4 atherosclerotic risk factors than in those with 0-2 atherosclerotic risk factors or in subjects with no atherosclerotic symptoms (P=0·04, in both cases). However, when we analysed just the poorly controlled diabetic patients, their glycated CD36 levels were lower. These data were corroborated by in vitro studies demonstrating that increasing glucose concentrations reduced glycated protein levels (P<0·05). CONCLUSIONS: Our results demonstrate that CD36 expression is altered by hyperglycaemia in atherosclerotic patients.

Telemedicine influence on the follow-up of type 2 diabetes patients.

OBJECTIVE: This study was designed to evaluate the impact of a teleassistance system on the metabolic control of type 2 diabetes patients. RESEARCH DESIGN AND METHODS: We conducted a 1-year controlled parallel-group trial comparing patients randomized (1) to an intervention group, assigned to a teleassistance system using real-time transmission of blood glucose results, with immediate reply when necessary, and telephone consultations, or (2) to a control group, being regularly followed-up at their healthcare center. Study subjects were type 2 diabetes patients >30 years of age followed in the primary care setting. RESULTS: A total of 328 type 2 diabetes patients were recruited from 35 family practices in the province of Málaga, Spain. There was a reduction in hemoglobin A1c after 12 months from 7.62 +/- 1.60% to 7.40 +/- 1.43% (P = 0.027) in the intervention group and from 7.44 +/- 1.31% to 7.35 +/- 1.38% (P = 0.303) in the control group. The difference in the change between groups was not statistically significant. There was also a significant decrease in systolic and diastolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, and body mass index in the intervention group. In the control group, the only significant decline was in low-density lipoprotein cholesterol. CONCLUSIONS: A teleassistance system using real-time transmission of blood glucose results with an option to make telephone consultations is feasible in the primary care setting as a support tool for family physicians in their follow-up of type 2 diabetes patients.