Proteomic Analyses in Diverse Populations Improved Risk Prediction and Identified New Drug Targets for Type 2 Diabetes.

OBJECTIVE: Integrated analyses of plasma proteomics and genetic data in prospective studies can help assess the causal relevance of proteins, improve risk prediction, and discover novel protein drug targets for type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We measured plasma levels of 2,923 proteins using Olink Explore among ∼2,000 randomly selected participants from China Kadoorie Biobank (CKB) without prior diabetes at baseline. Cox regression assessed associations of individual protein with incident T2D (n = 92 cases). Proteomic-based risk models were developed with discrimination, calibration, reclassification assessed using area under the curve (AUC), calibration plots, and net reclassification index (NRI), respectively. Two-sample Mendelian randomization (MR) analyses using cis-protein quantitative trait loci identified in a genome-wide association study of CKB and UK Biobank for specific proteins were conducted to assess their causal relevance for T2D, along with colocalization analyses to examine shared causal variants between proteins and T2D. RESULTS: Overall, 33 proteins were significantly associated (false discovery rate < 0.05) with risk of incident T2D, including IGFBP1, GHR, and amylase. The addition of these 33 proteins to a conventional risk prediction model improved AUC from 0.77 (0.73-0.82) to 0.88 (0.85-0.91) and NRI by 38%, with predicted risks well calibrated with observed risks. MR analyses provided support for the causal relevance for T2D of ENTR1, LPL, and PON3, with replication of ENTR1 and LPL in Europeans using different genetic instruments. Moreover, colocalization analyses showed strong evidence (pH4 > 0.6) of shared genetic variants of LPL and PON3 with T2D. CONCLUSIONS: Proteomic analyses in Chinese adults identified novel associations of multiple proteins with T2D with strong genetic evidence supporting their causal relevance and potential as novel drug targets for prevention and treatment of T2D.

The association of appendicular lean mass and grip strength with low-density lipoprotein, very low-density lipoprotein, and high-density lipoprotein particle diameter: a Mendelian randomization study of the UK Biobank cohort.

Aims: Reduced muscle mass and reduced strength are frequently associated with both alterations in blood lipids and poorer cardiometabolic outcomes in epidemiological studies; however, a causal association cannot be determined from such observations. Two-sample Mendelian randomization (MR) was applied to assess the association of genetically determined appendicular lean mass (ALM) and handgrip strength (HGS) with serum lipid particle diameter. Methods and results: Mendelian randomization was implemented using summary-level data from the largest genome-wide association studies on ALM (n = 450 243), HGS (n = 223 315), and lipoprotein [low-density lipoprotein (LDL), very LDL (VLDL), and high-density lipoprotein (HDL)] particle diameters (n = 115 078). Inverse variance-weighted (IVW) method was used to calculate the causal estimates. Weighted median-based method, MR-Egger, and leave-one-out method were applied as sensitivity analysis. Greater ALM had a statistically significant positive effect on HDL particle diameter (MR-Egger: ß = 0.055, SE = 0.031, P = 0.081; IVW: ß = 0.068, SE = 0.014, P < 0.001) and a statistically significant negative effect on VLDL particle diameter (MR-Egger: ß = -0.114, SE = 0.039, P = 0.003; IVW: ß = -0.081, SE = 0.017, P < 0.001). Similarly, greater HGS had a statistically significant positive effect on HDL particle diameter (MR-Egger: ß = 0.433, SE = 0.184, P = 0.019; IVW: ß = 0.121, SE = 0.052, P = 0.021) and a statistically significant negative effect on VLDL particle diameter (MR-Egger: ß = -0.416, SE = 0.163, P = 0.011; IVW: ß = -0.122, SE = 0.046, P = 0.009). There was no statistically significant effect of either ALM or HGS on LDL particle diameter. Conclusion: There were potentially causal associations between both increasing ALM and HGS and increasing HDL particle size and decreasing VLDL particle size. These causal associations may offer possibilities for interventions aimed at improving cardiovascular disease risk profile.

Dietary nitrate intake and association with markers of cardiometabolic risk in Iranian female adolescents.

Dietary nitrates are thought to confer several cardiometabolic health benefits, including improvements in blood pressure and the plasma lipid profile. However, existing data from Iran is conflicting and there is a dearth of literature focusing on non-adult populations. A total of 988 adolescent girls were recruited from schools in different areas of Mashhad and Sabzevar, Iran. Dietary nitrate intake was assessed using a food frequency questionnaire and participants were categorized into quartiles based on this. Differences in participant characteristics between quartiles were assessed using one-way ANOVA and associations between total nitrate intake, nitrate intake from vegetables and cardiometabolic risk markers (blood lipid profile, fasting blood glucose, systolic and diastolic blood pressure) were assessed using linear regression. Nitrate intake from vegetables was positively correlated with triglycerides, even after adjusting for several variables (ß = 0.086, 95% CI = 0.002-0.097; P = 0.043). Total nitrate intake was also significantly positively associated with serum triglycerides (ß = 0.097, 95% CI = 0.010-0.084; P = 0.012); however, this relationship disappeared after adjusting for several variables. Significant interaction effects were observed between total nitrate intake, nitrate intake from vegetables, and vitamin C upon triglycerides (P < 0.01). No significant relationships were found between total nitrate intake, nitrate intake from vegetables, and other cardiometabolic risk markers. Our findings suggest there may be neutral or possibly detrimental cardiovascular effects of dietary nitrate and/or vitamin C intake which are not in agreement with contemporary literature and warrant further investigation.

A systematic review and meta-analysis of randomized controlled trials to evaluate plant-based omega-3 polyunsaturated fatty acids in nonalcoholic fatty liver disease patient biomarkers and parameters.

CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is prevalent in 25-30% of British and European populations, representing a potential global public health crisis. Marine omega-3 (n-3) polyunsaturated fatty acids offer well-evidenced benefits to NAFLD biomarkers; however, the effect of plant-based n-3 has not been evaluated with a systematic review and meta-analysis. OBJECTIVE: The review aimed to systematically evaluate the effect of plant-based n-3 supplementation on NAFLD surrogate biomarkers and parameters. DATA SOURCES: Medline (EBSCO), PubMed, CINAHL (EBSCO), Cochrane Central Register of Controlled Trials, the International Clinical Trials Registry Platform, and Google Scholar databases were searched to identify randomized controlled trials published between January 1970 and March 2022 evaluating the impact of plant-based n-3 interventions on diagnosed NAFLD. The review followed the PRISMA checklist and is PROSPERO registered (CRD42021251980). DATA EXTRACTION: A random-effects model and generic inverse variance methods synthesized quantitative data, followed by a leave-one-out method for sensitivity analysis. We identified 986 articles; after the application of selection criteria, six studies remained with 362 patients with NAFLD. RESULTS: The meta-analysis showed that plant-based n-3 fatty acid supplementation significantly reduced alanine aminotransferase (ALT) (mean difference: 8.04 IU/L; 95% confidence interval: 14.70, 1.38; I2 = 48.61%) and plasma/serum triglycerides (44.51 mg/dL; 95% confidence interval: -76.93, -12.08; I2 = 69.93%), alongside body-composition markers in patients with NAFLD (P < 0.05). CONCLUSION: Plant-based n-3 fatty acid supplementation improves ALT enzyme biomarkers, triglycerides, body mass index, waist circumference, and weight loss when combined with lifestyle interventions to increase physical activity and a calorie-controlled diet. Further research is needed to identify the most effective plant-based n-3 sources in larger numbers of patients with NAFLD over longer study durations. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42021251980.

Plasma Proteomics to Identify Drug Targets for Ischemic Heart Disease.

BACKGROUND: Integrated analyses of plasma proteomic and genetic markers in prospective studies can clarify the causal relevance of proteins and discover novel targets for ischemic heart disease (IHD) and other diseases. OBJECTIVES: The purpose of this study was to examine associations of proteomics and genetics data with IHD in population studies to discover novel preventive treatments. METHODS: We conducted a nested case-cohort study in the China Kadoorie Biobank (CKB) involving 1,971 incident IHD cases and 2,001 subcohort participants who were genotyped and free of prior cardiovascular disease. We measured 1,463 proteins in the stored baseline samples using the OLINK EXPLORE panel. Cox regression yielded adjusted HRs for IHD associated with individual proteins after accounting for multiple testing. Moreover, cis-protein quantitative loci (pQTLs) identified for proteins in genome-wide association studies of CKB and of UK Biobank were used as instrumental variables in separate 2-sample Mendelian randomization (MR) studies involving global CARDIOGRAM+C4D consortium (210,842 IHD cases and 1,378,170 controls). RESULTS: Overall 361 proteins were significantly associated at false discovery rate <0.05 with risk of IHD (349 positively, 12 inversely) in CKB, including N-terminal prohormone of brain natriuretic peptide and proprotein convertase subtilisin/kexin type 9. Of these 361 proteins, 212 had cis-pQTLs in CKB, and MR analyses of 198 variants in CARDIOGRAM+C4D identified 13 proteins that showed potentially causal associations with IHD. Independent MR analyses of 307 cis-pQTLs identified in Europeans replicated associations for 4 proteins (FURIN, proteinase-activated receptor-1, Asialoglycoprotein receptor-1, and matrix metalloproteinase-3). Further downstream analyses showed that FURIN, which is highly expressed in endothelial cells, is a potential novel target and matrix metalloproteinase-3 a potential repurposing target for IHD. CONCLUSIONS: Integrated analyses of proteomic and genetic data in Chinese and European adults provided causal support for FURIN and multiple other proteins as potential novel drug targets for treatment of IHD.

Higher global diet quality score is related to lower prevalence of depression and poor quality of life among adolescent girls.

BACKGROUND: Adolescence is a key time for the development of depression symptoms and the diet quality may be associated with mental health conditions. The present study examined the association between depression and quality of life (QoL) and the global diet quality score (GDQS) as a simple and standardized metric diet quality in Iranian adolescents. METHODS: This cross-sectional study was conducted on 733 adolescent girls recruited using a random cluster sampling method. A 147-item food frequency questionnaire (FFQ) was used for dietary intake assessment. The GDQS is gained by summing points of all the 25 food groups, ranged from 0 to 49. Depression symptoms were assessed using a Persian version of the Beck Depression Inventory (BDI). For assessment of health-related QoL, the Short Form 12 Survey-version 2 (SF-12v2) questionnaire was employed. Multivariable logistic regression examined the association of depression and QoL with GDQS in crude and adjusted models. RESULTS: Adolescent girls in the highest tertile of GDQS score compared with the lowest tertile had a 41% lower odds of depressive symptoms (OR: 0.59; 95% CI: 0.39-0.90, P = 0.01). The participants in the third tertile of GDQS score had lower odds of poor QoL compared with the first tertile (OR: 0.56; 95% CI: 0.37-0.85, P < 0.01). These associations remained significant (both P = 0.01) after adjustment for age, energy intake, body mass index (BMI), physical activity, and menstruation (depressive symptoms: OR: 0.59; 95% CI: 0.38-0.92; QoL: OR: 0.59; 95% CI: 0.38-0.91, P = 0.01). CONCLUSION: We found that adolescent girls with a higher score of the GDQS had lower odds of depression and poor QoL Prospective and interventional investigations are needed to reach a clear vision.

Maternal High Fat Diet in Lactation Impacts Hypothalamic Neurogenesis and Neurotrophic Development, Leading to Later Life Susceptibility to Obesity in Male but Not Female Mice.

Early life nutrition can reprogram development and exert long-term consequences on body weight regulation. In mice, maternal high-fat diet (HFD) during lactation predisposed male but not female offspring to diet-induced obesity when adult. Molecular and cellular changes in the hypothalamus at important time points are examined in the early postnatal life in relation to maternal diet and demonstrated sex-differential hypothalamic reprogramming. Maternal HFD in lactation decreased the neurotropic development of neurons formed at the embryo stage (e12.5) and impaired early postnatal neurogenesis in the hypothalamic regions of both males and females. Males show a larger increased ratio of Neuropeptide Y (NPY) to Pro-opiomelanocortin (POMC) neurons in early postnatal neurogenesis, in response to maternal HFD, setting an obese tone for male offspring. These data provide insights into the mechanisms by which hypothalamic reprograming by early life overnutrition contributes to the sex-dependent susceptibility to obesity in adult life in mice.

Conventional and genetic associations of adiposity with 1463 proteins in relatively lean Chinese adults.

Adiposity is associated with multiple diseases and traits, but little is known about the causal relevance and mechanisms underlying these associations. Large-scale proteomic profiling, especially when integrated with genetic data, can clarify mechanisms linking adiposity with disease outcomes. We examined the associations of adiposity with plasma levels of 1463 proteins in 3977 Chinese adults, using measured and genetically-instrumented BMI. We further used two-sample bi-directional MR analyses to assess if certain proteins influenced adiposity, along with other (e.g. enrichment) analyses to clarify possible mechanisms underlying the observed associations. Overall, the mean (SD) baseline BMI was 23.9 (3.3) kg/m2, with only 6% being obese (i.e. BMI ≥ 30 kg/m2). Measured and genetically-instrumented BMI was significantly associated at FDR < 0.05 with levels of 1096 (positive/inverse: 826/270) and 307 (positive/inverse: 270/37) proteins, respectively, with FABP4, LEP, IL1RN, LSP1, GOLM2, TNFRSF6B, and ADAMTS15 showing the strongest positive and PON3, NCAN, LEPR, IGFBP2 and MOG showing the strongest inverse genetic associations. These associations were largely linear, in adiposity-to-protein direction, and replicated (> 90%) in Europeans of UKB (mean BMI 27.4 kg/m2). Enrichment analyses of the top > 50 BMI-associated proteins demonstrated their involvement in atherosclerosis, lipid metabolism, tumour progression and inflammation. Two-sample bi-directional MR analyses using cis-pQTLs identified in CKB GWAS found eight proteins (ITIH3, LRP11, SCAMP3, NUDT5, OGN, EFEMP1, TXNDC15, PRDX6) significantly affect levels of BMI, with NUDT5 also showing bi-directional association. The findings among relatively lean Chinese adults identified novel pathways by which adiposity may increase disease risks and novel potential targets for treatment of obesity and obesity-related diseases.

Psychological Stress and Gut Microbiota Composition: A Systematic Review of Human Studies.

INTRODUCTION: The associations between psychological stress and gut microbiota composition are not fully understood. This study investigated associations between psychological stress and gut microbiota composition and examined the potential modifying effects of age, sex, and ethnicity on such associations. METHODS: A systematic literature search was conducted using PubMed, Web of Science, PsycINFO, and Embase databases for studies published until November 2021 which examined associations between psychological stress and gut microbiota composition. RESULTS: During the search process, 10,790 studies were identified, and after screening, 13 met the eligibility criteria and were included. The median sample size was 70, and the median age of participants was 28.0 years. Most of the included studies did not report associations between measures of alpha- and beta diversity of the gut microbiota composition and psychological stress. A few studies reported that the Shannon index, Chao 1, Simpson index, and weighted UniFrac were negatively associated with psychological stress. Significant reductions in several taxa at the phyla-, family-, and genus-levels were observed in participants with higher psychological stress. At the phylum level, the abundance of Proteobacteria and Verrucomicrobia were negatively associated with psychological stress. At the family-level, no more than two studies reported associations of the same microbiota with psychological stress. At the genus level, the following results were found in more than two studies; psychological stress was negatively associated with the abundance of Lachnospira, Lachnospiraceae, Phascolarctobacterium, Sutterella, and Veillonella, and positively associated with the abundance of Methanobrevibacter, Rhodococcus, and Roseburia. However, it was not possible to determine the influence of age, sex, or ethnicity due to the limited studies included. CONCLUSION: Our findings provide evidence that psychological stress is associated with changes in the abundance of the gut microbiota. Larger sample longitudinal studies are needed to determine the causal relationship between psychological stress and the gut microbiota.

The association between ultra-processed foods and conventional markers of cardiovascular risk in an adult Iranian population.

BACKGROUND AND AIMS: According to the NOVA classification system, ultra-processed foods result from extensive industrial processing and use ingredients derived from food and non-food products, which can negatively impact on cardiovascular disease risk factors. Despite this, few studies have investigated UPFs in Middle Eastern populations regardless of high consumption in this region. METHODS AND RESULTS: This cross-sectional study was conducted on data from the Prospective Epidemiological Research Studies in Iran Kharemeh cohort (n = 6611). Food frequency questionnaires were assessed and the ratio of total UPFs energy/total energy intake was calculated. Data was categorized into tertiles of UPF consumption using the NOVA classification system. Kruskal-Wallis tests were used to assess differences in nutrient and food intakes between tertiles and logistic regression analysis was applied to assess the associations between UPFs and CVD risk factors. After adjustment for potential confounders the logistic regression analysis revealed significant positive relationships between intakes of UPFs and waist circumference (WC) (T2: OR; 1.34, 95% CI; 1.13-1.60 - T3: OR; 1.41, 95% CI; 1.18-1.69, P ˂0.001), low-density lipoprotein cholesterol (LDL-C) (T2: OR; 1.20, 95% CI; 1.05-1.37 - T3: OR; 1.27, 95% CI; 1.11-1.45, P ˂0.001), non-high-density lipoprotein cholesterol (non-HDL) (T2: OR; 1.21, 95% CI; 1.07-1.37 - T3: OR; 1.24, 95% CI; 1.10-1.41, P ˂0.001) and LDL-C to HDL-C ratio (T2: OR; 1.15, 95% CI; 1.02-1.31 - T3: OR; 1.21, 95% CI; 1.07-1.38, P = 0.002). CONCLUSION: The consumption of UPFs was positively associated with WC and atherogenic blood lipids. However, increased intakes of fiber and unsaturated fats were also found in those consuming more UPFs, which was not expected. These findings offer insights into an understudied population and warrant further research.

Association between war-related traumatic events and blood pressure trajectory: a population-based study among the mid-aged and older Palestinian adults living in Gaza.

Background: Little is known regarding health status in an environment characterized by instability and ongoing war risks. This study investigated hypertension disease burden and associations of war-related traumatic events with blood pressure (BP) trajectory over time amongst mid-aged and older Palestinian adults in Gaza Strip. Methods: From nine primary healthcare centers, medical records between 2013 and 2019 were collected for 1,000 mid-aged and older Palestinian adults living in Gaza. Multinomial logistic regression analysis examined associations between war-related traumatic events and BP trajectories derived using latent class trajectory analysis (LCTA). Results: The prevalence of self-reported injury (of participants or their family members), death of a family member, and violence due to house bombing was 51.4%, 54.1%, and 66.5%, respectively. In total, 22.4% and 21.4% of participants had constant-very-high (CVH) systolic BP (SBP) (>160 mmHg) and diastolic BP (DBP) (>95 mmHg), and normal-stable SBP and DBP was found only 54.9% and 52.6%, respectively. Injury (participants or family members), death of a family member, and violence due to house bombing during wars were associated with CVH SBP with odds ratios [95 CI, OR = 1.79 (1.28-2.48), 1.90 (1.36-2.65), and 1.44 (1.01-2.05)], respectively. The corresponding figures were [95 CI, OR = 1.92 (1.36-2.71), 1.90 (1.35-2.68), and 1.62 (1.13-2.38)] for CVH DBP. Living in debt was positively associated with CVH SBP, [95 CI, OR = 2.49 (1.73-3.60)] and CVH DBP, [95 CI, OR = 2.37 (1.63-3.45)]. Conclusion: The disease burden related to war-related traumatic events is high and positively related to adverse BP trajectory among the mid-aged and older Palestinians living in Gaza. Intervention programs are needed to manage and prevent chronic diseases in this vulnerable population.

Characterisation of Fasting and Postprandial NMR Metabolites: Insights from the ZOE PREDICT 1 Study.

BACKGROUND: Postprandial metabolomic profiles and their inter-individual variability are not well characterised. Here, we describe postprandial metabolite changes, their correlations with fasting values and their inter- and intra-individual variability, following a standardised meal in the ZOE PREDICT 1 cohort. METHODS: In the ZOE PREDICT 1 study (n = 1002 (NCT03479866)), 250 metabolites, mainly lipids, were measured by a Nightingale NMR panel in fasting and postprandial (4 and 6 h after a 3.7 MJ mixed nutrient meal, with a second 2.2 MJ mixed nutrient meal at 4 h) serum samples. For each metabolite, inter- and intra-individual variability over time was evaluated using linear mixed modelling and intraclass correlation coefficients (ICC) were calculated. RESULTS: Postprandially, 85% (of 250 metabolites) significantly changed from fasting at 6 h (47% increased, 53% decreased; Kruskal-Wallis), with 37 measures increasing by >25% and 14 increasing by >50%. The largest changes were observed in very large lipoprotein particles and ketone bodies. Seventy-one percent of circulating metabolites were strongly correlated (Spearman's rho >0.80) between fasting and postprandial timepoints, and 5% were weakly correlated (rho <0.50). The median ICC of the 250 metabolites was 0.91 (range 0.08-0.99). The lowest ICCs (ICC <0.40, 4% of measures) were found for glucose, pyruvate, ketone bodies (ß-hydroxybutyrate, acetoacetate, acetate) and lactate. CONCLUSIONS: In this large-scale postprandial metabolomic study, circulating metabolites were highly variable between individuals following sequential mixed meals. Findings suggest that a meal challenge may yield postprandial responses divergent from fasting measures, specifically for glycolysis, essential amino acid, ketone body and lipoprotein size metabolites.

Higher Plasma Levels of Valerate Produced by Gut Microbiota May Have a Beneficial Impact on Renal Function.

OBJECTIVE: Observational studies have evaluated the relationships among plasma short chain fatty acids (SCFA) produced by gut microbiota, renal function, and risk of chronic kidney disease (CKD). In the present study, Mendelian Randomization (MR) analysis was applied to obtain unconfounded estimates of the casual association of genetically determined plasma valerate (an SCFA) with kidney function and risk of CKD. METHOD: MR was performed by using summary-level data from the largest genome-wide association studies (GWAS) conducted on plasma valerate, CKD, and estimated glomerular filtration rate (eGFR; separately in diabetic and nondiabetic individuals). Inverse variance weighted method (IVW), weighted median-based method, MR-Egger, as well as MR-Pleiotropy RESidual Sum and Outlier (PRESSO) were applied. Sensitivity analysis was conducted using the leave-one-out method. RESULTS: No significant association was observed between plasma valerate and CKD (IVW: ß = 0.234, p = 0.744). In contrast, plasma valerate was positively associated with eGFR in the total population (IVW: ß = 0.049, p = 0.022) and among nondiabetic individuals (IVW: ß = 0.058, p = 0.009), but not in the diabetic population (IVW: ß = -0.052, p = 0.603). None of the estimated associations was subjected to significant level of heterogeneity. Furthermore, MR-PRESSO analysis did not show any chance of outlier for all estimates. The pleiotropy test, with very a negligible intercept and insignificant p value, also indicated no chance of pleiotropy for all of our estimations (all p > 0.539). The results of the MR-Robust Adjusted Profile Score were identical with the IVW estimates, highlighting again no possibility of pleiotropy. Results of the leave-one-out method demonstrated that the links were not driven by single-nucleotide polymorphisms. CONCLUSIONS: Individuals with higher plasma valerate levels had better renal function, defined by eGFR. This finding was observed in the total population and in nondiabetic subjects, but not in those with diabetes. Further research is needed to elucidate the links among plasma valerate, kidney function, and CKD.

Plasma Trans Fatty Acids Concentrations Are Inversely Related to Bone Mineral Density and This Appears to Be Independent of Inflammation.

OBJECTIVE: To investigate the association between plasma trans fatty acids (TFAs) and bone mineral density (BMD) and risk of fracture among US adults. Furthermore, we have evaluated the impact of inflammation on this relationship. METHODS: Participants (the National Health and Nutrition Examination Survey) with measured data on BMD and TFAs were included. TFAs were measured by gas chromatography-mass spectrometry and BMD was measured using dual-energy x-ray absorptiometry densitometers. RESULTS: Of the 4022 eligible participants, 48.1% were men. The mean age of the population sample was 44.6 years. In the model adjusted for age, sex, race, education, income, physical activity, smoking, fasting blood glucose, systolic and diastolic blood pressure, body mass index, diabetes, and hypertension, across the increasing quartiles (Q) of individual plasma TFAs, BMD decreased for most of the sites measure: for example, Q1 vs. Q4 1.04 vs. 0.095 g/cm2 for palmitelaidic acid and 1.11 vs. 0.099 g/cm2 for elaidic acid (all p < 0.001). In models using the same adjustment, linear regression displayed a significant negative association between plasma TFAs and BMD for most of the sites measured (all p < 0.001). Moderation analysis revealed that inflammation [assessed as a serum C-reactive protein (CRP)] was not significantly implicated in the relationship between BMD and TFAs. There was no significant difference in percentage of fractures (hip, spine, wrist) observed across quartiles of plasma TFAs (all p > 0.125). CONCLUSIONS: Our findings highlight, for the first time, the potentially detrimental impact of plasma TFAs on bone health that does not appear to be moderated through inflammation.

Effects of whey and soy protein supplementation on inflammatory cytokines in older adults: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Low-grade inflammation is a mediator of muscle proteostasis. This study aimed to investigate the effects of isolated whey and soy proteins on inflammatory markers. METHODS: We conducted a systematic literature search of randomised controlled trials (RCT) through MEDLINE, Web of Science, Scopus and Cochrane Library databases from inception until September 2021. To determine the effectiveness of isolated proteins on circulating levels of C-reactive protein (CRP), IL-6 and TNF-α, a meta-analysis using a random-effects model was used to calculate the pooled effects (CRD42021252603). RESULTS: Thirty-one RCT met the inclusion criteria and were included in the systematic review and meta-analysis. A significant reduction of circulating IL-6 levels following whey protein [Mean Difference (MD): -0·79, 95 % CI: -1·15, -0·42, I2 = 96 %] and TNF-α levels following soy protein supplementation (MD: -0·16, 95 % CI: -0·26, -0·05, I2 = 68 %) was observed. The addition of soy isoflavones exerted a further decline in circulating TNF-α levels (MD: -0·20, 95 % CI: -0·31, -0·08, I2 = 34 %). According to subgroup analysis, whey protein led to a statistically significant decrease in circulating IL-6 levels in individuals with sarcopenia and pre-frailty (MD: -0·98, 95 % CI: -1·56, -0·39, I2 = 0 %). These findings may be dependent on participant characteristics and treatment duration. CONCLUSIONS: These data support that whey and soy protein supplementation elicit anti-inflammatory effects by reducing circulating IL-6 and TNF-α levels, respectively. This effect may be enhanced by soy isoflavones and may be more prominent in individuals with sarcopenia.

The link between serum 25-hydroxyvitamin D, inflammation and glucose/insulin homoeostasis is mediated by adiposity factors in American adults.

We used an established mediation analysis to investigate the role of adiposity in the relation between serum 25(OH)D with markers of inflammation and glucose and insulin metabolism. We used data from National Health and Nutrition Examination Survey (2005-2010), to evaluate the associations between serum 25(OH)D and markers of insulin resistance (IR) or inflammation, and whether these associations are mediated by adiposity factors. Analysis of co-variance and conceptual causal mediation analysis were conducted taking into consideration the survey design and sample weights. BMI was found to have significant mediation effects (to varied extent) on the associations between serum 25(OH)D and CRP, apo-B, fasting glucose, insulin, HOMA-IR, HOMA-B and HbA1c (all P < 0·05). Both WC and apVAT were also found to partly mediate the associations between serum 25 25(OH)D with CRP, FBG, HbA1c, TAG and HDL-cholesterol (all P < 0·05). These findings support the importance of optimising 25(OH)D status in conditions with abnormal adiposity (i.e. obesity) and treatments for the prevention of cardiometabolic diseases affecting adipose tissue metabolism (i.e. weight loss).

Dietary habits are associated with the prevalence of type 2 diabetes: a study among a middle eastern population.

Worldwide type 2 diabetes (T2D) prevalence is increasing dramatically. The present study aimed to evaluate the association between dietary habits and T2D in an Iranian adult population using a cross-sectional analysis of the Shahedieh cohort study. Participants were adults aged 35-70 years (n 9261) from Zarch and Shahedieh, Yazd, Iran, who attended the baseline phase of the Shahedieh cohort study. Dietary habits including meal frequency, fried-food consumption, adding salt to prepared meals and grilled-food consumption were assessed by a standard questionnaire. T2D was defined as fasting plasma glucose (FPG) ≥126 mg/dl according to the American Diabetes Association. Multiple logistic regression assessed the association between dietary habits and T2D. Individuals who consumed a meal more than six times per day compared to three times per day had greater odds for T2D (OR 2⋅503, 95 % CI 1⋅651, 3⋅793). These associations remained significant in a fully adjusted model. There was a significant association between greater intakes of fried foods and prevalence of T2D (OR 1⋅294, 95 % CI 1⋅004, 1⋅668) in the adjusted model. No significant associations were observed between other dietary habits (adding salt to prepared meals and grilled-food consumption) and odds of T2D in all crude and adjusted models. In conclusion, we have highlighted the association between meal and fried-food consumption frequencies with risk of T2D. Large longitudinal studies in different ethnicities are needed to confirm these associations.

The Effect of Dietary Carbohydrate and Fat Manipulation on the Metabolome and Markers of Glucose and Insulin Metabolism: A Randomised Parallel Trial.

High carbohydrate, lower fat (HCLF) diets are recommended to reduce cardiometabolic disease (CMD) but low carbohydrate high fat (LCHF) diets can be just as effective. The effect of LCHF on novel insulin resistance biomarkers and the metabolome has not been fully explored. The aim of this study was to investigate the impact of an ad libitum 8-week LCHF diet compared with a HCLF diet on CMD markers, the metabolome, and insulin resistance markers. n = 16 adults were randomly assigned to either LCHF (n = 8, <50 g CHO p/day) or HCLF diet (n = 8) for 8 weeks. At weeks 0, 4 and 8, participants provided fasted blood samples, measures of body composition, blood pressure and dietary intake. Samples were analysed for markers of cardiometabolic disease and underwent non-targeted metabolomic profiling. Both a LCHF and HCLF diet significantly (p < 0.01) improved fasting insulin, HOMA IR, rQUICKI and leptin/adiponectin ratio (p < 0.05) levels. Metabolomic profiling detected 3489 metabolites with 78 metabolites being differentially regulated, for example, an upregulation in lipid metabolites following the LCHF diet may indicate an increase in lipid transport and oxidation, improving insulin sensitivity. In conclusion, both diets may reduce type 2 diabetes risk albeit, a LCHF diet may enhance insulin sensitivity by increasing lipid oxidation.

The association between dietary insulin index and load with mental health.

BACKGROUND: Depression, anxiety, and stress are common mental problems. The aim of this cross-sectional study was to investigate the association between two indexes that measure postprandial insulin response to different food, dietary insulin index (DII) and insulin load (DIL), with psychological disorders. METHOD: Participants (n = 10,000) aged 20-69 were randomly selected from 200 clusters in Yazd from the recruitment phase of the Yazd Health Study. The dietary intake of participants was collected by a reliable and validated food frequency questionnaire (FFQ) consisting of 178 food items. DII and DIL were calculated from the FFQ data using previously published reference values. To assess psychological disorders an Iranian validated short version of a self-reported questionnaire (Depression Anxiety Stress Scales 21 [DASS21]) was used. RESULTS: No significant association was observed between DIL and DII with odds of depression or anxiety using crude or adjusted models. However, individuals in the highest quartiles of DIL had the lowest odds of stress (OR: 0.69; 95% CI 0.48-1.01, P-trend = 0.047). This association remained significant after adjustment for potential confounders in model II including marital status, smoking, education, job status, salt intake, and multi-vitamin supplement use (OR: 0.38; 95% CI 0.16-0.91, P-trend = 0.039) and the third and final model which is further adjusted for BMI (OR: 0.39; 95% CI 0.16-0.91, P-trend = 0.041). CONCLUSION: Overall, consumption of foods with higher DII as well as DIL were associated with lower stress scores; however, no significant relationship was observed between DII or DIL with respective depression or anxiety scores.

Step-by-step diagnosis and management of the nocebo/drucebo effect in statin-associated muscle symptoms patients: a position paper from the International Lipid Expert Panel (ILEP).

Statin intolerance is a clinical syndrome whereby adverse effects (AEs) associated with statin therapy [most commonly statin-associated muscle symptoms (SAMS)] result in the discontinuation of therapy and consequently increase the risk of adverse cardiovascular outcomes. However, complete statin intolerance occurs in only a small minority of treated patients (estimated prevalence of only 3-5%). Many perceived AEs are misattributed (e.g. physical musculoskeletal injury and inflammatory myopathies), and subjective symptoms occur as a result of the fact that patients expect them to do so when taking medicines (the nocebo/drucebo effect)-what might be truth even for over 50% of all patients with muscle weakness/pain. Clear guidance is necessary to enable the optimal management of plasma in real-world clinical practice in patients who experience subjective AEs. In this Position Paper of the International Lipid Expert Panel (ILEP), we present a step-by-step patient-centred approach to the identification and management of SAMS with a particular focus on strategies to prevent and manage the nocebo/drucebo effect and to improve long-term compliance with lipid-lowering therapy.