Diet is a major contributor to metabolic disease risk, but there is controversy as to whether increased incidences of diseases such as non-alcoholic fatty liver disease arise from consumption of ...saturated fats or free sugars. Here, we investigate whether a sub-set of triacylglycerols (TAGs) were associated with hepatic steatosis and whether they arise from de novo lipogenesis (DNL) from the consumption of carbohydrates.
We conduct direct infusion mass spectrometry of lipids in plasma to study the association between specific TAGs and hepatic steatosis assessed by ultrasound and fatty liver index in volunteers from the UK-based Fenland Study and evaluate clustering of TAGs in the National Survey of Health and Development UK cohort. We find that TAGs containing saturated and monounsaturated fatty acids with 16-18 carbons are specifically associated with hepatic steatosis. These TAGs are additionally associated with higher consumption of carbohydrate and saturated fat, hepatic steatosis, and variations in the gene for protein phosphatase 1, regulatory subunit 3b (PPP1R3B), which in part regulates glycogen synthesis. DNL is measured in hyperphagic ob/ob mice, mice on a western diet (high in fat and free sugar) and in healthy humans using stable isotope techniques following high carbohydrate meals, demonstrating the rate of DNL correlates with increased synthesis of this cluster of TAGs. Furthermore, these TAGs are increased in plasma from patients with biopsy-confirmed steatosis.
A subset of TAGs is associated with hepatic steatosis, even when correcting for common confounding factors. We suggest that hepatic steatosis risk in western populations is in part driven by increased DNL following carbohydrate rich meals in addition to the consumption of saturated fat.
Accurate national information on dietary intakes, including heterogeneity among individuals, is critical to inform health implications and policy priorities. In low- and middle-income countries, ...household expenditure surveys constitute the major source of food data, but with uncertain validity for individual-level intakes.
To investigate how individualized dietary consumption estimated from household survey data compared with individual-level 24-hr dietary recalls (24hR); and to assess potential heterogeneity by method for individualizing household intakes, dietary indicator, and individual characteristics (age, sex, education, religion, household income).
We evaluated data from the 2011-2012 Bangladesh Household Integrated Survey (BIHS), which included household-level consumption data (5,503 households) and individual-level dietary data based on 24hR from these households (22,173 participants). Household and 24hR estimates were standardized and harmonized for 33 dietary indicators, including 9 food groups, total energy, 8 macronutrients, and 15 micronutrients. Individual consumption was estimated from household data using two approaches, the Adult Male Equivalent (AME) and per capita (PC) approach. For each dietary indicator, differences in household vs. individual mean estimates were evaluated overall and by strata of individual characteristics, using Spearman's correlations and univariate and multivariate linear regression models.
Individualized household estimates overestimated individual intakes from 24hR for all dietary factors using either estimation method (P<0.001 for each), except for starchy vegetables (AME: P = 0.15; PC: P = 0.85). For foods, overestimation ranged from 4% for seafood to about 240% for fruits, and for nutrients from 11% for carbohydrates and poly-unsaturated fats to 55% for vitamin C, with similar overestimation for the AME and the PC method. By strata, overestimation was modestly higher in men vs. women, in children (0-10y) vs. adolescents (11-19y) and adults (20-44y, ≥45y), among adults of higher (≥6y) vs. lower (<6y) education, in Muslims vs. other religions (Christians, Hindus), and for the lowest vs. all other income groups. This overestimation was notably higher in young children (0-5y) vs. all other age groups and in the lowest vs. all other income groups. Underestimation was rarely observed, for example for milk intake (-56%) in young children (0-5y). The PC approach did not capture heterogeneity in validity of estimation of different dietary factors by age, mainly in children (0-5y, 6-10y). Spearman's correlations between individualized household estimates and 24hR data were higher for the AME (0.30-0.70) than PC (0.20-0.50) approach. Findings were similar with and without multivariate regression, with proportions of variance (R2) in 24hR intakes explained by the AME being generally greater than PC estimates, yet still low to modest.
In this national survey, established methods for estimating individual level intakes from household surveys produce overestimation of intakes of nearly all dietary indicators, with significant variation depending on the dietary factor and modest variation depending on individual characteristics. These findings suggest a need for new methods to estimate individual-level consumption from household survey estimates.
Abstract Background & aims Associations of dietary sugars with metabolic and inflammatory markers may vary according to the source of the sugars. The aim of this study was to examine the association ...of dietary sugars from different sources beverages (liquids), foods (solids), extrinsic (free) or intrinsic (non-free) with metabolic and inflammatory markers. Methods Population-based cross-sectional study of adults in the East of England (n=9678). Sugar intakes were estimated using food frequency questionnaires. Fasting glycated haemoglobin, glucose, insulin, and C-Reactive Protein (CRP) were measured and indices of metabolic risk were derived (homeostatic model of insulin resistance, HOMA-IR and metabolic risk z-score). Results In multiple linear regression analyses adjusted for potential confounders including BMI and TEI, sugars from liquids were positively associated with ln-CRP b-coefficient (95%CI), 0.14(0.05,0.22) per 10%TEI and metabolic risk z-score 0.13(0.07,0.18). Free sugars were positively associated with ln-HOMA-IR 0.05(0.03,0.08) and metabolic risk z-score 0.09(0.06,0.12). Sugars from solids were not associated with any outcome. Among major dietary contributors to intakes (g/d), sugars in fruit, vegetables, dairy products/egg dishes, cakes/biscuits/confectionary and squash/juice drinks were not associated, but sugar added to tea, coffee, cereal was significantly positively associated with all outcomes. Sugars in 100% juice 0.16(0.06,0.25) per 10%TEI and other non-alcoholic beverages 0.13(0.03,0.23) were positively associated with metabolic risk z-score. Conclusion Higher intakes of sugars from non-alcoholic beverages and sugar added to tea, coffee, cereal were associated with glycaemia and inflammatory markers. Sugars from solids were not associated, irrespective of whether they were intrinsic or extrinsic. Positive associations of free sugars were largely explained by contribution of beverages to intake.
Low circulating concentrations of 25-hydroxyvitamin D (25OHD), a marker of vitamin D status, are associated with an increased risk of type 2 diabetes, but whether this association is causal remains ...unclear. We aimed to estimate the unconfounded, causal association between 25(OH)D concentration and risk of type 2 diabetes using a mendelian randomisation approach.
Using several data sources from populations of European descent, including type 2 diabetes cases and non-cases, we did a mendelian randomisation analysis using single nucleotide polymorphisms (SNPs) within or near four genes related to 25(OH)D synthesis and metabolism: DHCR7 (related to vitamin D synthesis), CYP2R1 (hepatic 25-hydroxylation), DBP (also known as GC; transport), and CYP24A1 (catabolism). We assessed each SNP for an association with circulating 25(OH)D concentration (5449 non-cases; two studies), risk of type 2 diabetes (28 144 cases, 76 344 non-cases; five studies), and glycaemic traits (concentrations of fasting glucose, 2-h glucose, fasting insulin, and HbA1c; 46 368 non-cases; study consortium). We combined these associations in a likelihood-based mendelian randomisation analysis to estimate the causal association of 25(OH)D concentration with type 2 diabetes and the glycaemic traits, and compared them with that from a meta-analysis of data from observational studies (8492 cases, 89 698 non-cases; 22 studies) that assessed the association between 25(OH)D concentration and type 2 diabetes.
All four SNPs were associated with 25(OH)D concentrations (p<10−6). The mendelian randomisation-derived unconfounded odds ratio for type 2 diabetes was 1·01 (95% CI 0·75–1·36; p=0·94) per 25·0 nmol/L (1 SD) lower 25(OH)D concentration. The corresponding (potentially confounded) relative risk from the meta-analysis of data from observational studies was 1·21 (1·16–1·27; p=7·3 × 10−19). The mendelian randomisation-derived estimates for glycaemic traits were not significant (p>0·25).
The association between 25(OH)D concentration and type 2 diabetes is unlikely to be causal. Efforts to increase 25(OH)D concentrations might not reduce the risk of type 2 diabetes as would be expected on the basis of observational evidence. These findings warrant further investigations to identify causal factors that might increase 25(OH)D concentration and also reduce the risk of type 2 diabetes.
UK Medical Research Council Epidemiology Unit and European Union Sixth Framework Programme.
Physical activity has multiple health benefits but may also increase the risk of developing musculoskeletal pain (MSP). However, the relationship between physical activity and MSP has not been well ...characterized. This study examined the dose-response relationship between sports activity and MSP among adolescents. Two school-based serial surveys were conducted 1 year apart in adolescents aged 12 to 18 years in Unnan, Japan. Self-administered questionnaires were completed by 2403 students. Associations between time spent in organized sports activity and MSP were analyzed cross-sectionally (n = 2403) and longitudinally (n = 374, students free of pain and in seventh or 10th grade at baseline) with repeated-measures Poisson regression and restricted cubic splines, with adjustment for potential confounders. The prevalence of overall pain, defined as having pain recently at least several times a week in at least one part of the body, was 27.4%. In the cross-sectional analysis, sports activity was significantly associated with pain prevalence. Each additional 1 h/wk of sports activity was associated with a 3% higher probability of having pain (prevalence ratio = 1.03, 95% confidence interval = 1.02-1.04). Similar trends were found across causes (traumatic and nontraumatic pain) and anatomic locations (upper limbs, lower back, and lower limbs). In longitudinal analysis, the risk ratio for developing pain at 1-year follow-up per 1 h/wk increase in baseline sports activity was 1.03 (95% confidence interval = 1.02-1.05). Spline models indicated a linear association (P < 0.001) but not a nonlinear association (P ≥ 0.45). The more the adolescents played sports, the more likely they were to have and develop pain.
To examine the association of erythrocyte n-6 polyunsaturated fatty acid (PUFA) biomarkers with incident type 2 diabetes and explore the potential role of gut microbiota in the association.
We ...evaluated 2,731 participants without type 2 diabetes recruited between 2008 and 2013 in the Guangzhou Nutrition and Health Study (Guangzhou, China). Case subjects with type 2 diabetes were identified with clinical and biochemical information collected at follow-up visits. Using stool samples collected during the follow-up in the subset (
= 1,591), 16S rRNA profiling was conducted. Using multivariable-adjusted Poisson or linear regression, we examined associations of erythrocyte n-6 PUFA biomarkers with incident type 2 diabetes and diversity and composition of gut microbiota.
Over 6.2 years of follow-up, 276 case subjects with type 2 diabetes were identified (risk 0.10). Higher levels of erythrocyte γ-linolenic acid (GLA), but not linoleic or arachidonic acid, were associated with higher type 2 diabetes incidence. Comparing the top to the bottom quartile groups of GLA levels, relative risk was 1.72 (95% CI 1.21, 2.44) adjusted for potential confounders. Baseline GLA was inversely associated with gut microbial richness and diversity (α-diversity, both
< 0.05) during follow-up and significantly associated with microbiota β-diversity (
= 0.002). α-Diversity acted as a potential mediator in the association between GLA and type 2 diabetes (
< 0.05). Seven genera (
,
,
,
,
,
, and
) were enriched in quartile 1 of GLA and in participants without type 2 diabetes.
Relative concentrations of erythrocyte GLA were positively associated with incident type 2 diabetes in a Chinese population and also with gut microbial profiles. These results highlight that gut microbiota may play an important role linking n-6 PUFA metabolism and type 2 diabetes etiology.
Prospective associations between n-3 fatty acid biomarkers and type 2 diabetes (T2D) risk are not consistent in individual studies. We aimed to summarize the prospective associations of biomarkers of ...α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with T2D risk through an individual participant-level pooled analysis.
For our analysis we incorporated data from a global consortium of 20 prospective studies from 14 countries. We included 65,147 participants who had blood measurements of ALA, EPA, DPA, or DHA and were free of diabetes at baseline. De novo harmonized analyses were performed in each cohort following a prespecified protocol, and cohort-specific associations were pooled using inverse variance-weighted meta-analysis.
A total of 16,693 incident T2D cases were identified during follow-up (median follow-up ranging from 2.5 to 21.2 years). In pooled multivariable analysis, per interquintile range (difference between the 90th and 10th percentiles for each fatty acid), EPA, DPA, DHA, and their sum were associated with lower T2D incidence, with hazard ratios (HRs) and 95% CIs of 0.92 (0.87, 0.96), 0.79 (0.73, 0.85), 0.82 (0.76, 0.89), and 0.81 (0.75, 0.88), respectively (all
< 0.001). ALA was not associated with T2D (HR 0.97 95% CI 0.92, 1.02) per interquintile range. Associations were robust across prespecified subgroups as well as in sensitivity analyses.
Higher circulating biomarkers of seafood-derived n-3 fatty acids, including EPA, DPA, DHA, and their sum, were associated with lower risk of T2D in a global consortium of prospective studies. The biomarker of plant-derived ALA was not significantly associated with T2D risk.
Prior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites with type 2 diabetes (T2D), with total 25(OH)D and 25(OH)D3 inversely associated with T2D, but the ...epimeric form (C3-epi-25(OH)D3) positively associated with T2D. Whether or not these observational associations are causal remains uncertain. We aimed to examine the potential causality of these associations using Mendelian randomisation (MR) analysis.
We performed a meta-analysis of genome-wide association studies for total 25(OH)D (N = 120,618), 25(OH)D3 (N = 40,562), and C3-epi-25(OH)D3 (N = 40,562) in participants of European descent (European Prospective Investigation into Cancer and Nutrition EPIC-InterAct study, EPIC-Norfolk study, EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We identified genetic variants for MR analysis to investigate the causal association of the 25(OH)D metabolites with T2D (including 80,983 T2D cases and 842,909 non-cases). We also estimated the observational association of 25(OH)D metabolites with T2D by performing random effects meta-analysis of results from previous studies and results from the EPIC-InterAct study. We identified 10 genetic loci associated with total 25(OH)D, 7 loci associated with 25(OH)D3 and 3 loci associated with C3-epi-25(OH)D3. Based on the meta-analysis of observational studies, each 1-standard deviation (SD) higher level of 25(OH)D was associated with a 20% lower risk of T2D (relative risk RR: 0.80; 95% CI 0.77, 0.84; p < 0.001), but a genetically predicted 1-SD increase in 25(OH)D was not significantly associated with T2D (odds ratio OR: 0.96; 95% CI 0.89, 1.03; p = 0.23); this result was consistent across sensitivity analyses. In EPIC-InterAct, 25(OH)D3 (per 1-SD) was associated with a lower risk of T2D (RR: 0.81; 95% CI 0.77, 0.86; p < 0.001), while C3-epi-25(OH)D3 (above versus below lower limit of quantification) was positively associated with T2D (RR: 1.12; 95% CI 1.03, 1.22; p = 0.006), but neither 25(OH)D3 (OR: 0.97; 95% CI 0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D3 (OR: 0.98; 95% CI 0.93, 1.04; p = 0.53) was causally associated with T2D risk in the MR analysis. Main limitations include the lack of a non-linear MR analysis and of the generalisability of the current findings from European populations to other populations of different ethnicities.
Our study found discordant associations of biochemically measured and genetically predicted differences in blood 25(OH)D with T2D risk. The findings based on MR analysis in a large sample of European ancestry do not support a causal association of total 25(OH)D or 25(OH)D metabolites with T2D and argue against the use of vitamin D supplementation for the prevention of T2D.
The risk of hepatic steatosis may be reduced through changes to dietary intakes, but evidence is sparse, especially for dietary patterns including the Mediterranean diet. We investigated the ...association between adherence to the Mediterranean diet and prevalence of hepatic steatosis.
Cross-sectional analysis of data from two population-based adult cohorts: the Fenland Study (England, n = 9645, 2005-2015) and CoLaus Study (Switzerland, n = 3957, 2009-2013). Habitual diet was assessed using cohort-specific food frequency questionnaires. Mediterranean diet scores (MDSs) were calculated in three ways based on adherence to the Mediterranean dietary pyramid, dietary cut-points derived from a published review, and cohort-specific tertiles of dietary consumption. Hepatic steatosis was assessed by abdominal ultrasound and fatty liver index (FLI) in Fenland and by FLI and non-alcoholic fatty liver disease (NAFLD) score in CoLaus. FLI includes body mass index (BMI), waist circumference, gamma-glutamyl transferase, and triglyceride; NAFLD includes diabetes, fasting insulin level, fasting aspartate-aminotransferase (AST), and AST/alanine transaminase ratio. Associations were assessed using Poisson regression.
In Fenland, the prevalence of hepatic steatosis was 23.9% and 27.1% based on ultrasound and FLI, respectively, and in CoLaus, 25.3% and 25.7% based on FLI and NAFLD score, respectively. In Fenland, higher adherence to pyramid-based MDS was associated with lower prevalence of hepatic steatosis assessed by ultrasound (prevalence ratio (95% confidence interval), 0.86 (0.81, 0.90) per one standard deviation of MDS). This association was attenuated 0.95 (0.90, 1.00) after adjustment for body mass index (BMI). Associations of similar magnitude were found for hepatic steatosis assessed by FLI in Fenland 0.82 (0.78, 0.86) and in CoLaus 0.85 (0.80, 0.91), and these were also attenuated after adjustment for BMI. Findings were similar when the other two MDS definitions were used.
Greater adherence to the Mediterranean diet was associated with lower prevalence of hepatic steatosis, largely explained by adiposity. These findings suggest that an intervention promoting a Mediterranean diet may reduce the risk of hepatic steatosis.
Tracking olfactory bulb mitral cell development with BrdU labeling, we find that mitral cells are generated from Pax6+ radial glial cells in the ventricular zone of the embryonic olfactory bulb. ...Unlike cortical projection neurons, postmitotic mitral cell precursors express both Tbr1 and Tbr2. Our tracking experiments revealed that down-regulation of Pax6 preceded up-regulation of Tbrs, and that Tbr1 emerged earlier than Tbr2. Using in utero electroporation, we also show that Pax6 negatively regulates the expression of Tbr1 and Tbr2 in postmitotic mitral cell precursors. Exogenous expression of Pax6 in embryonic olfactory bulb postmitotic precursors decreased the number of cells that progressed to a mitral cell fate. In contrast, exogenous expression of Pax6 resulted in an increase of GABAergic and/or dopaminergic interneurons. These results indicate that Pax6 is a regulator of fate determination of precursor cells.
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