Plasma metabolite predictors of metabolic syndrome incidence and reversion

Journal of Clinical Medicine

Background: Lifestyles influence atrial fibrillation (AF) risk. Determining the effect of lifestyle interventions on blood concentrations of biomarkers of AF-related pathways could help understand AF pathophysiology and contribute to AF prevention. Methods: We studied 532 participants enrolled in the PREDIMED-Plus trial, a Spanish randomized trial conducted in adults (55–75 years) with metabolic syndrome and body mass index between 27–40 kg/m2. Eligible participants were randomized 1:1 to an intensive lifestyle intervention, emphasizing physical activity, weight loss, and adherence to an energy-reduced Mediterranean diet or to a control group. Serum biomarkers [carboxy-terminal propeptide of procollagen type I (PICP), high-sensitivity troponin T (hsTnT), high-sensitivity C reactive protein (hsCRP), 3-nitrotyrosine (3-NT), and N-terminal propeptide of B-type natriuretic peptide (NT-proBNP)] were measured at baseline, 3 and 5 years after randomization. Mixed models were used to evaluate the effect of intervention on changes in biomarkers through year 5. Mediation analysis was performed to examine the proportion mediated by each component of the intervention. Results: At baseline, participants’ mean age was 65, 40% were female, and 50% were assigned to the intervention. After five years, mean changes in log-transformed biomarkers were −0.01 (PICP), 0.20 (hsTnT), −0.17 (hsCRP), 0.12 (3-NT), and 0.27 (NT-proBNP). Compared to the control group, participants in the intervention group experienced greater decreases in hsCRP (−14%, 95% confidence interval (CI) −26%, 0%) or smaller increases in 3-NT (−16%, 95% CI −25%, −5 …

Diabetes Care

OBJECTIVE Breastfeeding duration is inversely associated with risks of cardiovascular disease (CVD) and type 2 diabetes in parous women. However, the association among women at high risk, including women with type 2 diabetes or gestational diabetes (GDM) is unclear. RESEARCH DESIGN AND METHODS We included 15,146 parous women with type 2 diabetes from the Nurses’ Health Study I and II (NHS, NHS II) and 4,537 women with a history of GDM from NHS II. Participants reported history of breastfeeding via follow-up questionnaires. Incident CVD by 2017 comprised stroke or coronary heart disease (CHD: myocardial infarction, coronary revascularization). Adjusted hazard ratios (aHRs) and 95% CIs were estimated using Cox models. RESULTS We documented 1,159 incident CVD cases among women with type 2 diabetes in both cohorts during …

Clinical Pediatrics

Dr. Lester F. Soyka: E. M., a 13-year-old girl, was referred to the Massachusetts General Hospital because of uncontrolled hyper-tension. She was in apparent good health until four years ago when she had an episode of dysuria and pyuria diagnosed as cystitis and treated with Furadantin. She had two subsequent attacks three years ago and one year ago similarly treated. She seemed well until six weeks prior to admission when gross hematuria developed with no associated symptoms and no previous history of recent upper respiratory infection. Penicillin was started. In the next few days she developed headache, abdominal cramps, and anorexia. On admission to another hospital it was found that her blood pressure was 270/190, there was marked arteriolar spasm on funduscopy, and her urine was loaded with red and white blood cells with no casts. Intravenous and retrograde pyelography showed a shrunken …

Healthy blood vessels supply neurons to preserve metabolic function. In blinding proliferative retinopathies (PRs), pathological neovascular tufts often emerge in lieu of needed physiological revascularization of the ischemic neuroretina. Here we show that metabolic shifts in the neurovascular niche define angiogenic fate. Fatty acid oxidation (FAO) metabolites accumulated in human and murine retinopathy samples. Neovascular tufts with a distinct single-cell transcriptional signature highly expressed FAO enzymes. The deletion of Sirt3, an FAO regulator, shifted the neurovascular niche metabolism from FAO to glycolysis and suppressed tuft formation. This metabolic transition increased Vegf expression in astrocytes and reprogrammed pathological EC to a physiological phenotype, hastening vascular regeneration of the ischemic retina. Hence, strategies to change the metabolic environment of vessels could promote a regenerative phenotype in vascular diseases.

BackgroundThe objective of this systematic review is to identify prognostic factors among women and their offspring affected by gestational diabetes mellitus (GDM), focusing on endpoints of cardiovascular disease (CVD) and type 2 diabetes (T2D) for women, and cardiometabolic profile for offspring.MethodsThis review included studies published in English language from January 1st, 1990, through September 30th, 2021, that focused on the above outcomes of interest with respect to sociodemographic factors, lifestyle and behavioral characteristics, traditional clinical traits, and ‘omics biomarkers in the mothers and offspring during the perinatal/postpartum periods and across the lifecourse. Studies that did not report associations of prognostic factors with outcomes of interest among GDM-exposed women or children were excluded.ResultsHere, we identified 109 publications comprising 98 observational studies …

Environment International

Los disruptores endocrinos (DE) se han convertido en posibles contribuyentes al desarrollo de la diabetes tipo 2. El sulfonato de perfluorooctano (PFOS) es uno de estos DE vinculados con enfermedades crónicas y que atrajo atención debido a su presencia generalizada en los alimentos. Objetivo Evaluar al inicio y después de 1 año de seguimiento las asociaciones entre la ingesta dietética estimada (DI) de PFOS y los parámetros de homeostasis de la glucosa y el índice de masa corporal (IMC) en una población de personas mayores de 4600 participantes no diabéticos del PREDIMED. -más estudio. Métodos Se realizaron modelos de regresión lineal multivariable para evaluar las asociaciones entre el valor inicial de PFOS-DI en el límite inferior (LB) y el límite superior (UB) establecidos por la EFSA, los parámetros de homeostasis de la glucosa y el IMC. Resultados En comparación con aquellos en el tercil más bajo, los participantes en el tercil más alto de PFOS-DI inicial en LB y UB mostraron niveles más altos de HbA1c [coeficiente β (CI)] [0,01 % (0,002 a 0,026) y [0,06 mg/dL (0,026 a 0,087), ambas tendencia p ≤ 0,001] y glucosa plasmática en ayunas en el LB PFOS-DI [1,05 mg/dL (0,050 a 2,046), tendencia p = 0,022]. Prospectivamente, se demostró una asociación positiva entre el LB de PFOS-DI y el IMC [0,06 kg/m 2 (0,014 a 0,106) por incremento de 1 DE de PFOS-DI ajustado en función de la energía. Los participantes en el tercil superior mostraron un aumento en HOMA-IR [0,06 (0,016 a 0,097), tendencia p = 0,005] en comparación con los participantes en el tercil de referencia después de 1 año de seguimiento. Discusión …

EBioMedicine

BackgroundLung function trajectories (LFTs) have been shown to be an important measure of long-term health in asthma. While there is a growing body of metabolomic studies on asthma status and other phenotypes, there are no prospective studies of the relationship between metabolomics and LFTs or their genomic determinants.MethodsWe utilized ordinal logistic regression to identify plasma metabolite principal components associated with four previously-published LFTs in children from the Childhood Asthma Management Program (CAMP) (n = 660). The top significant metabolite principal component (PCLF) was evaluated in an independent cross-sectional child cohort, the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (n = 1151) and evaluated for association with spirometric measures. Using meta-analysis of CAMP and GACRS, we identified associations between PCLF and microRNA, and …

Journal of Allergy and Clinical Immunology

BackgroundThere are increasing numbers of metabolomic studies in food allergy (FA) and asthma, which, however, are predominantly limited by cross-sectional designs, small sample size, and being conducted in European populations.ObjectiveWe sought to identify metabolites unique to and shared by children with FA and/or asthma in a racially diverse prospective birth cohort, the Boston Birth Cohort.MethodsMass spectrometry–based untargeted metabolomic profiling was performed using venous plasma collected in early childhood (n = 811). FA was diagnosed according to clinical symptoms consistent with an acute hypersensitivity reaction at food ingestion and food specific-IgE > 0.35 kU/L. Asthma was defined on the basis of physician diagnosis. Generalized estimating equations were applied to analyze metabolomic associations with FA and asthma, adjusting for potential confounders.ResultsDuring a …

EClinicalMedicine

BackgroundUltra-processed foods (UPFs) are emerging as a risk factor for colorectal cancer (CRC), yet how post-diagnostic UPF intake may impact CRC prognosis remains unexplored.MethodsData collected from food frequency questionnaires were used to estimate intakes of total UPFs and UPF subgroups (serving/d) at least 6 months but less than 4 years post-diagnosis among 2498 patients diagnosed with stages I–III CRC within the Nurses' Health Study and Health Professionals Follow-up Study during 1980–2016. Hazard ratios (HR) and 95% confidence intervals (CIs) of all-cause, CRC- and cardiovascular disease (CVD)-specific mortality in association with UPF consumption were estimated using an inverse probability weighted multivariable Cox proportional hazards regression model, adjusted for confounders.FindingsThe mean (SD) age of patients at diagnosis was 68.5 (9.4) years. A total of 1661 deaths …

The American Journal of Clinical Nutrition

BackgroundThe health benefits of the Mediterranean diet (MedDiet) have been linked to the presence of beneficial gut microbes and related metabolites. However, its impact on the fecal metabolome remains poorly understood.ObjectivesOur goal was to investigate the weight-loss effects of a 1-y lifestyle intervention based on an energy-reduced MedDiet coupled with physical activity (intervention group), compared with an ad libitum MedDiet (control group), on fecal metabolites, fecal microbiota, and their potential association with cardiovascular disease risk factors.MethodsA total of 400 participants (200 from each study group), aged 55–75 y, and at high cardiovascular disease risk, were included. Dietary and lifestyle information, anthropometric measurements, blood biochemical parameters, and stool samples were collected at baseline and after 1 y of follow-up. Liquid chromatography-tandem mass spectrometry …

Journal of Allergy and Clinical Immunology

MethodsUntargeted metabolomic profiling was conducted on plasma samples from 4 timepoints during a longitudinal peanut OIT interventional trial in children ages 7-18. After OIT, participants were challenged before and after a 4-week avoidance period and categorized as either having persistent protection (sustained unresponsiveness (SU)) or loss of protection (transient desensitization (TD)). Using linear and logistic regression and time series analyses, we identified changes in metabolites and pathways associated with (1) OIT over time, and (2) differences between SU and TD participants.ResultsWe identified decreases in arachidonic acid (p= 1.3 e-23) and linoleic acid (p= 1.0 e-04) pathways during OIT. Comparing SU versus TD revealed differing concentrations of bile acid (p= 3.7 e-08), arachidonic acid (p= 3.2 e-09), and histidine pathways. Notably, the bile acid metabolite, lithocholate (3.48 [1.53, 9.24], p …

Cell Metabolism

Common genetic variants in glucokinase regulator (GCKR), which encodes GKRP, a regulator of hepatic glucokinase (GCK), influence multiple metabolic traits in genome-wide association studies (GWASs), making GCKR one of the most pleiotropic GWAS loci in the genome. It is unclear why. Prior work has demonstrated that GCKR influences the hepatic cytosolic NADH/NAD+ ratio, also referred to as reductive stress. Here, we demonstrate that reductive stress is sufficient to activate the transcription factor ChREBP and necessary for its activation by the GKRP-GCK interaction, glucose, and ethanol. We show that hepatic reductive stress induces GCKR GWAS traits such as increased hepatic fat, circulating FGF21, and circulating acylglycerol species, which are also influenced by ChREBP. We define the transcriptional signature of hepatic reductive stress and show its upregulation in fatty liver disease and …

medRxiv

Aims To explore the associations between breakfast energy intake and quality and time trajectories of cardiometabolic traits in high cardiovascular risk. Methods 383 participants aged 55-75 from the PREDIMED-Plus cohort were included. Longitudinal averages of breakfast energy intake and quality were calculated. Three categories were defined for energy intake: 20-30% (reference), <20% (low), and >30% (high). Quality was estimated using the Meal Balance Index; categories were above (reference) or below the median score (low). Smoothed cubic spline mixed effects regressions described trajectories of cardiometabolic indicators (anthropometry, blood pressure, lipids, glucose, glycated hemoglobin, and estimated glomerular filtration rate) at breakfast groups. Inter-group differences in predicted values were estimated by linear regressions. Results At 36 months, compared to the reference, low- or high-energy breakfasts were associated with differences in: body mass index (low: 0.62 kg/m2 [95% confidence interval: 0.28; 0.96]; high: 1.17 kg/m2 [0.79; 1.56]), waist circumference (low: 2.24 cm [1.16; 3.32]; high: 4.55 cm [3.32; 5.78]), triglycerides (low: 18.3 mg/dL [15.3; 21.4]; high: 34.5 cm [31.0; 38.1]), and HDL cholesterol (low: -2.13 mg/dL [-3.40; -0.86]; high: -4.56 mg/dL [-6.02; -3.10]). At 36 months, low-quality breakfast was associated with higher waist circumference (1.49 cm [0.67; 2.31]), and triglycerides (3.46 mg/dL [1.13; 5.80]) and less HDL cholesterol (-1.65 mg/dL [-2.61; -0.69]) and glomerular filtration rate (-1.21 mL/min/1.73m2 [-2.01; -0.41]). Conclusions Low- or high-energy and low-quality breakfasts were associated with higher …

Cancer Research

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of all cancer types. A key — yet poorly understood — facet in the disease state is cachexia, a multi-organ pathological state characterized by physical wasting and tissue catabolism. It occurs in 80% of PDAC patients, and to date there are no preventative or early detection methods. Cachexia leads to limited tolerance to anti-cancer therapy and contributes to disease lethality. Here, we present the first-of-its-kind systemic metabolomic analysis across cachectic stages to better understand disease progression. We used the well-established mutant KRASG12D(LSL/+) mutant p53 inducible mouse model of PDAC. Model physiology faithfully recaptures human cachexia: we observe progressive overall weight loss as well as loss of skeletal muscle and adipose tissue. As with human disease, weight loss occurs prior to loss of appetite in the animals …

The American Journal of Clinical Nutrition

BackgroundThe health benefits of the Mediterranean diet (MedDiet) have been linked to the presence of beneficial gut microbes and related metabolites. However, its impact on the fecal metabolome remains poorly understood.ObjectivesOur goal was to investigate the weight-loss effects of a 1-y lifestyle intervention based on an energy-reduced MedDiet coupled with physical activity (intervention group), compared with an ad libitum MedDiet (control group), on fecal metabolites, fecal microbiota, and their potential association with cardiovascular disease risk factors.MethodsA total of 400 participants (200 from each study group), aged 55–75 y, and at high cardiovascular disease risk, were included. Dietary and lifestyle information, anthropometric measurements, blood biochemical parameters, and stool samples were collected at baseline and after 1 y of follow-up. Liquid chromatography-tandem mass spectrometry …

Public Health

ObjectiveThis article aims to estimate the differences in environmental impact (greenhouse gas [GHG] emissions, land use, energy used, acidification and potential eutrophication) after one year of promoting a Mediterranean diet (MD).MethodsBaseline and 1-year follow-up data from 5800 participants in the PREDIMED-Plus study were used. Each participant's food intake was estimated using validated semi-quantitative food frequency questionnaires, and the adherence to MD using the Dietary Score. The influence of diet on environmental impact was assessed through the EAT-Lancet Commission tables. The influence of diet on environmental impact was assessed through the EAT-Lancet Commission tables. The association between MD adherence and its environmental impact was calculated using adjusted multivariate linear regression models.ResultsAfter one year of intervention, the kcal/day consumed was …

The American Journal of Clinical Nutrition

BackgroundDistinct circulating bile acid (BA) subtypes may play roles in regulating lipid homeostasis and atherosclerosis.ObjectivesWe investigated whether changes in circulating BA subtypes induced by weight-loss dietary interventions were associated with improved lipid profiles and atherosclerotic cardiovascular disease (ASCVD) risk estimates.MethodsThis study included adults with overweight or obesity (n=536) who participated in a randomized weight-loss diet intervention trial. Circulating primary and secondary unconjugated BAs and their taurine-/glycine-conjugates were measured at baseline and 6 months after weight-loss diet interventions. The ASCVD risk estimates were calculated by the validated equations.ResultsAt baseline, higher levels of specific BA subtypes were related to higher levels of atherogenic VLDL lipid subtypes and ASCVD risk estimates. Weight-loss diet-induced decreases in …

Metabolism

BackgroundMetabolic Syndrome (MetS) is a progressive pathophysiological state defined by a cluster of cardiometabolic traits. However, little is known about metabolites that may be predictors of MetS incidence or reversion. Our objective was to identify plasma metabolites associated with MetS incidence or MetS reversion.MethodsThe study included 1468 participants without cardiovascular disease (CVD) but at high CVD risk at enrollment from two case-cohort studies nested within the PREvención con DIeta MEDiterránea (PREDIMED) study with baseline metabolomics data. MetS was defined in accordance with the harmonized International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute criteria, which include meeting 3 or more thresholds for waist circumference, triglyceride, HDL cholesterol, blood pressure, and fasting blood glucose. MetS incidence was …

Metabolism

BackgroundMetabolic Syndrome (MetS) is a progressive pathophysiological state defined by a cluster of cardiometabolic traits. However, little is known about metabolites that may be predictors of MetS incidence or reversion. Our objective was to identify plasma metabolites associated with MetS incidence or MetS reversion.MethodsThe study included 1468 participants without cardiovascular disease (CVD) but at high CVD risk at enrollment from two case-cohort studies nested within the PREvención con DIeta MEDiterránea (PREDIMED) study with baseline metabolomics data. MetS was defined in accordance with the harmonized International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute criteria, which include meeting 3 or more thresholds for waist circumference, triglyceride, HDL cholesterol, blood pressure, and fasting blood glucose. MetS incidence was …

Metabolism

BackgroundHepatocellular carcinoma (HCC) continues to pose a significant health challenge and is often diagnosed at advanced stages. Metabolic reprogramming is a hallmark of many cancer types, including HCC and it involves alterations in various metabolic or nutrient-sensing pathways within liver cells to facilitate the rapid growth and progression of tumours. However, the role of STAT3-NFκB in metabolic reprogramming is still not clear.Approach and resultsDiethylnitrosamine (DEN) administered animals showed decreased body weight and elevated level of serum enzymes. Also, Transmission electron microscopy (TEM) analysis revealed ultrastructural alterations. Increased phosphorylated signal transducer and activator of transcription-3 (p-STAT3), phosphorylated nuclear factor kappa B (p-NFκβ), dynamin related protein 1 (Drp-1) and alpha-fetoprotein (AFP) expression enhance the carcinogenicity as …

Metabolism

BackgroundHigh body mass index (BMI) is a major risk factor for cancer development, but its impact on the global burden of cancer remains unclear.MethodsWe estimated global and regional temporal trends in the burden of cancer attributable to high BMI, and the contributions of various cancer types using the framework of the Global Burden of Disease Study.ResultsFrom 2010 to 2019, there was a 35 % increase in deaths and a 34 % increase in disability-adjusted life-years from cancers attributable to high BMI. The age-standardized death rates for cancer attributable to high BMI increased over the study period (annual percentage change [APC] +0.48 %, 95 % CI 0.22 to 0.74 %). The greatest number of deaths from cancer attributable to high BMI occurred in Europe, but the fastest-growing age-standardized death rates and disability-adjusted life-years occurred in Southeast Asia. Liver cancer was the fastest …

Metabolism

BackgroundBariatric surgery has long-term beneficial effects on body weight and metabolic status, but there is an apparent lack of comprehensive cardiometabolic, renal, liver, and metabolomic/lipidomic panels, whereas the underlying mechanisms driving the observed postoperative ameliorations are still poorly investigated. We aimed to study the long-term effects of bariatric surgery on metabolic profile, cardiorenal and liver outcomes in association with underlying postoperative gut hormone adaptations.Methods28 individuals who underwent bariatric surgery [17 sleeve gastrectomy (SG), 11 Roux-en-Y gastric bypass (RYGB)] were followed up 3, 6 and 12 and at 10 years following surgery. Participants at 10 years were cross-sectionally compared with an age-, sex- and adiposity-matched group of non-operated individuals (n = 9) and an age-matched pilot group of normal-weight individuals (n = 4).ResultsThere …

Metabolism

Background and aimsSubcutaneous adipose tissue (SAT) dysfunction contributes to NAFLD pathogenesis and may be influenced by the gut microbiota. Whether transcript profiles of SAT are associated with liver fibrosis and are influenced by synbiotic treatment (that changes the gut microbiome) is unknown. We investigated: (a) whether the presence of clinically significant, ≥F2 liver fibrosis associated with adipose tissue (AT) dysfunction, differential gene expression in SAT, and/or a marker of tissue fibrosis (Composite collagen gene expression (CCGE)); and (b) whether synbiotic treatment modified markers of AT dysfunction and the SAT transcriptome.MethodsSixty-two patients with NAFLD (60 % men) were studied before and after 12 months of treatment with synbiotic or placebo and provided SAT samples. Vibration-controlled transient elastography (VCTE)-validated thresholds were used to assess liver fibrosis …

Metabolism

BackgroundBariatric surgery has long-term beneficial effects on body weight and metabolic status, but there is an apparent lack of comprehensive cardiometabolic, renal, liver, and metabolomic/lipidomic panels, whereas the underlying mechanisms driving the observed postoperative ameliorations are still poorly investigated. We aimed to study the long-term effects of bariatric surgery on metabolic profile, cardiorenal and liver outcomes in association with underlying postoperative gut hormone adaptations.Methods28 individuals who underwent bariatric surgery [17 sleeve gastrectomy (SG), 11 Roux-en-Y gastric bypass (RYGB)] were followed up 3, 6 and 12 and at 10 years following surgery. Participants at 10 years were cross-sectionally compared with an age-, sex- and adiposity-matched group of non-operated individuals (n = 9) and an age-matched pilot group of normal-weight individuals (n = 4).ResultsThere …

Metabolism

Background & aimsDysbiosis contributes to alcohol-associated liver disease (ALD); however, the precise mechanisms remain elusive. Given the critical role of the gut microbiota in ammonia production, we herein aim to investigate whether and how gut-derived ammonia contributes to ALD.MethodsBlood samples were collected from human subjects with/without alcohol drinking. Mice were exposed to the Lieber-DeCarli isocaloric control or ethanol-containing diets with and without rifaximin (a nonabsorbable antibiotic clinically used for lowering gut ammonia production) supplementation for five weeks. Both in vitro (NH4Cl exposure of AML12 hepatocytes) and in vivo (urease administration for 5 days in mice) hyperammonemia models were employed. RNA sequencing and fecal amplicon sequencing were performed. Ammonia and triglyceride concentrations were measured. The gene and protein expression of …

Metabolism

BackgroundExcessive hepatic glucose production is a hallmark that contributes to hyperglycemia in type 2 diabetes (T2D). The regulatory network governing this process remains incompletely understood. Here, we demonstrate that TOX3, a high-mobility group family member, acts as a major transcriptional driver for hepatic glucose production.MethodsTox3-overexpressed and knockout mice were constructed to explore its metabolic functions. Transcriptomic and chromatin-immunoprecipitation sequencing (ChIP-seq) were used to identify downstream targets of TOX3. Both FoxO1 silencing and inhibitor approaches were used to assess the contribution of FoxO1. TOX3 expression levels were examined in the livers of mice and human subjects. Finally, Tox3 was genetically manipulated in diet-induced obese mice to evaluate its therapeutic potential.ResultsHepatic Tox3 overexpression activates the gluconeogenic …

Metabolism

The Developmental Origins of Health and Disease hypothesis sustains that exposure to different stressors during prenatal development prepares the offspring for the challenges to be encountered after birth. We studied the gestational period as a particularly vulnerable window where different stressors can have strong implications for fetal programming of the offspring's life-long metabolic status via alterations of specific placentally expressed nutrient transporters. To study this mechanism, we used a murine prenatal stress model, human preeclampsia, early miscarriage, and healthy placental tissue samples, in addition to in vitro models of placental cells. In stressed mice, placental overexpression of L-type amino acid transporter 1 (Lat1) and subsequent global placental DNA hypermethylation was accompanied by fetal and adult hypothalamic dysregulation in global DNA methylation and gene expression as well as …

Metabolism

BackgroundCardiac glucose oxidation is decreased in heart failure with reduced ejection fraction (HFrEF), contributing to a decrease in myocardial ATP production. In contrast, circulating ketones and cardiac ketone oxidation are increased in HFrEF. Since ketones compete with glucose as a fuel source, we aimed to determine whether increasing ketone concentration both chronically with the SGLT2 inhibitor, dapagliflozin, or acutely in the perfusate has detrimental effects on cardiac glucose oxidation in HFrEF, and what effect this has on cardiac ATP production.Methods8-week-old male C57BL6/N mice underwent sham or transverse aortic constriction (TAC) surgery to induce HFrEF over 3 weeks, after which TAC mice were randomized to treatment with either vehicle or the SGLT2 inhibitor, dapagliflozin (DAPA), for 4 weeks (raises blood ketones). Cardiac function was assessed by echocardiography. Cardiac …

Metabolism

BackgroundMetabolic Syndrome (MetS) is a progressive pathophysiological state defined by a cluster of cardiometabolic traits. However, little is known about metabolites that may be predictors of MetS incidence or reversion. Our objective was to identify plasma metabolites associated with MetS incidence or MetS reversion.MethodsThe study included 1468 participants without cardiovascular disease (CVD) but at high CVD risk at enrollment from two case-cohort studies nested within the PREvención con DIeta MEDiterránea (PREDIMED) study with baseline metabolomics data. MetS was defined in accordance with the harmonized International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute criteria, which include meeting 3 or more thresholds for waist circumference, triglyceride, HDL cholesterol, blood pressure, and fasting blood glucose. MetS incidence was …

Metabolism

BackgroundClinical trials and Mendelian randomization (MR) studies reported null effects of high-density lipoprotein cholesterol (HDLsingle bondC) on risk of cardiovascular disease (CVD), which might have overlooked a nonlinear causal association. We aimed to investigate the dose-response relationship between circulating HDL-C concentrations and CVD in observational and MR frameworks.MethodsWe included 348,636 participants (52,919 CVD cases and 295,717 non-cases) of European ancestry with genetic data from the UK Biobank (UKB) and acquired genome-wide association summary data for HDL-C of Europeans from the Global Lipids Genetics Consortium (GLGC). Observational analyses were conducted in the UKB. Stratified MR analyses were conducted combing genetic data for CVD from UKB and lipids from GLGC.ResultsObservational analyses showed L-shaped associations of HDL-C with …

Metabolism

BackgroundEpidemiological evidence links the proprotein convertase subtilisin/kexin 7 (PCSK7) to triglyceride (TG) metabolism. We associated the known PCSK7 gain-of-function non-coding SNP rs236918 with higher levels of plasma apolipoprotein B (apoB) and the loss-of-function coding variant p.Pro777Leu (SNP rs201598301) with lower apoB and TG. Herein, we aimed to unravel the in vivo role of liver PCSK7.MethodsWe biochemically defined the functional role of PCSK7 in lipid metabolism using hepatic cell lines and Pcsk7−/− mice. Our findings were validated following subcutaneous administration of hepatocyte-targeted N-acetylgalactosamine (GalNAc)-antisense oligonucleotides (ASOs) against Pcsk7.ResultsIndependent of its proteolytic activity, membrane-bound PCSK7 binds apoB100 in the endoplasmic reticulum and enhances its secretion. Mechanistically, the loss of PCSK7/Pcsk7 leads to …

Metabolism

BackgroundClinical trials and Mendelian randomization (MR) studies reported null effects of high-density lipoprotein cholesterol (HDLsingle bondC) on risk of cardiovascular disease (CVD), which might have overlooked a nonlinear causal association. We aimed to investigate the dose-response relationship between circulating HDL-C concentrations and CVD in observational and MR frameworks.MethodsWe included 348,636 participants (52,919 CVD cases and 295,717 non-cases) of European ancestry with genetic data from the UK Biobank (UKB) and acquired genome-wide association summary data for HDL-C of Europeans from the Global Lipids Genetics Consortium (GLGC). Observational analyses were conducted in the UKB. Stratified MR analyses were conducted combing genetic data for CVD from UKB and lipids from GLGC.ResultsObservational analyses showed L-shaped associations of HDL-C with …

Metabolism

BackgroundComputed tomography (CT) imaging is widely used for diagnosing and determining the severity of coronavirus disease 2019 (COVID-19). Chest CT imaging can be used to calculate the epicardial adipose tissue (EAT) and upper abdominal visceral adipose tissue (Abd-VAT) areas. The EAT is the main source of inflammatory cytokines involved in chest inflammatory diseases; thus, the EAT area might be a more useful severity predictor than the Abd-VAT area for COVID-19. However, to the best of our knowledge, there are no large-scale reports that sufficiently consider this issue. In addition, there are no reports on the characteristics of patients with normal body mass index (BMI) and high adipose tissue.AimThe purpose of this study was to analyze whether the EAT area, among various adipose tissues, was the most associated factor with COVID-19 severity. Using a multicenter COVID-19 patient …

Metabolism

BackgroundHigh body mass index (BMI) is a major risk factor for cancer development, but its impact on the global burden of cancer remains unclear.MethodsWe estimated global and regional temporal trends in the burden of cancer attributable to high BMI, and the contributions of various cancer types using the framework of the Global Burden of Disease Study.ResultsFrom 2010 to 2019, there was a 35 % increase in deaths and a 34 % increase in disability-adjusted life-years from cancers attributable to high BMI. The age-standardized death rates for cancer attributable to high BMI increased over the study period (annual percentage change [APC] +0.48 %, 95 % CI 0.22 to 0.74 %). The greatest number of deaths from cancer attributable to high BMI occurred in Europe, but the fastest-growing age-standardized death rates and disability-adjusted life-years occurred in Southeast Asia. Liver cancer was the fastest …

Metabolism

BackgroundWeight loss and lifestyle intervention improve glucose tolerance delaying the onset of type 2 diabetes (T2D), but individual responses are highly variable. Determining the predictive factors linked to the beneficial effects of weight loss on glucose tolerance could provide tools for individualized prevention plans. Thus, the aim was to investigate the relationship between pre-intervention values of insulin sensitivity and secretion and the improvement in glucose metabolism after weight loss.MethodsIn the DEXLIFE cohort (373 individuals at high risk of T2D, assigned 3:1 to a 12-week lifestyle intervention or a control arm, Trial Registration: ISRCTN66987085), K-means clustering and logistic regression analysis were performed based on pre-intervention indices of insulin sensitivity, insulin secretion (AUC-I), and glucose-stimulated insulin response (ratio of incremental areas of insulin and glucose, iAUC I/G …

Metabolism

BackgroundHigh body mass index (BMI) is a major risk factor for cancer development, but its impact on the global burden of cancer remains unclear.MethodsWe estimated global and regional temporal trends in the burden of cancer attributable to high BMI, and the contributions of various cancer types using the framework of the Global Burden of Disease Study.ResultsFrom 2010 to 2019, there was a 35 % increase in deaths and a 34 % increase in disability-adjusted life-years from cancers attributable to high BMI. The age-standardized death rates for cancer attributable to high BMI increased over the study period (annual percentage change [APC] +0.48 %, 95 % CI 0.22 to 0.74 %). The greatest number of deaths from cancer attributable to high BMI occurred in Europe, but the fastest-growing age-standardized death rates and disability-adjusted life-years occurred in Southeast Asia. Liver cancer was the fastest …

Metabolism

BackgroundMetabolic Syndrome (MetS) is a progressive pathophysiological state defined by a cluster of cardiometabolic traits. However, little is known about metabolites that may be predictors of MetS incidence or reversion. Our objective was to identify plasma metabolites associated with MetS incidence or MetS reversion.MethodsThe study included 1468 participants without cardiovascular disease (CVD) but at high CVD risk at enrollment from two case-cohort studies nested within the PREvención con DIeta MEDiterránea (PREDIMED) study with baseline metabolomics data. MetS was defined in accordance with the harmonized International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute criteria, which include meeting 3 or more thresholds for waist circumference, triglyceride, HDL cholesterol, blood pressure, and fasting blood glucose. MetS incidence was …