Type 2 diabetes metabolomics score and risk of progression to type 2 diabetes among women with a history of gestational diabetes mellitus.

BACKGROUND: Several metabolites are individually related to incident type 2 diabetes (T2D) risk. We prospectively evaluated a novel T2D-metabolite pattern with a risk of progression to T2D among high-risk women with a history of gestational diabetes mellitus (GDM). METHODS: The longitudinal Nurses' Health Study II cohort enroled 116,429 women in 1989 and collected blood samples from 1996 to 1999. We profiled plasma metabolites in 175 incident T2D cases and 175 age-matched controls, all with a history of GDM before the blood draw. We derived a metabolomics score from 21 metabolites previously associated with incident T2D in the published literature by scoring according to the participants' quintile (1-5 points) of each metabolite. We modelled the T2D metabolomics score categorically in quartiles and continuously per 1 standard deviation (SD) with the risk of incident T2D using conditional logistic regression models adjusting for body mass index at the blood draw, and other established T2D risk factors. RESULTS: The percentage of women progressing to T2D ranged from 10% in the bottom T2D metabolomics score quartile to 78% in the highest score quartile. Adjusting for established T2D risk factors, women in the highest quartile had more than a 20-fold greater diabetes risk than women in the lowest quartile (odds ratios [OR] = 23.1 [95% CI = 8.6, 62.1]; p for trend<0.001). The continuous T2D metabolomics score was strongly and positively associated with incident T2D (adjusted OR = 2.7 per SD [95% CI = 1.9, 3.7], p < 0.0001). CONCLUSIONS: A pattern of plasma metabolites among high-risk women is associated with a markedly elevated risk of progression to T2D later in life.

Missing the forest-plot for the trees.

Systematic reviews and meta-analyses are methods increasingly used in biomedical research since their introduction in the 1970s. They serve to replace other non-systematic and cherry-picked narrative reviews, which are highly variable in their approach, structure and content. Their increase in popularity parallels the increase in overall scientific output, and when properly conducted, systematic reviews can contribute highly impactful summaries of a fast-growing evidence base. Meta-analyses offer statistical summaries, called forest plots, which similarly provide a powerful synopsis unachievable by individual studies. Thus, it is not difficult to imagine why systematic reviews are published more often. Should scientists be concerned by the accelerated output of research, from systematic reviews or other? If quantity comes at the expense of quality, then yes, of course; but should important manuscripts be rationed out otherwise? A new scientific technique can seem scary at first, especially to the researcher who is unfamiliar with its application or uncertain of its validity. In that case, we should become familiar with new and popular methods, and understand their strengths and limitations. There is a rightful place for systematic reviews and meta-analyses among respectable research tools. Importantly, however, despite standard operating procedures and best practices, the quality of systematic reviews today is highly variable, warranting serious concerns for quantity exceeding quality. Therefore, the appropriate response should be to instil researchers with an appreciation for the complexity of conducting and interpreting a systematic review and meta-analysis, to create more knowledgeable authors, reviewers and editors, who collectively will improve, rather than dismiss, these important scientific contributions.

Sugar-Sweetened and Artificially Sweetened Beverages and Risk of Liver Cancer and Chronic Liver Disease Mortality.

Importance: Approximately 65% of adults in the US consume sugar-sweetened beverages daily. Objective: To study the associations between intake of sugar-sweetened beverages, artificially sweetened beverages, and incidence of liver cancer and chronic liver disease mortality. Design, Setting, and Participants: A prospective cohort with 98 786 postmenopausal women aged 50 to 79 years enrolled in the Women's Health Initiative from 1993 to 1998 at 40 clinical centers in the US and were followed up to March 1, 2020. Exposures: Sugar-sweetened beverage intake was assessed based on a food frequency questionnaire administered at baseline and defined as the sum of regular soft drinks and fruit drinks (not including fruit juice); artificially sweetened beverage intake was measured at 3-year follow-up. Main Outcomes and Measures: The primary outcomes were (1) liver cancer incidence, and (2) mortality due to chronic liver disease, defined as death from nonalcoholic fatty liver disease, liver fibrosis, cirrhosis, alcoholic liver diseases, and chronic hepatitis. Cox proportional hazards regression models were used to estimate multivariable hazard ratios (HRs) and 95% CIs for liver cancer incidence and for chronic liver disease mortality, adjusting for potential confounders including demographics and lifestyle factors. Results: During a median follow-up of 20.9 years, 207 women developed liver cancer and 148 died from chronic liver disease. At baseline, 6.8% of women consumed 1 or more sugar-sweetened beverage servings per day, and 13.1% consumed 1 or more artificially sweetened beverage servings per day at 3-year follow-up. Compared with intake of 3 or fewer servings of sugar-sweetened beverages per month, those who consumed 1 or more servings per day had a significantly higher risk of liver cancer (18.0 vs 10.3 per 100 000 person-years [P value for trend = .02]; adjusted HR, 1.85 [95% CI, 1.16-2.96]; P = .01) and chronic liver disease mortality (17.7 vs 7.1 per 100 000 person-years [P value for trend <.001]; adjusted HR, 1.68 [95% CI, 1.03-2.75]; P = .04). Compared with intake of 3 or fewer artificially sweetened beverages per month, individuals who consumed 1 or more artificially sweetened beverages per day did not have significantly increased incidence of liver cancer (11.8 vs 10.2 per 100 000 person-years [P value for trend = .70]; adjusted HR, 1.17 [95% CI, 0.70-1.94]; P = .55) or chronic liver disease mortality (7.1 vs 5.3 per 100 000 person-years [P value for trend = .32]; adjusted HR, 0.95 [95% CI, 0.49-1.84]; P = .88). Conclusions and Relevance: In postmenopausal women, compared with consuming 3 or fewer servings of sugar-sweetened beverages per month, those who consumed 1 or more sugar-sweetened beverages per day had a higher incidence of liver cancer and death from chronic liver disease. Future studies should confirm these findings and identify the biological pathways of these associations.

Plasma metabolite profiles related to plant-based diets and the risk of type 2 diabetes.

AIMS/HYPOTHESIS: Plant-based diets, especially when rich in healthy plant foods, have been associated with a lower risk of type 2 diabetes. However, whether plasma metabolite profiles related to plant-based diets reflect this association was unknown. The aim of this study was to identify the plasma metabolite profiles related to plant-based diets, and to evaluate the associations between the identified metabolite profiles and the risk of type 2 diabetes. METHODS: Within three prospective cohorts (Nurses' Health Study, Nurses' Health Study II and Health Professionals Follow-up Study), we measured plasma metabolites from 10,684 participants using high-throughput LC MS. Adherence to plant-based diets was assessed by three indices derived from the food frequency questionnaire: an overall Plant-based Diet Index (PDI), a Healthy Plant-based Diet Index (hPDI), and an Unhealthy Plant-based Diet Index (uPDI). Multi-metabolite profiles related to plant-based diet were identified using elastic net regression with a training/testing approach. The prospective associations between metabolite profiles and incident type 2 diabetes were evaluated using multivariable Cox proportional hazards regression. Metabolites potentially mediating the association between plant-based diets and type 2 diabetes risk were further identified. RESULTS: We identified multi-metabolite profiles comprising 55 metabolites for PDI, 93 metabolites for hPDI and 75 metabolites for uPDI. Metabolite profile scores based on the identified metabolite profiles were correlated with the corresponding diet index (Pearson r = 0.33-0.35 for PDI, 0.41-0.45 for hPDI, and 0.37-0.38 for uPDI, all p<0.001). Metabolite profile scores of PDI (HR per 1 SD higher = 0.81 [95% CI 0.75, 0.88]) and hPDI (HR per 1 SD higher = 0.77 [95% CI 0.71, 0.84]) showed an inverse association with incident type 2 diabetes, whereas the metabolite profile score for uPDI was not associated with the risk. Mutual adjustment for metabolites selected in the metabolite profiles, including trigonelline, hippurate, isoleucine and a subset of triacylglycerols, attenuated the associations of diet indices PDI and hPDI with lower type 2 diabetes risk. The explainable proportion of PDI/hPDI-related diabetes risk by these metabolites ranged between 8.5% and 37.2% (all p<0.05). CONCLUSIONS/INTERPRETATION: Plasma metabolite profiles related to plant-based diets, especially a healthy plant-based diet, were associated with a lower risk of type 2 diabetes among a generally healthy population. Our findings support the beneficial role of healthy plant-based diets in diabetes prevention and provide new insights for future investigation.

Physical activity from menarche-to-first pregnancy and risk of breast cancer: the California teachers study.

PURPOSE: A longer menarche-to-first pregnancy window of susceptibility (WOS) is associated with increased breast cancer risk. Whether physical activity, an established preventive risk factor, during the menarche-to-first pregnancy WOS offsets breast cancer risk overall or for specific molecular subtypes is unclear. METHODS: We examined the prospective association between physical activity during the menarche-to-first pregnancy WOS and breast cancer risk in the California Teachers Study (N = 78,940). Recreational physical activity at multiple timepoints were recalled at cohort entry, and converted to metabolic equivalent of task hours per week (MET-hrs/wk). We used multivariable Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We observed 5,157 invasive breast cancer cases over 21.6 years of follow-up. Longer menarche-to-first pregnancy WOS (≥ 20 vs. < 15 years) was associated with higher breast cancer risk (HR = 1.23, 95% CI = 1.13-1.34). Women with higher physical activity level during menarche-to-first pregnancy had lower risk of invasive breast cancer (≥ 40 vs. < 9 MET-hrs/wk: HR = 0.89, 95% CI = 0.83-0.97) and triple-negative subtype (≥ 40 vs. < 9 MET-hrs/wk: HR = 0.53, 95% CI = 0.32-0.87). No association was observed for luminal A-like and luminal B-like subtypes. Higher physical activity level was associated with lower breast cancer risk among women with moderate (15-19 years) menarche-to-first pregnancy intervals (≥ 40 vs. < 9 MET-hrs/wk: HR = 0.80, 95% CI = 0.69-0.92), but not with short (< 15 years) or long (≥ 20 years) intervals. CONCLUSION: Physical activity during a WOS was associated with lower breast cancer risk in our cohort. Understanding timing of physical activity throughout the life course in relationship with breast cancer risk maybe important for cancer prevention strategies.

Association of Modifiable Lifestyle Factors with Plasma Branched-Chain Amino Acid Metabolites in Women.

BACKGROUND: Circulating branched-chain amino acids (BCAAs-isoleucine, leucine, and valine) are strongly associated with higher risk of incident type 2 diabetes (T2D); however, determinants of elevated fasting BCAA concentrations are largely unknown. OBJECTIVES: We aimed to characterize the modifiable lifestyle factors related to plasma BCAAs. METHODS: We performed a cross-sectional analysis among n = 18,897 women (mean ± SD age: 54.9 ± 7.2 y) in the Women's Health Study, free of T2D and cardiovascular disease at baseline blood draw. Lifestyle factors, weight, and height were self-reported via questionnaire, including smoking status, alcohol, leisure-time physical activity (LTPA), diet quality scores [2010 Alternative Healthy Eating Index (without alcohol) (aHEI); alternate Mediterranean Diet (aMED)], and dietary sources of BCAAs. Plasma BCAAs were quantified via NMR spectroscopy. We calculated multivariable-adjusted percentage mean differences (95% CIs) and P values for linear trend of BCAAs stratified by categoric lifestyle factors. We estimated R2 from univariate cubic spline regression models to estimate the variability in BCAAs explained. RESULTS: Compared with women with BMI (in kg/m2) <25.0, BCAAs were 8.6% (95% CI: 8.0%, 9.3%), 15.3% (95% CI: 14.4%, 16.3%), and 21.0% (95% CI: 18.2%, 23.9%) higher for the BMI strata 25.0-29.9, 30.0-39.9, and ≥40.0, respectively (P-trend < 0.0001). Women with higher LTPA and higher alcohol intake compared with lower had modestly (∼1%) lower plasma BCAAs (P-trend = 0.014 and 0.0003, respectively). Differences in smoking status, aHEI, and aMED score were not related to plasma BCAAs. Women with higher dietary BCAAs had dose-response higher plasma BCAA concentrations, 3.4% (95% CI: 2.5%, 4.4%) higher when comparing the highest with the lowest quintile (P-trend < 0.0001). BMI explained 11.6% of the variability of BCAAs, whereas other factors explained between 0.1% and 1%. CONCLUSIONS: Our findings among a large cohort of US women indicate that BMI, but less so diet, physical activity, and other lifestyle factors, is related to plasma BCAAs.This trial was registered at clinicaltrials.gov as NCT00000479.

Gestational weight gain during the second and third trimesters and adverse pregnancy outcomes, results from a prospective pregnancy cohort in urban Tanzania.

BACKGROUND: Appropriate gestational weight gain (GWG) is important for optimal pregnancy outcomes. This study prospectively evaluated the associations between GWG during the second and third trimesters of pregnancy and adverse pregnancy outcomes in an urban Tanzanian pregnancy cohort. METHODS: We used data from a randomized clinical trial conducted among pregnant women recruited by 27 weeks of gestation in Dar es Salaam, Tanzania (N = 1230). Women's gestational weight was measured at baseline and at monthly antenatal visits. Weekly GWG rate during the second and third trimesters was calculated and characterized as inadequate, adequate, or excessive, in conjunction with measured or imputed early-pregnancy BMI status according to the 2009 Institute of Medicine (IOM) GWG guidelines. We used multivariable Poisson regression with a sandwich variance estimator to calculate risk ratios (RR) for associations of GWG with low birth weight, preterm birth, small for gestational age (SGA), and large for gestational age (LGA). Degree of appropriate GWG defined using additional metrics (i.e., percentage of adequacy, z-score) and potential effect modification by maternal BMI were additionally evaluated. RESULTS: According to the IOM guidelines, 517 (42.0%), 270 (22.0%), and 443 (36.0%) women were characterized as having inadequate, adequate, and excessive GWG, respectively. Overall, compared to women with adequate GWG, women with inadequate GWG had a lower risk of LGA births (RR = 0.54, 95% CI: 0.36-0.80) and a higher risk of SGA births (RR = 1.32, 95% CI: 0.95-1.81). Women with inadequate GWG as defined by percentage of GWG adequacy had a higher risk of LBW (OR = 1.93, 95% CI: 1.03-3.63). In stratified analyses by early-pregnancy BMI, excessive GWG among women with normal BMI was associated with a higher risk of preterm birth (RR = 1.59, 95% CI: 1.03-2.44). CONCLUSIONS: A comparatively high percentage of excessive GWG was observed among healthy pregnant women in Tanzania. Both inadequate and excessive GWGs were associated with elevated risks of poor pregnancy outcomes. Future studies among diverse SSA populations are warranted to confirm our findings, and clinical recommendations on optimal GWG should be developed to promote healthy GWG in SSA settings. TRIAL REGISTRATION: This trial was registered as "Prenatal Iron Supplements: Safety and Efficacy in Tanzania" (NCT01119612; http://clinicaltrials.gov/show/NCT01119612 ).

Pregnancy is a critical lifetime event for both mother and the offspring, with implications in short-term and long-term health consequences. Gestational weight gain (GWG) is an important modifiable factor for pregnancy outcomes related to infant body size and weight and prematurity. Countries in sub-Saharan Africa (SSA) have long had poor rates of insufficient GWG and pregnancy complications associated with insufficient GWG. Nevertheless, some SSA countries are experiencing economic transitions accompanied with changes in lifestyle and nutrition, which might impact pregnancy experiences, including GWG and pregnancy outcomes. This study aimed to characterize recent GWG patterns and the associations of both inadequate and excessive GWG with adverse pregnancy outcomes, using an urban pregnancy cohort in Tanzania. This study found that 42.0%. 22.0%, and 36.0% of women had insufficient, adequate, and excessive GWG, respectively. Insufficient GWG was associated with higher risks of small infant size and low infant body weight, and excessive GWG was associated with higher risk of preterm birth, particularly among women with body mass index 18.5­25.0 kg/m². Results from the present study highlight that both insufficient and excessive GWG are of potential public health concerns in urban centers of SSA, concerning upward trends in obesity and possibly obesity-related pregnancy consequences. Local public health practitioners should continue to advocate longitudinal GWG monitoring and care among African pregnant women, and optimal GWG with feasible and effective clinical guidelines should be developed to prevent both over- and under-gaining of maternal weight during pregnancy.

Dietary diversity and diet quality with gestational weight gain and adverse birth outcomes, results from a prospective pregnancy cohort study in urban Tanzania.

Healthy maternal diets during pregnancy are an important protective factor for pregnancy-related outcomes, including gestational weight gain (GWG) and birth outcomes. We prospectively examined the associations of maternal dietary diversity and diet quality, using Minimum Dietary Diversity for Women (MDD-W) and Prime Diet Quality Score (PDQS), with GWG and birth outcomes among women enrolled in a trial in Tanzania (n = 1190). MDD-W and PDQS were derived from a baseline food frequency questionnaire. Women were monthly followed until delivery, during which weight was measured. GWG was classified based on the 2009 Institute of Medicine guidelines. Adverse birth outcomes were classified as low birth weight (LBW), small for gestational age, large for gestational age, and preterm birth. 46.2% participants had MDD-W ≥ 5. Mean score of PDQS was 23.3. Maternal intakes of nuts, poultry, and eggs were low, whereas intakes of sugar-sweetened beverages and refined grains were high. MDD-W was not associated with GWG or birth outcomes. For PDQS, compared to the lowest tertile, women in the highest tertile had lower risk of inappropriate GWG (risk ratio [RR] = 0.93, 95% confidence interval [CI]: 0.87-1.00). Women in the middle tertile group of PDQS (RR = 0.72, 95% CI: 0.51-1.00) had lower risk of preterm birth. After excluding women with prior complications, higher PDQS was associated with lower risk of LBW (middle tertile: RR = 0.55, 95% CI: 0.31-0.99, highest tertile: RR = 0.52, 95% CI: 0.29-0.94; continuous per SD: RR = 0.77, 95% CI: 0.60-0.99). Our findings support continuing efforts to improve maternal diet quality for optimal GWG and infant outcomes among Tanzanian women.

A prospective study of endometriosis and risk of type 2 diabetes.

AIMS/HYPOTHESIS: The objective of this study was to investigate the association between laparoscopically confirmed endometriosis and risk of type 2 diabetes. METHODS: We used data from the Nurses' Health Study II, a prospective cohort of female nurses followed for >25 years (N = 112,037). We used Cox proportional hazards models to estimate the HRs and 95% CIs of incident, confirmed type 2 diabetes (n = 8496 participants) adjusted a priori for confounding factors. We additionally investigated differences in the relationship between endometriosis and type 2 diabetes by age (<50 or ≥50 years), BMI (<30 or ≥30 kg/m2), infertility history, menopausal status and history of gestational diabetes mellitus (GDM; restricted to parous women). RESULTS: We saw no association between laparoscopically confirmed endometriosis and risk of type 2 diabetes in multivariable confounder-adjusted models (HR 1.06 [95% CI 0.98, 1.13]) or models accounting for potential mediating factors (HR 0.94 [95% CI 0.87, 1.00]). However, we observed modest differences in the association between endometriosis and type 2 diabetes by BMI group, history of infertility and history of GDM. Among non-obese women (HR 1.17 [95% CI 1.02, 1.35]), women who never experienced infertility (HR 1.14 [95% CI 1.04, 1.25]) and women who never experienced GDM (HR 1.11 [95% CI 1.01, 1.22]), endometriosis was associated with greater risk of type 2 diabetes. CONCLUSIONS/INTERPRETATION: Overall, women with endometriosis were not at increased risk of type 2 diabetes. However, among subgroups at low risk for type 2 diabetes (i.e. non-obese women and women with no prior history of infertility or GDM), endometriosis was associated with a modest increased risk of type 2 diabetes.

Dietary intake of branched-chain amino acids and survival after colorectal cancer diagnosis.

Branched-chain amino acids (BCAAs), including leucine, isoleucine and valine, may potentially influence cancer progression by various mechanisms including its role in insulin resistance. However, the association of BCAAs with survival among patients with established colorectal cancer (CRC) remains unclear. We evaluated the associations between postdiagnostic BCAA intake with CRC-specific mortality and overall mortality among 1674 patients with nonmetastatic CRC in the Nurses' Health Study and the Health Professionals Follow-up Study. Patients completed a validated food frequency questionnaire. Multivariable hazard ratios (HRs) were calculated using Cox proportional-hazards regression model after adjustment for tumor characteristics and potential confounding factors. Comparing the highest with the lowest quartile intake of postdiagnostic total BCAA, the multivariable HRs were 1.18 (95% confidence interval [CI], 0.75-1.85, P for trend = .46 across quartiles) for CRC-specific mortality and 1.30 (95% CI, 1.01-1.69, P for trend = .04) for all-cause mortality. The multivariable HRs (the highest vs the lowest quartile) for all-cause mortality were 1.33 (95% CI, 1.03-1.73, Ptrend = .02) for valine, 1.28 (95% CI, 0.99-1.66, P for trend = .05) for leucine and 1.25 (95% CI, 0.96-1.61, P for trend = .06) for isoleucine. No statistically significant associations with each of the BCAA intake were observed for CRC-specific mortality (all P for trend > .30). Our findings suggest positive associations between higher intake of dietary BCAAs and risk of all-cause mortality in CRC patients. These findings need to be confirmed and potential mechanisms underlying this association need to be elucidated.

Changes of Plasma Phospholipid Fatty Acids Profiles in Pregnancy in Relation to the Diagnosis and Treatment of Gestational Diabetes Mellitus.

BACKGROUND: Plasma phospholipid fatty acids (FAs) in early and mid-pregnancy have been prospectively related to gestational diabetes mellitus (GDM) risk. Yet, changes of FAs following GDM diagnosis and treatment and their implications for glucose metabolism and control remain understudied. METHODS: From the Eunice Kennedy Shriver National Institute Child Health and Human Development Fetal Growth Studies-Singleton Cohort of 2802 pregnant women, we ascertained 85 GDM cases using the Carpenter and Coustan criteria and 85 non-GDM controls after exclusion. Using plasma collected before (23-31 weeks) and after GDM diagnosis (33-39 weeks), we quantified 25 saturated, poly- and monounsaturated FAs levels. We estimated the fold change of FAs before and after GDM diagnosis, using multiple linear mixed models adjusting for confounders. RESULTS: Eight FAs showed significant fold changes from the baseline values (23-31 weeks) among GDM cases as compared to women without GDM. Five FAs showed reduced fold changes [myristic acid (14:0): ß: -0.22 (95% CI: -0.30, -0.14), palmitic acid (16:0): ß: -0.02 (95% CI: -0.04, -0.01), cis-palmitoleic acid (16:1n7): ß: -0.15 (95% CI: -0.24, -0.05), alpha-linolenic acid (18:3n3): ß: -0.19 (95% CI: -0.31, -0.07], and dihomo-gamma-linoleic acid (20:3n6): ß:-0.16; 95% CI: -0.21, -0.11)], whereas 3 showed increases [heptadecanoic acid (17:0): ß: 0.17 (95% CI: 0.11, 0.22), cis-vaccenic acid (18:1n7): ß: 0.06 (95% CI: 0.03, 0.10), and arachidonic acid (20:4n6): ß: 0.10 (95% CI: 0.06, 0.13)]. CONCLUSIONS: Our study identified 8 FAs with unique patterns of change before and after GDM diagnosis that differed significantly between women with and without GDM. Our findings may shed light on the role of FA metabolism in the pathophysiology and disease management and progression of GDM. CLINICAL TRIAL REGISTRY: NCT00912132.

The Mediterranean diet, plasma metabolome, and cardiovascular disease risk.

AIMS: To investigate whether metabolic signature composed of multiple plasma metabolites can be used to characterize adherence and metabolic response to the Mediterranean diet and whether such a metabolic signature is associated with cardiovascular disease (CVD) risk. METHODS AND RESULTS: Our primary study cohort included 1859 participants from the Spanish PREDIMED trial, and validation cohorts included 6868 participants from the US Nurses' Health Studies I and II, and Health Professionals Follow-up Study (NHS/HPFS). Adherence to the Mediterranean diet was assessed using a validated Mediterranean Diet Adherence Screener (MEDAS), and plasma metabolome was profiled by liquid chromatography-tandem mass spectrometry. We observed substantial metabolomic variation with respect to Mediterranean diet adherence, with nearly one-third of the assayed metabolites significantly associated with MEDAS (false discovery rate < 0.05). Using elastic net regularized regressions, we identified a metabolic signature, comprised of 67 metabolites, robustly correlated with Mediterranean diet adherence in both PREDIMED and NHS/HPFS (r = 0.28-0.37 between the signature and MEDAS; P = 3 × 10-35 to 4 × 10-118). In multivariable Cox regressions, the metabolic signature showed a significant inverse association with CVD incidence after adjusting for known risk factors (PREDIMED: hazard ratio [HR] per standard deviation increment in the signature = 0.71, P < 0.001; NHS/HPFS: HR = 0.85, P = 0.001), and the association persisted after further adjustment for MEDAS scores (PREDIMED: HR = 0.73, P = 0.004; NHS/HPFS: HR = 0.85, P = 0.004). Further genome-wide association analysis revealed that the metabolic signature was significantly associated with genetic loci involved in fatty acids and amino acids metabolism. Mendelian randomization analyses showed that the genetically inferred metabolic signature was significantly associated with risk of coronary heart disease (CHD) and stroke (odds ratios per SD increment in the genetically inferred metabolic signature = 0.92 for CHD and 0.91 for stroke; P < 0.001). CONCLUSIONS: We identified a metabolic signature that robustly reflects adherence and metabolic response to a Mediterranean diet, and predicts future CVD risk independent of traditional risk factors, in Spanish and US cohorts.

Markers of Inflammation and Incident Breast Cancer Risk in the Women's Health Study.

Chronic inflammation may be a risk factor for the development and progression of breast cancer, yet it is unknown which inflammatory biomarkers and pathways are especially relevant. The present study included 27,071 participants (mean age = 54.5 years) in the Women's Health Study who were free of cancer and cardiovascular disease at enrollment (1992-1995), with baseline measures of 4 inflammatory biomarkers: high-sensitivity C-reactive protein, fibrinogen, N-acetyl side-chains of acute phase proteins, and soluble intercellular adhesion molecule-1. We used Cox proportional hazards regression models to evaluate associations between baseline concentrations of biomarkers and incident breast cancer, and adjusted for baseline and time-varying factors such as age and body mass index. Self-reported invasive breast cancer was confirmed against medical records for 1,497 incident cases (90% postmenopausal). We observed different patterns of risk depending on the inflammatory biomarker. There was a significant direct association between fibrinogen and breast cancer risk (for quintile 5 vs. quintile 1, adjusted hazard ratio = 1.25, 95% confidence interval: 1.03, 1.51; P for trend = 0.01). In contrast, soluble intercellular adhesion molecule-1 was inversely associated with breast cancer (for quintile 5 vs. quintile 1, adjusted hazard ratio = 0.79, 95% confidence interval: 0.66, 0.94; P for trend = 0.02). N-acetyl side-chains of acute phase proteins and high-sensitivity C-reactive protein were not associated with breast cancer. The complex association of chronic inflammation and breast cancer may be considered when formulating anti-inflammatory cancer prevention or intervention strategies.

Dietary Intakes and Circulating Concentrations of Branched-Chain Amino Acids in Relation to Incident Type 2 Diabetes Risk Among High-Risk Women with a History of Gestational Diabetes Mellitus.

BACKGROUND: Circulating branched-chain amino acids (BCAAs; isoleucine, leucine, valine) are consistently associated with increased type 2 diabetes (T2D) risk, but the relationship with dietary intake of BCAAs is less clear. METHODS: The longitudinal Nurses' Health Study II cohort conducted a blood collection from 1996 to 1999. We profiled plasma metabolites among 172 incident T2D cases and 175 age-matched controls from women reporting a history of gestational diabetes before blood draw. We estimated dietary energy-adjusted BCAAs from food frequency questionnaires. We used conditional logistic regression models to estimate odds ratios (OR) and 95% CI of T2D risk across quartiles (Q1-Q4) of BCAAs, adjusting for age, body mass index (BMI), physical activity, family history, and other established risk factors. We also assessed joint exposure to below/above medians of diet and plasma concentrations, with lower diet/lower plasma as reference. RESULTS: Dietary and plasma BCAA concentrations were positively associated with incident T2D (diet Q4 vs Q1 OR = 4.6, CI = 1.6, 13.4; plasma Q4 vs Q1 OR = 4.4, CI = 1.4, 13.4). Modeling the joint association indicated that higher diet BCAAs were associated with T2D when plasma concentrations were also higher (OR = 6.0, CI = 2.1, 17.2) but not when concentrations were lower (OR = 1.6, CI = 0.61, 4.1). Conversely, higher plasma BCAAs were associated with increased T2D for either lower or higher diet. CONCLUSIONS: Independent of BMI and other risk factors, higher diet and plasma BCAA concentrations were associated with an increased incident T2D risk among high-risk women with a history of gestational diabetes, supporting impaired BCAA metabolism as conferring T2D risk.

Altered branched chain amino acid metabolism: toward a unifying cardiometabolic hypothesis.

PURPOSE OF REVIEW: Atherosclerotic cardiovascular disease (CVD) and type II diabetes (T2D) share common etiologic pathways that may long precede the development of clinically evident disease. Early identification of risk markers could support efforts to individualize risk prediction and improve the efficacy of primary prevention, as well as uncover novel therapeutic targets. RECENT FINDINGS: Altered metabolism of branched-chain amino acids (BCAAs), and their subsequent accumulation in circulation, may precede the development of insulin resistance and clinically manifest cardiometabolic diseases. BCAAs - the essential amino acids leucine, isoleucine and valine - likely promote insulin resistance through activation of mammalian target of rapamycin complex 1. Epidemiologic studies demonstrate robust associations between BCAAs and incident T2D, and Mendelian randomization supports a potentially causal relationship. More recently, there is emerging evidence that BCAAs are also associated with incident atherosclerotic CVD, possibly mediated by the development of T2D. SUMMARY: In this article, we review the biochemistry of BCAAs, their potential contribution to cardiometabolic risk, the available evidence from molecular epidemiologic studies to date, and, finally, consider future research and clinical directions. Overall, BCAAs represent a promising emerging target for risk stratification and possible intervention, to support efforts to mitigate the burden of cardiometabolic disease in the population.

Changes in Types of Dietary Fats Influence Long-term Weight Change in US Women and Men.

Background: The relation between dietary fat intake and body weight remains controversial. Few studies have examined long-term changes in types of dietary fat and weight change in longitudinal studies. Objective: The objective of this study was to examine associations between intake of different types of fat and long-term weight change in US women and men. Methods: The association between changes in consumption of varying types of fat and weight change was examined every 4 y through the use of multivariate models adjusted for age, baseline body mass index, and change in percentage energy from protein, intake of cereal fiber, fruits, and vegetables, alcohol use, and other lifestyle covariates in 3 prospective US cohorts, including 121,335 men and women free of diabetes, cardiovascular disease, cancer, or obesity over a 20- to 24-y follow-up. Dietary intakes and body weight were assessed via validated questionnaires. Cohort-specific results were pooled with the use of a random-effect meta-analysis. Results: Compared with equivalent changes in carbohydrate intake, a 5% increase in energy from saturated fatty acid (SFA) and a 1% increase in energy from trans-fat were associated with 0.61 kg (95% CI: 0.54, 0.68 kg) and 0.69 kg (95% CI: 0.56, 0.84 kg) greater weight gain per 4-y period, respectively. A 5% increase in energy from polyunsaturated fatty acid (PUFA) was associated with less weight gain (-0.55 kg; 95% CI: -0.81, -0.29 kg). Increased intake of monounsaturated fatty acid (MUFA) from animal sources by 1% was associated with weight gain of 0.29 kg (95% CI: 0.25, 0.33 kg), whereas MUFA from plant sources was not associated with weight gain. Conclusions: Different dietary fats have divergent associations with long-term weight change in US men and women. Replacing saturated and trans-fats with unsaturated fats, especially PUFAs, contributes to the prevention of age-related weight gain. These trials were registered at clinicaltrials.gov as NCT00005152 and NCT00005182.

Prediction and Prevention of Type 2 Diabetes in Women with a History of GDM.

PURPOSE OF THE REVIEW: Women with a history of gestational diabetes mellitus (GDM) have an alarmingly high risk of developing type 2 diabetes (T2D); yet, mechanisms underlying this progression are largely unknown. RECENT FINDINGS: Clinical characteristics of a GDM pregnancy and postpartum metabolomics may contribute to risk prediction of T2D to identify those women at highest risk of progression and need for intervention. Evidence for effective postpartum lifestyle interventions from observational studies include adherence to a healthy dietary pattern, increasing physical activity, and maintaining a healthy body weight. Larger clinical trials with greater participant engagement are warranted to confirm the effectiveness of lifestyle interventions in women with recent GDM. Research is needed to refine prediction models of T2D after GDM, and to determine the most effective strategies to delay or prevent T2D onset. Incorporating novel biomarkers in the postpartum period, such as metabolomics, could offer a powerful approach.

Body-mass index and mortality among adults with incident type 2 diabetes.

BACKGROUND: The relation between body weight and mortality among persons with type 2 diabetes remains unresolved, with some studies suggesting decreased mortality among overweight or obese persons as compared with normal-weight persons (an "obesity paradox"). METHODS: We studied participants with incident diabetes from the Nurses' Health Study (8970 participants) and Health Professionals Follow-up Study (2457 participants) who were free of cardiovascular disease and cancer at the time of a diagnosis of diabetes. Body weight shortly before diagnosis and height were used to calculate the body-mass index (BMI, the weight in kilograms divided by the square of the height in meters). Multivariable Cox models were used to estimate the hazard ratios and 95% confidence intervals for mortality across BMI categories. RESULTS: There were 3083 deaths during a mean period of 15.8 years of follow-up. A J-shaped association was observed across BMI categories (18.5 to 22.4, 22.5 to 24.9 [reference], 25.0 to 27.4, 27.5 to 29.9, 30.0 to 34.9, and ≥35.0) for all-cause mortality (hazard ratio, 1.29 [95% confidence interval {CI}, 1.05 to 1.59]; 1.00; 1.12 [95% CI, 0.98 to 1.29]; 1.09 [95% CI, 0.94 to 1.26]; 1.24 [95% CI, 1.08 to 1.42]; and 1.33 [95% CI, 1.14 to 1.55], respectively). This relationship was linear among participants who had never smoked (hazard ratios across BMI categories: 1.12, 1.00, 1.16, 1.21, 1.36, and 1.56, respectively) but was nonlinear among participants who had ever smoked (hazard ratios across BMI categories: 1.32, 1.00, 1.09, 1.04, 1.14, and 1.21) (P=0.04 for interaction). A direct linear trend was observed among participants younger than 65 years of age at the time of a diabetes diagnosis but not among those 65 years of age or older at the time of diagnosis (P<0.001 for interaction). CONCLUSIONS: We observed a J-shaped association between BMI and mortality among all participants and among those who had ever smoked and a direct linear relationship among those who had never smoked. We found no evidence of lower mortality among patients with diabetes who were overweight or obese at diagnosis, as compared with their normal-weight counterparts, or of an obesity paradox. (Funded by the National Institutes of Health and the American Diabetes Association.).

Physical activity from menarche to first pregnancy and risk of breast cancer.

Breast tissue is particularly susceptible to exposures between menarche and first pregnancy, and a longer interval between these reproductive events is associated with elevated breast cancer risk. Physical activity during this time period may offset breast cancer risk, particularly for those at highest risk with longer menarche-to-first-pregnancy intervals. We used data from 65,576 parous women in the Nurses' Health Study II free of cancer in 1989 (baseline) and recalled their leisure-time physical activity at ages 12-34 in 1997. Current activity was collected at baseline and over follow-up. Relative risks (RRs) were estimated using multivariable Cox proportional hazards regression models. Between 1989 and 2011, 2,069 invasive breast cancer cases were identified. Total recreational activity between menarche and first pregnancy was not significantly associated with the risk of breast cancer. However, physical activity between menarche and first pregnancy was associated with significantly lower breast cancer risk among women in the highest category of a menarche-to first-pregnancy interval (≥20 years; RR for the highest versus the lowest quartile = 0.73, 95% confidence interval = 0.55-0.97; Ptrend = 0.045; Pinteraction = 0.048). This was not observed in women with a shorter interval. Physical activity between menarche and first pregnancy was associated with a lower risk of breast cancer among women with at least 20 years between these reproductive events. This may provide a modifiable factor that women can intervene on to mitigate their breast cancer risk associated with a longer interval.