Dairy Intake in 2 American Adult Cohorts Associates with Novel and Known Targeted and Nontargeted Circulating Metabolites.

BACKGROUND: The role of dairy in health can be elucidated by investigating circulating metabolites associated with intake. OBJECTIVES: We sought to identify metabolites associated with quantity and type of dairy intake in the Framingham Heart Study Offspring and Third Generation (Gen3) cohorts. METHODS: Dairy intake (total dairy, milk, cheese, yogurt, and cream/butter) was analyzed in relation to targeted (Offspring, n = 2205, 55.1 ± 9.8 y, 52% female, 217 signals; Gen3, n = 866, 40.5 ± 8.8 y, 54.9% female, 79 signals) and nontargeted metabolites (Gen3, ∼7031 signals) in a 2-step analysis including orthogonal projections to latent structures with discriminant analysis (OPLS-DA) in discovery subsets to identify metabolites distinguishing between high and low intake; and linear regression in confirmation subsets to assess putative associations, subsequently tested in the total samples. Previously reported associations were also investigated. RESULTS: OPLS-DA in the Offspring targeted discovery subset resulted in a variable importance in projection (VIP) >1 of 65, 60, 58, 66, and 60 metabolites for total dairy, milk, cream/butter, cheese, and yogurt, respectively, of which 5, 3, 1, 6, and 4 metabolites, respectively, remained after confirmation. In the Gen3 targeted discovery subset, OPLS-DA resulted in a VIP >1 of 17, 15, 13, 7, and 6 metabolites for total dairy, milk, cream/butter, cheese, and yogurt, respectively. In the Gen3 nontargeted discovery subset, OPLS-DA resulted in a VIP >2 of 203, 503, 78, 186, and 206 metabolites, respectively. Combining targeted and nontargeted results in Gen3, significant associations of 7 (6 unannotated), 2, 12 (11 unannotated), 0, and 61 (all unannotated) metabolites, respectively, remained. Candidate identities of unannotated signals included fatty acids and food flavorings. Results supported relations previously reported for C14:0 sphingomyelin, and marginal associations for deoxycholates. CONCLUSIONS: Dairy in 2 American adult cohorts associated with numerous circulating metabolites. Reports about diet-metabolite relations and confirmation of previous findings might be limited by specificity of dietary intake and breadth of measured metabolites.

Behavioral correlates of self-reported health status in US active duty military.

Trends and relationships between health behaviors and conditions in US active duty military and Coast Guard personnel are understudied. Self-reported data from the 2011 and 2015 Department of Defense Health Related Behaviors Surveys were analyzed to estimate associations between seven behaviors (reasons for not exercising; moderate, vigorous, and strength training exercise; alcohol intake; sleep; and smoking) and five health conditions (high blood pressure [BP], blood sugar [BG], cholesterol [CH]; overweight/obesity [OW]; or obesity [OB]). In 33,531 respondents, 14.8%, 1.7%, 13.6%, 65.5%, and 12.1% had high BP, BG, CH, OW, or OB, respectively. Respondents in 2015, versus 2011, had higher odds of BP, BG, OW, and OB. Compared to exercising as much as desired, citing a disability or injury, or work commitments as reasons for not exercising associated with higher odds of each condition. Longer sleep associated with lower odds of each condition except BG. Current and former smoking associated with higher odds of BP; former smoking also associated with higher odds of high CH and OW. Three behaviors contributing to the best predictive models of each condition resulted in associations of reasons for not exercising with all conditions; strength training for OW and OB; alcohol intake for BP and BG; sleep for BP and CH; and moderate exercise for BG. Disability and injury and time constraints limiting exercise were consistent markers of self-reported health conditions. Military-specific initiatives to promote strategies for overcoming barriers to exercising, continued emphasis on adequate sleep, and reduction of alcohol intake and smoking are warranted.

Plasma Ceramides, Mediterranean Diet, and Incident Cardiovascular Disease in the PREDIMED Trial (Prevención con Dieta Mediterránea).

BACKGROUND: Although in vitro studies and investigations in animal models and small clinical populations have suggested that ceramides may represent an intermediate link between overnutrition and certain pathological mechanisms underlying cardiovascular disease (CVD), no prospective studies have investigated the association between plasma ceramides and risk of CVD. METHODS: The study population consisted of 980 participants from the PREDIMED trial (Prevención con Dieta Mediterránea), including 230 incident cases of CVD and 787 randomly selected participants at baseline (including 37 overlapping cases) followed for ≤7.4 years. Participants were randomized to a Mediterranean diet supplemented with extra virgin olive oil, a Mediterranean diet supplemented with nuts, or a control diet. Plasma ceramide concentrations were measured on a liquid chromatography tandem mass spectrometry metabolomics platform. The primary outcome was a composite of nonfatal acute myocardial infarction, nonfatal stroke, or cardiovascular death. Hazard ratios were estimated with weighted Cox regression models using Barlow weights to account for the case-cohort design. RESULTS: The multivariable hazard ratios (HR) and 95% confidence intervals (CIs) comparing the extreme quartiles of plasma concentrations of C16:0, C22:0, C24:0, and C24:1 ceramides were 2.39 (1.49-3.83, Ptrend<0.001), 1.91 (1.21-3.01, Ptrend=0.003), 1.97 (1.21-3.20, Ptrend=0.004), and 1.73 (1.09-2.74, Ptrend=0.011), respectively. The ceramide score, calculated as a weighted sum of concentrations of four ceramides, was associated with a 2.18-fold higher risk of CVD across extreme quartiles (HR, 2.18; 95% CI, 1.36-3.49; Ptrend<0.001). The association between baseline ceramide score and incident CVD varied significantly by treatment groups (Pinteraction=0.010). Participants with a higher ceramide score and assigned to either of the 2 active intervention arms of the trial showed similar CVD risk to those with a lower ceramide score, whereas participants with a higher ceramide score and assigned to the control arm presented significantly higher CVD risk. Changes in ceramide concentration were not significantly different between Mediterranean diet and control groups during the first year of follow-up. CONCLUSIONS: Our study documented a novel positive association between baseline plasma ceramide concentrations and incident CVD. In addition, a Mediterranean dietary intervention may mitigate potential deleterious effects of elevated plasma ceramide concentrations on CVD. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.com. Unique identifier: ISRCTN35739639.

Dietary protein and changes in markers of cardiometabolic health across 20 years of follow-up in middle-aged Americans.

OBJECTIVE: Dietary protein plays a role in counteracting age-related muscle loss. However, limited long-term data exist on protein intake and markers of cardiometabolic health, which tend to deteriorate with age. DESIGN: Prospective cohort study. FFQ-derived protein intake (g/d) and cardiometabolic markers were assessed up to five times across 20 years. Markers included systolic (SBP) and diastolic (DBP) blood pressures, circulating lipids (total, HDL and LDL cholesterol; TAG), estimated glomerular filtration rate (eGFR), fasting glucose (FG), weight and waist circumference (WC). Mixed models accounting for repeated measures were used to estimate adjusted mean annualized changes in outcomes per quartile category of protein. SETTING: Framingham Heart Study Offspring cohort, USA. SUBJECTS: Participants (n 3066) with 12 333 unique observations, baseline (mean (sd)) age=54·0 (9·7) years, BMI=27·4 (4·9) kg/m2, 53·5 % female. RESULTS: In fully adjusted models, there were favourable associations (mean (se)) of total protein with annualized changes in SBP (lowest v. highest intake: 0·34 (0·06) v. 0·04 (0·06) mmHg, P trend=0·001) and eGFR (-1·03 (0·06) v. -0·87 (0·05) ml/min per 1·73 m2, P trend=0·046), unfavourable associations with changes in FG (0·013 (0·004) v. 0·028 (0·004) mmol/l, P trend=0·004) and no associations with weight, WC, DBP or lipids. Animal protein was favourably associated with SBP and unfavourably with FG and WC; plant protein was favourably associated with FG and WC. CONCLUSIONS: The present study provides evidence that protein intake may influence changes in cardiometabolic health independent of change in weight in healthy adults and that protein's role in cardiometabolic health may depend on the protein source.

Self-reported health behaviors, including sleep, correlate with doctor-informed medical conditions: data from the 2011 Health Related Behaviors Survey of U.S. Active Duty Military Personnel.

BACKGROUND: Health behaviors and cardiometabolic disease risk factors may differ between military and civilian populations; therefore, in U.S. active duty military personnel, we assessed relationships between demographic characteristics, self-reported health behaviors, and doctor-informed medical conditions. METHODS: Data were self-reported by 27,034 active duty military and Coast Guard personnel who responded to the 2011 Department of Defense Health Related Behaviors Survey. Multivariate linear and logistic regressions were used to estimate cross-sectional associations between (1) demographic characteristics (age, sex, service branch, marital status, children, race/ethnicity, pay grade) and self-reported behaviors (exercise, diet, smoking, alcohol, sleep); (2) demographic characteristics and doctor-informed medical conditions (hypertension, hypercholesterolemia, low high density lipoprotein (HDL) cholesterol, hyperglycemia) and overweight/obesity; and (3) behaviors and doctor-informed medical conditions. RESULTS: Among respondents (age 29.9 ± 0.1 years, 14.7% female), females reported higher intake than men of fruit, vegetables, and dairy; those with higher education reported higher intakes of whole grains; those currently married and/or residing with children reported higher intake of starches. Older age and female sex were associated with higher odds (ORs 1.25 to 12.54 versus the youngest age group) of overweight/obesity. Older age and female sex were also associated with lower odds (ORs 0.29 to 0.65 versus male sex) of doctor-informed medical conditions, except for blood glucose, for which females had higher odds. Those currently married had higher odds of high cholesterol and overweight/obesity, and separated/divorced/widowed respondents had higher odds of high blood pressure and high cholesterol. Short sleep duration (< 5 versus 7-8 h/night) was associated with higher odds (ORs 1.36to 2.22) of any given doctor-informed medical condition. Strength training was associated with lower probability of high cholesterol, high triglycerides, and low HDL, and higher probability of overweight/obesity. Dietary factors were variably associated with doctor-informed medical conditions and overweight/obesity. CONCLUSIONS: This study observed pronounced associations between health behaviors-especially sleep-and medical conditions, thus adding to evidence that sleep is a critical, potentially modifiable behavior within this population. When possible, adequate sleep should continue to be promoted as an important part of overall health and wellness throughout the military community.

Associations of Dairy Intake with Incident Prediabetes or Diabetes in Middle-Aged Adults Vary by Both Dairy Type and Glycemic Status.

Background: Inconsistent evidence describes the association between dietary intake of dairy and milk-based products and type 2 diabetes (T2D) risk.Objective: Our objective was to assess associations between consumption of milk-based products, incident prediabetes, and progression to T2D in the Framingham Heart Study Offspring Cohort.Methods: Total dairy and milk-based product consumption was assessed by ≤4 food-frequency questionnaires across a mean of 12 y of follow-up in 2809 participants [mean ± SD age: 54.0 ± 9.7 y; body mass index (in kg/m2): 27.1 ± 4.7; 54% female]. Prediabetes was defined as the first occurrence of fasting plasma glucose ≥5.6 to <7.0 mmol/L (≥100 to <126 mg/dL), and T2D was defined as the first occurrence of fasting plasma glucose ≥7.0 mmol/L (≥126 mg/dL) or diabetes treatment. Proportional hazards models were used to estimate the risk of incident outcomes relative to dairy product intake in subsets of the cohort who were at risk of developing the outcomes. Spline regressions were used to examine potential nonlinear relations.Results: Of 1867 participants free of prediabetes at baseline, 902 (48%) developed prediabetes. Total, low-fat, and high-fat dairy consumptions were associated with a 39%, 32%, and 25% lower risk of incident prediabetes, respectively, in the highest compared with the lowest intakes (≥14 compared with <4 servings/wk). Total, low-fat and skim milk, whole-milk, and yogurt intakes were associated nonlinearly with incident prediabetes; moderate intake was associated with the greatest relative risk reduction. Neither cheese nor cream and butter was associated with prediabetes. Of 925 participants with prediabetes at baseline, 196 (21%) developed T2D. Only high-fat dairy and cheese showed evidence of dose-response, inverse associations with incident T2D, with 70% and 63% lower risk, respectively, of incident T2D between the highest and lowest intake categories (≥14 compared with <1 serving/wk for high-fat dairy, ≥4 compared with <1 serving/wk for cheese).Conclusion: Associations of dairy with incident prediabetes or diabetes varied both by dairy product and type and by baseline glycemic status in this middle-aged US population. Baseline glycemic status may partially underlie prior equivocal evidence regarding the role of dairy intake in diabetes.

Dietary Protein Modifies the Effect of the MC4R Genotype on 2-Year Changes in Appetite and Food Craving: The POUNDS Lost Trial.

Background: The melanocortin-4 receptor (MC4R) plays a pivotal role in the regulation of appetite and eating behavior. Variants in the MC4R gene have been related to appetite and obesity.Objective: We aimed to examine whether weight-loss diets modified the effect of the "obesity-predisposing" MC4R genotype on appetite-related measures in a randomized controlled trial.Methods: A total of 811 overweight and obese subjects [25 ≤ body mass index (BMI; kg/m2) ≤ 40] aged 30-70 y were included in the 2-y POUNDS Lost (Preventing Overweight Using Novel Dietary Strategies) trial. We genotyped MC4R rs7227255 in 735 overweight adults and assessed appetite-related characteristics, including craving, fullness, hunger, and prospective consumption, as well as a composite appetite score. We examined the effects of the genotype-by-weight-loss diet intervention interaction on appetite variables by using general linear models in both the whole population and in white participants only.Results: We found that dietary protein intake (low compared with high: 15% of energy compared with 25% of energy, respectively) significantly modified MC4R genetic effects on changes in appetite score and craving (P-interaction = 0.03 and 0.02, respectively) at 2 y, after adjustment for age, sex, ethnicity, baseline BMI, weight change, and baseline perspective phenotype. The obesity-predisposing A allele was associated with a greater increase in overall appetite score (ß = 0.10, P = 0.05) and craving (ß = 0.13, P = 0.008) compared with the non-A allele among participants who consumed a high-protein diet. MC4R genotype did not modify the effects of fat or carbohydrate intakes on appetite measures. Similar interaction patterns were observed in whites.Conclusion: Our data suggest that individuals with the MC4R rs7227255 A allele rather than the non-A allele might experience greater increases in appetite and food craving when consuming a high-protein weight-loss diet. This trial was registered at clinicaltrials.gov as NCT00072995.

Gallstones and Risk of Coronary Heart Disease: Prospective Analysis of 270 000 Men and Women From 3 US Cohorts and Meta-Analysis.

OBJECTIVE: Gallstone disease has been related to cardiovascular risk factors; however, whether presence of gallstones predicts coronary heart disease (CHD) is not well established. APPROACH AND RESULTS: We followed up 269 142 participants who were free of cancer and cardiovascular disease at baseline from 3 US cohorts: the Nurses' Health Study (112 520 women; 1980-2010), Nurses' Health Study II (112 919 women; 1989-2011), and the Health Professionals Follow-up Study (43 703 men; 1986-2010) and documented 21 265 incident CHD cases. After adjustment for potential confounders, the hazard ratio for the participants with a history of gallstone disease compared with those without was 1.15 (95% confidence interval, 1.10-1.21) in Nurses' Health Study, 1.33 (95% confidence interval, 1.17-1.51) in Nurses' Health Study II, and 1.11 (95% confidence interval, 1.04-1.20) in Health Professionals Follow-up Study. The associations seemed to be stronger in individuals who were not obese, not diabetic, or were normotensive, compared with their counterparts. We identified 4 published prospective studies by searching PUBMED and EMBASE up to October 2015, coupled with our 3 cohorts, involving 842 553 participants and 51 123 incident CHD cases. The results from meta-analysis revealed that a history of gallstone disease was associated with a 23% (15%-33%) increased CHD risk. CONCLUSION: Our findings support that a history of gallstone disease is associated with increased CHD risk, independently of traditional risk factors.

Plasma Branched-Chain Amino Acids and Incident Cardiovascular Disease in the PREDIMED Trial.

BACKGROUND: The role of branched-chain amino acids (BCAAs) in cardiovascular disease (CVD) remains poorly understood. We hypothesized that baseline BCAA concentrations predict future risk of CVD and that a Mediterranean diet (MedDiet) intervention may counteract this effect. METHODS: We developed a case-cohort study within the Prevención con Dieta Mediterránea (PREDIMED), with 226 incident CVD cases and 744 noncases. We used LC-MS/MS to measure plasma BCAAs (leucine, isoleucine, and valine), both at baseline and after 1 year of follow-up. The primary outcome was a composite of incident stroke, myocardial infarction, or cardiovascular death. RESULTS: After adjustment for potential confounders, baseline leucine and isoleucine concentrations were associated with higher CVD risk: the hazard ratios (HRs) for the highest vs lowest quartile were 1.70 (95% CI, 1.05-2.76) and 2.09 (1.27-3.44), respectively. Stronger associations were found for stroke. For both CVD and stroke, we found higher HRs across successive quartiles of BCAAs in the control group than in the MedDiet groups. With stroke as the outcome, a significant interaction (P = 0.009) between baseline BCAA score and intervention with MedDiet was observed. No significant effect of the intervention on 1-year changes in BCAAs or any association between 1-year changes in BCAAs and CVD were observed. CONCLUSIONS: Higher concentrations of baseline BCAAs were associated with increased risk of CVD, especially stroke, in a high cardiovascular risk population. A Mediterranean-style diet had a negligible effect on 1-year changes in BCAAs, but it may counteract the harmful effects of BCAAs on stroke.

An Increase in Dietary Quality Is Associated with Favorable Plasma Biomarkers of the Brain-Adipose Axis in Apparently Healthy US Women.

BACKGROUND: The associations between long-term dietary quality and biomarkers of the brain-adipose axis have not been examined. OBJECTIVE: We evaluated both cross-sectional and longitudinal associations between dietary quality and several biomarkers involved in the brain-adipose axis. METHODS: In the Nurses' Health Study II, 831 women [baseline mean age: 45 y; body mass index (BMI; in kg/m(2)): 24.6] were randomly selected from women who provided 2 fasting blood samples in 1996-1999 and 2010-2011 to measure plasma concentrations of leptin, soluble leptin receptor (sOB-R), adiponectin, insulin, retinol binding protein-4 (RBP-4), interleukin-6 (IL-6), and C-reactive protein (CRP). Dietary quality was assessed by the Alternative Healthy Eating Index (AHEI-2010) with the use of semiquantitative food-frequency questionnaires administered in 1995 and 2011. We used linear mixed models to evaluate the cross-sectional associations between dietary quality and biomarker concentrations. We also examined change in dietary quality in relation to change in biomarker concentrations. RESULTS: In cross-sectional analyses that compared the highest with the lowest quintile of AHEI-2010, we observed significantly lower leptin (P-trend < 0.0001), insulin (P-trend < 0.0001), and CRP (P-trend = 0.02) and significantly higher sOB-R (P-trend < 0.0001) and adiponectin (P-trend = 0.0003). These associations, except for CRP, remained significant after adjustment for BMI. In longitudinal analyses, women in the highest quintile of AHEI-2010 score change (most improvement) had a 13% increase in leptin, compared with a 42% increase (P-trend < 0.0001) in the lowest quintile (least improvement). The corresponding multivariable-adjusted percentage changes for other biomarkers were 4% compared with -1% for sOB-R (P-trend = 0.04), 14% compared with 6% for adiponectin (P-trend = 0.02), and -11% compared with 16% for CRP (P-trend = 0.02). Adjustment for interim weight change attenuated these associations. No associations were observed for RBP-4 or IL-6. CONCLUSION: Improvement in dietary quality was associated with favorable profiles of several biomarkers of the brain-adipose axis in women.

The Circulating Concentration and 24-h Urine Excretion of Magnesium Dose- and Time-Dependently Respond to Oral Magnesium Supplementation in a Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Accurate determination of Mg status is important for improving nutritional assessment and clinical risk stratification. OBJECTIVE: We aimed to quantify the overall responsiveness of Mg biomarkers to oral Mg supplementation among adults without severe diseases and their dose- and time responses using available data from randomized controlled trials (RCTs). METHODS: We identified 48 Mg supplementation trials (n = 2131) through searches of MEDLINE and the Cochrane Library up to November 2014. Random-effects meta-analysis was used to estimate weighted mean differences of biomarker concentrations between intervention and placebo groups. Restricted cubic splines were used to determine the dose- and time responses of Mg biomarkers to supplementation. RESULTS: Among the 35 biomarkers assessed, serum, plasma, and urine Mg were most commonly measured. Elemental Mg supplementation doses ranged from 197 to 994 mg/d. Trials ranged from 3 wk to 5 y (median: 12 wk). Mg supplementation significantly elevated circulating Mg by 0.04 mmol/L (95% CI: 0.02, 0.06) and 24-h urine Mg excretion by 1.52 mmol/24 h (95% CI: 1.20, 1.83) as compared to placebo. Circulating Mg concentrations and 24-h urine Mg excretion responded to Mg supplementation in a dose- and time-dependent manner, gradually reaching a steady state at doses of 300 mg/d and 400 mg/d, or after ~20 wk and 40 wk, respectively (all P-nonlinearity ≤ 0.001). The higher the circulating Mg concentration at baseline, the lower the responsiveness of circulating Mg to supplementation, and the higher the urinary excretion (all P-linearity < 0.05). In addition, RBC Mg, fecal Mg, and urine calcium were significantly more elevated by Mg supplementation than by placebo (all P-values < 0.05), but there is insufficient evidence to determine their responses to increasing Mg doses. CONCLUSIONS: This meta-analysis of RCTs demonstrated significant dose- and time responses of circulating Mg concentration and 24-h urine Mg excretion to oral Mg supplementation.

Sugar-Sweetened Beverage but Not Diet Soda Consumption Is Positively Associated with Progression of Insulin Resistance and Prediabetes.

BACKGROUND: Previous studies have shown an inconsistent relation between habitual beverage consumption and insulin resistance and prediabetes. OBJECTIVE: The objective of the present study was to test the hypothesis that the consumption of sugar-sweetened beverages (SSBs), rather than diet soda, is associated with long-term progression of insulin resistance and the development of prediabetes. METHODS: We analyzed the prospective association between cumulative mean consumption of SSBs or diet soda and incident prediabetes (n = 1685) identified across a median of 14 y of follow-up in participants [mean ± SD age: 51.9 ± 9.2 y; 59.6% women; mean ± SD body mass index (BMI; kg/m2): 26.3 ± 4.4] of the Framingham Offspring cohort. The prospective association between beverage consumption and change in homeostasis model assessment of insulin resistance (HOMA-IR; n = 2076) over ∼7 y was also analyzed. The cumulative mean consumption of SSBs and diet soda was estimated by using food-frequency questionnaires. Multivariable Cox proportional hazards models and linear regression models were implemented to estimate the HRs of incident prediabetes and change in HOMA-IR, respectively. RESULTS: After adjustment for multiple potential confounders, including baseline BMI, we observed that SSB intake was positively associated with incident prediabetes (P-trend < 0.001); the highest SSB consumers (>3 servings/wk; median: 6 servings/wk) had a 46% higher risk of developing prediabetes than did the SSB nonconsumers (HR: 1.46; 95% CI: 1.16, 1.83). Higher SSB intake was also associated with a greater increase in HOMA-IR (P-trend = 0.006). No prospective associations were observed between diet soda intake and risk of prediabetes (P-trend = 0.24) or changes in HOMA-IR (P-trend = 0.25). These associations were similar after additional adjustment for change in BMI. CONCLUSION: Regular SSB intake, but not diet soda intake, is associated with a greater increase in insulin resistance and a higher risk of developing prediabetes in a group of middle-aged adults.

Determinants and Consequences of Obesity.

OBJECTIVES: To review the contribution of the Nurses' Health Studies (NHS and NHS II) in addressing hypotheses regarding risk factors for and consequences of obesity. METHODS: Narrative review of the publications of the NHS and NHS II between 1976 and 2016. RESULTS: Long-term NHS research has shown that weight gain and being overweight or obese are important risk factors for type 2 diabetes, cardiovascular diseases, certain types of cancers, and premature death. The cohorts have elucidated the role of dietary and lifestyle factors in obesity, especially sugar-sweetened beverages, poor diet quality, physical inactivity, prolonged screen time, short sleep duration or shift work, and built environment characteristics. Genome-wide association and gene-lifestyle interaction studies have shown that genetic factors predispose individuals to obesity but that such susceptibility can be attenuated by healthy lifestyle choices. This research has contributed to evolving clinical and public health guidelines on the importance of limiting weight gain through healthy dietary and lifestyle behaviors. CONCLUSIONS: The NHS cohorts have contributed to our understanding of the risk factors for and consequences of obesity and made a lasting impact on clinical and public health guidelines on obesity prevention.

Plasma alkylresorcinols, biomarkers of whole-grain intake, are not associated with progression of coronary artery atherosclerosis in postmenopausal women with coronary artery disease.

OBJECTIVE: The objective of the present study was to examine the relationship between plasma alkyresorcinol (AR) concentrations, which are biomarkers of whole-grain intake, and atherosclerotic progression over 3 years in postmenopausal women with coronary artery disease. DESIGN: Plasma AR concentrations were measured by a validated GC-MS method in fasting plasma samples. Atherosclerosis progression was assessed using change in mean minimal coronary artery diameter (MCAD) and percentage diameter stenosis (%ST), based on mean proximal vessel diameter across up to ten coronary segments. Dietary intake was estimated using a 126-item interviewer-administered FFQ. SETTING: A prospective study of postmenopausal women participating in the Estrogen Replacement and Atherosclerosis trial. SUBJECTS: For the analysis of plasma AR concentrations and atherosclerotic progression, plasma samples and follow-up data on angiography were available for 182 women. RESULTS: Mean whole-grain intake was 9·6 (se 0·6) servings per week. After multivariate adjustment, no significant associations were observed between plasma AR concentrations and change in mean MCAD or progression of %ST. Plasma AR concentrations were significantly correlated with dietary whole grains (r=0·35, P<0·001), cereal fibre (r=0·33, P<0·001), bran (r=0·15, P=0·05), total fibre (r=0·22, P=0·003) and legume fibre (r=0·15, P=0·04), but not refined grains, fruit fibre or vegetable fibre. CONCLUSIONS: Plasma AR concentrations were not significantly associated with coronary artery progression over a 3-year period in postmenopausal women with coronary artery disease. A moderate association was observed between plasma AR concentrations and dietary whole grains and cereal fibre, suggesting it may be a useful biomarker in observational studies.

Intervention Trials with the Mediterranean Diet in Cardiovascular Prevention: Understanding Potential Mechanisms through Metabolomic Profiling.

Large observational epidemiologic studies and randomized trials support the benefits of a Mediterranean dietary pattern on cardiovascular disease (CVD). Mechanisms postulated to mediate these benefits include the reduction of low-grade inflammation, increased adiponectin concentrations, decreased blood coagulation, enhanced endothelial function, lower oxidative stress, lower concentrations of oxidized LDL, and improved apolipoprotein profiles. However, the metabolic pathways through which the Mediterranean diet influences CVD risk remain largely unknown. Investigating specific mechanisms in the context of a large intervention trial with the use of high-throughput metabolomic profiling will provide more solid public health messages and may help to identify key molecular targets for more effective prevention and management of CVD. Although metabolomics is not without its limitations, the techniques allow for an assessment of thousands of metabolites, providing wide-ranging profiling of small molecules related to biological status. Specific candidate plasma metabolites that may be associated with CVD include branched-chain and aromatic amino acids; the glutamine-to-glutamate ratio; some short- to medium-chain acylcarnitines; gut flora metabolites (choline, betaine, and trimethylamine N-oxide); urea cycle metabolites (citrulline and ornithine); and specific lipid subclasses. In addition to targeted metabolites, the role of a large number of untargeted metabolites should also be assessed. Large intervention trials with the use of food patterns for the prevention of CVD provide an unparalleled opportunity to examine the effects of these interventions on plasma concentrations of specific metabolites and determine whether such changes mediate the benefits of the dietary interventions on CVD risk.

Meta-analysis investigating associations between healthy diet and fasting glucose and insulin levels and modification by loci associated with glucose homeostasis in data from 15 cohorts.

Whether loci that influence fasting glucose (FG) and fasting insulin (FI) levels, as identified by genome-wide association studies, modify associations of diet with FG or FI is unknown. We utilized data from 15 U.S. and European cohort studies comprising 51,289 persons without diabetes to test whether genotype and diet interact to influence FG or FI concentration. We constructed a diet score using study-specific quartile rankings for intakes of whole grains, fish, fruits, vegetables, and nuts/seeds (favorable) and red/processed meats, sweets, sugared beverages, and fried potatoes (unfavorable). We used linear regression within studies, followed by inverse-variance-weighted meta-analysis, to quantify 1) associations of diet score with FG and FI levels and 2) interactions of diet score with 16 FG-associated loci and 2 FI-associated loci. Diet score (per unit increase) was inversely associated with FG (ß = -0.004 mmol/L, 95% confidence interval: -0.005, -0.003) and FI (ß = -0.008 ln-pmol/L, 95% confidence interval: -0.009, -0.007) levels after adjustment for demographic factors, lifestyle, and body mass index. Genotype variation at the studied loci did not modify these associations. Healthier diets were associated with lower FG and FI concentrations regardless of genotype at previously replicated FG- and FI-associated loci. Studies focusing on genomic regions that do not yield highly statistically significant associations from main-effect genome-wide association studies may be more fruitful in identifying diet-gene interactions.

Higher magnesium intake is associated with lower fasting glucose and insulin, with no evidence of interaction with select genetic loci, in a meta-analysis of 15 CHARGE Consortium Studies.

Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (ln-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [ß = -0.009 mmol/L (95% CI: -0.013, -0.005), P < 0.0001] and insulin [-0.020 ln-pmol/L (95% CI: -0.024, -0.017), P < 0.0001]. No magnesium-related SNP or interaction between any SNP and magnesium reached significance after correction for multiple testing. However, rs2274924 in magnesium transporter-encoding TRPM6 showed a nominal association (uncorrected P = 0.03) with glucose, and rs11558471 in SLC30A8 and rs3740393 near CNNM2 showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with other studies, a higher magnesium intake was associated with lower fasting glucose and insulin. Nominal evidence of TRPM6 influence and magnesium interaction with select loci suggests that further investigation is warranted.

Protein Intake and Human Health: Implications of Units of Protein Intake.

Understanding the health effects of protein intake is bedeviled by a number of factors, including protein quality and source. In addition, different units, including grams, grams per kilogram body weight (g/kg BW), and percent energy, may contribute to confusion about protein's effects on health, especially BW-based units in increasingly obese populations. We aimed to review the literature and to conduct a modeling demonstration of various units of protein intake in relation to markers of cardiometabolic health. Data from the Framingham Heart Study Offspring (n = 1847; 60.3 y; 62.5% women) and Third Generation (n = 2548; 46.2 y; 55.3% women) cohorts and the NHANES 2003-04 (n = 1625; 46.2 y; 49.7% women) and 2005-06 (n = 1347; 43.7 y; 49.5% women) cycles were used to model cross-sectional associations between 7 protein units (grams, percent energy, g/kg ideal BW, g/kg actual BW, BW-adjusted g/kg actual BW, g/kg lean BW, and g/kg fat-free BW) and 9 cardiometabolic outcomes (fasting glucose, systolic and diastolic blood pressure, total and HDL cholesterol, triglycerides, BMI, waist circumference, and estimated glomerular filtration rate). The literature review indicated the use of myriad units of protein intake, with differential results on cardiometabolic outcomes. The modeling demonstration showed units expressed in BW were confounded by BW, irrespective of outcome. Units expressed in grams, percent energy, and ideal BW showed similar results, with or without adjustment for body size. After adjusting for BW, results of units expressed in BW aligned with results of grams, percent energy, and ideal BW. In conclusion, protein intake in cardiometabolic health appears to depend on protein's unit of expression. Authors should be specific about the use of WHO (g/kg ideal BW) compared with US (g/kg actual BW) units, and ideally use gram or percent energy in observational studies. In populations where overweight/obesity are prevalent, intake based on actual BW should be reevaluated.

Symptoms of depression, anxiety, and post-traumatic stress disorder and their relationship to health-related behaviors in over 12,000 US military personnel: Bi-directional associations.

Background Military personnel are at greater risk of psychological disorders and related symptoms than civilians. Limited participation in health-promoting behaviors may increase presence of these disorders. Alternatively, these symptoms may limit engagement in health-promoting behaviors. Methods Self-reported data from the 2015 Department of Defense Health Related Behaviors Survey were used to assess bi-directional relationships between health-related behaviors (obesity, physical activity [PA], alcohol, smoking, sleep) and self-reported psychological disorders (generalized anxiety disorder [GAD], depression, post-traumatic disorder [PTSD]) in U.S. military personnel. Outcomes Among 12 708 respondents (14.7% female; 28.2% 17-24 y; 13.7% obese), self-reported depression was reported by 9.2%, GAD by 13.9%, and PTSD by 8.2%. Obesity and short sleep were associated with self-reported depression, GAD, and PTSD; current smoking was associated with higher odds of GAD; higher levels of vigorous PA were associated with lower odds of GAD; higher levels of moderate PA associated with lower odds of PTSD; and higher alcohol intake associated with higher odds of depression and PTSD. Self-reported depression, GAD, and PTSD were associated with higher odds of short sleep, obesity, and low levels of PA. Interpretation Obesity, short sleep, and limited engagement in health-promoting behaviors are associated with higher likelihood of self-reported psychological disorders, and vice-versa. Encouraging and improving health-promoting behaviors may contribute to positive mental health in military personnel.

Protein Intake and Functional Integrity in Aging: The Framingham Heart Study Offspring.

BACKGROUND: Higher protein intake is linked to maintenance of muscle mass and strength, but few studies have related protein to physical function and disability in aging. METHODS: In participants of the Framingham Heart Study Offspring, we examined associations between protein intake (g/d), estimated from food frequency questionnaires, and maintenance of functional integrity, as a functional integrity score based on responses to 17 questions from Katz Activities of Daily Living, Nagi, and Rosow-Breslau questionnaires, repeated up to five times (1991/1995-2011/2014) over 23 years of follow-up. Cox proportional hazard models were used to estimate risk of incident loss of functional integrity (functional integrity score ≤ 15th percentile). RESULTS: In 2,917 participants (age 54.5 [9.8] years), baseline protein intake was 77.2 (15.6) g/d. The functional integrity score (baseline, mean 98.9, range 82.4-100.0) was associated with objective performance (gait speed, grip strength) and lower odds of falls, fractures, and frailty. Across follow-up, there were 731 incident cases of loss of functional integrity. In fully adjusted models, participants in the highest category of protein intake (median 92.2 g/d) had 30% lower risk of loss of functional integrity (hazard ratio [95% confidence interval] 0.70 [0.52, 0.95], p trend = .03), versus those with the lowest intake (median 64.4 g/d). However, sex-stratified analyses indicated the association was driven by the association in women alone (hazard ratio [95% confidence interval] 0.49 [0.32, 0.74], p trend = .002) and was nonsignificant in men (hazard ratio [95% confidence interval] 1.14 [0.70, 1.86], p trend = .59). CONCLUSIONS: Higher protein intake was beneficially associated with maintenance of physical function in middle-aged, high-functioning U.S. adults over the span of two decades. This association was particularly evident in women.