Omega-3 Blood Levels and Stroke Risk: A Pooled and Harmonized Analysis of 183 291 Participants From 29 Prospective Studies.

BACKGROUND: The effect of marine omega-3 PUFAs on risk of stroke remains unclear. METHODS: We investigated the associations between circulating and tissue omega-3 PUFA levels and incident stroke (total, ischemic, and hemorrhagic) in 29 international prospective cohorts. Each site conducted a de novo individual-level analysis using a prespecified analytical protocol with defined exposures, covariates, analytical methods, and outcomes; the harmonized data from the studies were then centrally pooled. Multivariable-adjusted HRs and 95% CIs across omega-3 PUFA quintiles were computed for each stroke outcome. RESULTS: Among 183 291 study participants, there were 10 561 total strokes, 8220 ischemic strokes, and 1142 hemorrhagic strokes recorded over a median of 14.3 years follow-up. For eicosapentaenoic acid, comparing quintile 5 (Q5, highest) with quintile 1 (Q1, lowest), total stroke incidence was 17% lower (HR, 0.83 [CI, 0.76-0.91]; P<0.0001), and ischemic stroke was 18% lower (HR, 0.82 [CI, 0.74-0.91]; P<0.0001). For docosahexaenoic acid, comparing Q5 with Q1, there was a 12% lower incidence of total stroke (HR, 0.88 [CI, 0.81-0.96]; P=0.0001) and a 14% lower incidence of ischemic stroke (HR, 0.86 [CI, 0.78-0.95]; P=0.0001). Neither eicosapentaenoic acid nor docosahexaenoic acid was associated with a risk for hemorrhagic stroke. These associations were not modified by either baseline history of AF or prevalent CVD. CONCLUSIONS: Higher omega-3 PUFA levels are associated with lower risks of total and ischemic stroke but have no association with hemorrhagic stroke.

Protein intake and type 2 diabetes mellitus: an umbrella review of systematic reviews for the evidence-based guideline for protein intake of the German Nutrition Society.

PURPOSE: Protein-rich foods show heterogeneous associations with the risk of type 2 diabetes (T2D) and it remains unclear whether habitual protein intake is related to T2D risk. We carried out an umbrella review of systematic reviews (SR) of randomised trials and/or cohort studies on protein intake in relation to risks of T2D. METHODS: Following a pre-specified protocol (PROSPERO: CRD42018082395), we retrieved SRs on protein intake and T2D risk published between July 1st 2009 and May 22nd 2022, and assessed the methodological quality and outcome-specific certainty of the evidence using a modified version of AMSTAR 2 and NutriGrade, respectively. The overall certainty of evidence was rated according to predefined criteria. RESULTS: Eight SRs were identified of which six contained meta-analyses. The majority of SRs on total protein intake had moderate or high methodological quality and moderate outcome-specific certainty of evidence according to NutriGrade, however, the latter was low for the majority of SRs on animal and plant protein. Six of the eight SRs reported risk increases with both total and animal protein. According to one SR, total protein intake in studies was ~ 21 energy percentage (%E) in the highest intake category and 15%E in the lowest intake category. Relative Risks comparing high versus low intake in most recent SRs ranged from 1.09 (two SRs, 95% CIs 1.02-1.15 and 1.06-1.13) to 1.11 (1.05-1.16) for total protein (between 8 and 12 cohort studies included) and from 1.13 (1.08-1.19) to 1.19 (two SRs, 1.11-1.28 and 1.11-1.28) (8-9 cohort studies) for animal protein. However, SRs on RCTs examining major glycaemic traits (HbA1c, fasting glucose, fasting insulin) do not support a clear biological link with T2D risk. For plant protein, some recent SRs pointed towards risk decreases and non-linear associations, however, the majority did not support an association with T2D risk. CONCLUSION: Higher total protein intake was possibly associated with higher T2D risk, while there is insufficient evidence for a risk increase with higher intakes of animal protein and a risk decrease with plant protein intake. Given that most SRs on plant protein did not indicate an association, there is possibly a lack of an effect.

Protein intake and body weight, fat mass and waist circumference: an umbrella review of systematic reviews for the evidence-based guideline on protein intake of the German Nutrition Society.

PURPOSE: This umbrella review aimed to assess whether dietary protein intake with regard to quantitative (higher vs. lower dietary protein intake) and qualitative considerations (total, plant-based or animal-based protein intake) affects body weight (BW), fat mass (FM) and waist circumference (WC). METHODS: A systematic literature search was conducted in PubMed, Embase and Cochrane Database of Systematic Reviews for systematic reviews (SRs) with and without meta-analyses of prospective studies published between 04 October 2007 and 04 January 2022. Methodological quality and outcome-specific certainty of evidence of the retrieved SRs were assessed by using AMSTAR 2 and NutriGrade, respectively, in order to rate the overall certainty of evidence using predefined criteria. RESULTS: Thirty-three SRs were included in this umbrella review; 29 were based on randomised controlled trials, a few included cohort studies. In studies without energy restriction, a high-protein diet did not modulate BW, FM and WC in adults in general (all "possible" evidence); for older adults, overall certainty of evidence was "insufficient" for all parameters. Under hypoenergetic diets, a high-protein diet mostly decreased BW and FM, but evidence was "insufficient" due to low methodological quality. Evidence regarding an influence of the protein type on BW, FM and WC was "insufficient". CONCLUSION: "Possible" evidence exists that the amount of protein does not affect BW, FM and WC in adults under isoenergetic conditions. Its impact on the reduction in BW and FM under hypoenergetic conditions remains unclear; evidence for an influence of protein type on BW, FM and WC is "insufficient".

Dietary protein and blood pressure: an umbrella review of systematic reviews and evaluation of the evidence.

INTRODUCTION: This umbrella review aimed to investigate the evidence of an effect of dietary intake of total protein, animal and plant protein on blood pressure (BP), and hypertension (PROSPERO: CRD42018082395). METHODS: PubMed, Embase and Cochrane Database were systematically searched for systematic reviews (SRs) of prospective studies with or without meta-analysis published between 05/2007 and 10/2022. The methodological quality and outcome-specific certainty of evidence were assessed by the AMSTAR 2 and NutriGrade tools, followed by an assessment of the overall certainty of evidence. SRs investigating specific protein sources are described in this review, but not included in the assessment of the overall certainty of evidence. RESULTS: Sixteen SRs were considered eligible for the umbrella review. Ten of the SRs investigated total protein intake, six animal protein, six plant protein and four animal vs. plant protein. The majority of the SRs reported no associations or effects of total, animal and plant protein on BP (all "possible" evidence), whereby the uncertainty regarding the effects on BP was particularly high for plant protein. Two SRs addressing milk-derived protein showed a reduction in BP; in contrast, SRs investigating soy protein found no effect on BP. The outcome-specific certainty of evidence of the SRs was mostly rated as low. DISCUSSION/CONCLUSION: This umbrella review showed uncertainties whether there are any effects on BP from the intake of total protein, or animal or plant proteins, specifically. Based on data from two SRs with milk protein, it cannot be excluded that certain types of protein could favourably influence BP.

Protein intake and cancer: an umbrella review of systematic reviews for the evidence-based guideline of the German Nutrition Society.

PURPOSE: It has been proposed that a higher habitual protein intake may increase cancer risk, possibly via upregulated insulin-like growth factor signalling. Since a systematic evaluation of human studies on protein intake and cancer risk based on a standardised assessment of systematic reviews (SRs) is lacking, we carried out an umbrella review of SRs on protein intake in relation to risks of different types of cancer. METHODS: Following a pre-specified protocol (PROSPERO: CRD42018082395), we retrieved SRs on protein intake and cancer risk published before January 22th 2024, and assessed the methodological quality and outcome-specific certainty of the evidence using a modified version of AMSTAR 2 and NutriGrade, respectively. The overall certainty of evidence was rated according to predefined criteria. RESULTS: Ten SRs were identified, of which eight included meta-analyses. Higher total protein intake was not associated with risks of breast, prostate, colorectal, ovarian, or pancreatic cancer incidence. The methodological quality of the included SRs ranged from critically low (kidney cancer), low (pancreatic, ovarian and prostate cancer) and moderate (breast and prostate cancer) to high (colorectal cancer). The outcome-specific certainty of the evidence underlying the reported findings on protein intake and cancer risk ranged from very low (pancreatic, ovarian and prostate cancer) to low (colorectal, ovarian, prostate, and breast cancer). Animal and plant protein intakes were not associated with cancer risks either at a low (breast and prostate cancer) or very low (pancreatic and prostate cancer) outcome-specific certainty of the evidence. Overall, the evidence for the lack of an association between protein intake and (i) colorectal cancer risk and (ii) breast cancer risk was rated as possible. By contrast, the evidence underlying the other reported results was rated as insufficient. CONCLUSION: The present findings suggest that higher total protein intake may not be associated with the risk of colorectal and breast cancer, while conclusions on protein intake in relation to risks of other types of cancer are restricted due to insufficient evidence.

Protein intake and bone health: an umbrella review of systematic reviews for the evidence-based guideline of the German Nutrition Society.

This umbrella review aimed at assessing whether a protein intake exceeding the current recommendation for younger (0.8 g/kg body weight [BW]/day) and older (1.0 g/kg BW/day) adults affects bone mineral density and fracture risk. Moreover, the effect of animal or plant protein was evaluated. A systematic literature search was conducted in PubMed, Embase, and Cochrane Database of Systematic Reviews for systematic reviews (SRs) with or without meta-analysis of prospective studies published between 11/2008 and 08/2021. Methodological quality, outcome-specific certainty of evidence, and overall certainty of evidence of the retrieved SRs were assessed using established tools and predefined criteria. Eleven SRs of randomized controlled trials (RCTs) and/or cohort studies were included. In SRs of cohort studies and RCTs, protein intake/kg BW/day ranged between 0.21-0.95 g (low intake) and > 1.24 g (high intake), respectively, and between 0.67-1.1 g (control groups) and 1.01-1.69 g (intervention groups), respectively. The vast majority of outcome-specific certainty of evidence was rated "low" or "very low." The overall certainty of evidence for an association (cohort studies) or effect (RCTs) of total, animal or plant protein intake on each of the investigated outcomes was rated "insufficient," with the exception of possible evidence for a reduced hip fracture risk by high vs. low protein intake. Since protein intakes in low/control and high/intervention groups were very heterogeneous and with low certainty of evidence, it remains unclear whether a dose above the current recommendation or type of protein intake (animal or plant protein) affects bone health overall. However, there is possible evidence for reduced hip fracture risk with high versus low protein intake.

Protein intake and risk of urolithiasis and kidney diseases: an umbrella review of systematic reviews for the evidence-based guideline of the German Nutrition Society.

PURPOSE: Changes in dietary protein intake metabolically affect kidney functions. However, knowledge on potential adverse consequences of long-term higher protein intake (HPI) for kidney health is lacking. To summarise and evaluate the available evidence for a relation between HPI and kidney diseases, an umbrella review of systematic reviews (SR) was conducted. METHODS: PubMed, Embase and Cochrane Database of SRs published until 12/2022 were searched for the respective SRs with and without meta-analyses (MA) of randomised controlled trials or cohort studies. For assessments of methodological quality and of outcome-specific certainty of evidence, a modified version of AMSTAR 2 and the NutriGrade scoring tool were used, respectively. The overall certainty of evidence was assessed according to predefined criteria. RESULTS: Six SRs with MA and three SRs without MA on various kidney-related outcomes were identified. Outcomes were chronic kidney disease, kidney stones and kidney function-related parameters: albuminuria, glomerular filtration rate, serum urea, urinary pH and urinary calcium excretion. Overall certainty of evidence was graded as 'possible' for stone risk not to be associated with HPI and albuminuria not to be elevated through HPI (above recommendations (> 0.8 g/kg body weight/day)) and graded as 'probable' or 'possible' for most other kidney function-related parameters to be physiologically increased with HPI. CONCLUSION: Changes of the assessed outcomes may have reflected mostly physiological (regulatory), but not pathometabolic responses to higher protein loads. For none of the outcomes, evidence was found that HPI does specifically trigger kidney stones or diseases. However, for potential recommendations long-term data, also over decades, are required.

A Specifically Tailored Multistrain Probiotic and Micronutrient Mixture Affects Nonalcoholic Fatty Liver Disease-Related Markers in Patients with Obesity after Mini Gastric Bypass Surgery.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is frequent among patients undergoing bariatric surgery. Beyond weight reduction, dietary supplements like micronutrients or probiotics that modify insulin resistance and lipotoxicity can be used to prevent or delay the progression of liver disease. OBJECTIVES: We evaluated the effect of a dietary approach with a specifically tailored multistrain probiotic and micronutrient mixture compared with a basic care micronutrient supplement on serum alanine aminotransferase (ALAT) in obese patients after mini gastric bypass (MGB) surgery. METHODS: This randomized, double-blind, controlled trial included 60 obese patients (age: 40 ± 10 y; BMI: 44 ± 3 kg/m²). Patients received a combination of specifically tailored multistrain probiotic powder and a specific micronutrient mixture (Pro+SM) or a control treatment consisting of a placebo and a basic care micronutrient mixture (Con+BM), with some micronutrients in lower doses than SM, for 12 wk after hospital discharge. Primary (serum ALAT) and secondary outcomes [serum aspartate aminotransferase (ASAT), fatty liver index, NAFLD fibrosis score, glucose metabolism, blood pressure (BP), heart rate] were assessed at week 0 and week 12. Data were analyzed using unpaired Student's t-tests or Mann-Whitney U tests to compare the changes due to each treatment to one another. RESULTS: A total of 48 patients were included in the analyses. Changes in serum ALAT concentrations did not differ between groups. Compared with Con+BM, Pro+SM improved serum ASAT (difference: -8.0 U/L, 95% CI: -17.0, -4.0; P = 0.043), NAFLD fibrosis score (difference: -0.39; 95% CI: -0.78, 0; P = 0.048), serum triglycerides (difference: -22.8 mg/dL; 95% CI: -45.6, -0.1; P = 0.049) and the visceral adiposity index (difference: -0.70; 95% CI: -1.31, -0.08; P = 0.027). CONCLUSION: Supplementation with a specifically tailored probiotic and micronutrient mixture improved NAFLD-related markers more than a basic micronutrient mixture in obese patients following MGB surgery. The trial was registered under clinicaltrials.gov as NCT03585413.

Influence of a proinflammatory state on postprandial outcomes in elderly subjects with a risk phenotype for cardiometabolic diseases.

PURPOSE: Low-grade inflammation in obesity is associated with insulin resistance and other metabolic disturbances. In response to high-energy meal intake, blood concentrations of inflammatory markers, glucose and insulin rise. The aim of this study was to examine whether a basal inflammatory state influences postprandial responses. METHODS: A randomized crossover trial was performed in 60 participants with a cardiometabolic risk phenotype (age 70 ± 5 years; BMI 30.9 ± 3.1 kg/m2). Each participant consumed three different iso-energetic meals (4300 kJ): a Western diet-like high-fat meal (WDHF), a Western diet-like high-carbohydrate meal (WDHC) and a Mediterranean diet-like meal (MED). Blood samples were collected when fasted and hourly for 5 h postprandially and analyzed for glucose, insulin, interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and endothelial adhesion molecules. Based on fasting serum C-reactive protein (CRP) concentrations, participants were assigned to a high inflammation (CRP ≥ 2.0 mg/L; n = 30) or low inflammation (CRP < 2.0 mg/L; n = 30) group, and postprandial outcomes were compared. RESULTS: Plasma IL-6, glucose and serum insulin increased after all meals, while IL-1ß and endothelial adhesion molecules were unchanged. The high inflammation group had higher fasting and postprandial IL-6 concentrations than the low inflammation group, although the IL-6 response slope was similar between groups. In response to the WDHC meal, participants in the high inflammation group experienced a higher glycaemic response than those in the low inflammation group. CONCLUSION: A basal proinflammatory state results in higher absolute fasting and postprandial IL-6 concentrations, but the increase in IL-6 relative to basal levels is not different between high and low inflammation groups. Elevated glycaemic response in the high inflammation group may be due to inflammation-induced short-term insulin resistance. The trial was registered at http://www.germanctr.de and http://www.drks.de under identifier DRKS00009861 (registration date, January 22, 2016).

Dietary protein intake and health-related outcomes: a methodological protocol for the evidence evaluation and the outline of an evidence to decision framework underlying the evidence-based guideline of the German Nutrition Society.

PURPOSE: The present work aimed to delineate (i) a revised protocol according to recent methodological developments in evidence generation, to (ii) describe its interpretation, the assessment of the overall certainty of evidence and to (iii) outline an Evidence to Decision framework for deriving an evidence-based guideline on quantitative and qualitative aspects of dietary protein intake. METHODS: A methodological protocol to systematically investigate the association between dietary protein intake and several health outcomes and for deriving dietary protein intake recommendations for the primary prevention of various non-communicable diseases in the general adult population was developed. RESULTS: The developed methodological protocol relies on umbrella reviews including systematic reviews with or without meta-analyses. Systematic literature searches in three databases will be performed for each health-related outcome. The methodological quality of all selected systematic reviews will be evaluated using a modified version of AMSTAR 2, and the outcome-specific certainty of evidence for systematic reviews with or without meta-analysis will be assessed with NutriGrade. The general outline of the Evidence to Decision framework foresees that recommendations in the derived guideline will be given based on the overall certainty of evidence as well as on additional criteria such as sustainability. CONCLUSION: The methodological protocol permits a systematic evaluation of published systematic reviews on dietary protein intake and its association with selected health-related outcomes. An Evidence to Decision framework will be the basis for the overall conclusions and the resulting recommendations for dietary protein intake.

Moderate Postmeal Walking Has No Beneficial Effects Over Resting on Postprandial Lipemia, Glycemia, Insulinemia, and Selected Oxidative and Inflammatory Parameters in Older Adults with a Cardiovascular Disease Risk Phenotype: A Randomized Crossover Trial.

BACKGROUND: Research suggests that postprandial events, as risk factors for cardiovascular diseases (CVDs), are influenced by meal composition and exercise. OBJECTIVES: We investigated the effect of walking versus rest on postprandial metabolic, inflammatory, and oxidative events following the consumption of test meals reflecting 2 different dietary patterns in older adults with an increased CVD risk. METHODS: A randomized crossover trial was conducted in 26 men and women (aged 70 ± 5 y; BMI 30.3 ± 2.3 kg/m2). Each adult participated in 4 treatments combining 1 of 2 iso-energetic (4300 kJ) meals [Western diet high-fat meal (WD): total fat, 59.4 g; saturated fatty acids, 32.0 g, dietary fiber, 4.2 g; or Mediterranean-type diet meal (MD): total fat, 40.1 g; saturated fatty acids, 5.1 g; dietary fiber, 14.5 g] with 30 min walking (4.6 ± 0.1 km/h) or rest. Primary (serum triglycerides) and secondary [serum nonesterified fatty acids (NEFAs); parameters of glucose metabolism, inflammation, endothelial activation, oxidation; blood pressure/heart rate] outcomes were measured at fasting and 1.5, 3.0, and 4.5 h postprandially. Data were analyzed by linear mixed models. RESULTS: Triglycerides were higher after the WD than after the MD [AUC in mmol/L × min: Western diet high-fat meal plus postprandial walking (WD-W), 218 ± 15.2; Western diet high-fat meal plus postprandial resting (WD-R), 207 ± 12.6; Mediterranean-type diet meal plus postprandial walking (MD-W), 139 ± 9.83; Mediterranean-type diet meal plus postprandial resting (MD-R), 149 ± 8.15; P  < 0.001]. No meal or activity effect was observed for NEFAs based on AUC data (WD-W, -43.5 ± 7.08; WD-R, -49.2 ± 6.94; MD-W, -48.0 ± 11.6; MD-R, -67.6 ± 7.58). Plasma glucose was higher after the MD than after the WD (WD-W, 222 ± 34.9; WD-R, 177 ± 32.8; MD-W, 314 ± 44.4; MD-R, 275 ± 57.8; P  < 0.001), as was serum insulin (AUC in nmol/L × min: WD-W, 82.0 ± 10.3; WD-R, 88.6 ± 12.8; MD-W, 129 ± 14.7; MD-R, 138 ± 20.5; P < 0.001). Plasma IL-6 was higher after walking than after resting (AUC in pg/mL × min: WD-W, 72.0 ± 34.0; WD-R, 14.3 ± 38.8; MD-W, 70.8 ± 39.4; MD-R, 5.60 ± 26.0; P < 0.05). Plasma vitamin C was higher after the MD than after the WD (P < 0.001) and after walking than after resting (P < 0.05; AUC in mg/L × min: WD-W, -305 ± 59.6; WD-R, -396 ± 84.0; MD-W, 113 ± 56.4; MD-R, -44.5 ± 48.1). We observed no meal or activity effects on parameters of oxidation and endothelial adhesion molecules. Our data revealed no significant meal × activity effects on all outcomes. CONCLUSIONS: In older adults with an increased CVD risk, the MD was associated with superior effects on several postprandial parameters (e.g., triglycerides), in comparison to the WD. Data revealed no relevant differences regarding the effects of postmeal walking and resting. None of the 4 treatments can be rated as superior regarding their acute effects on the shown postprandial metabolic, oxidative, and inflammatory parameters. The trial was registered at German Clinical Trials Register (DRKS; http://www.germanctr.de and http://www.drks.de) under identifier DRKS00012409.

Flavonoid intake from fruit and vegetables during adolescence is prospectively associated with a favourable risk factor profile for type 2 diabetes in early adulthood.

PURPOSE: Flavonoid consumption during adolescence could contribute to preventing adult onset of type 2 diabetes mellitus. We investigated the prospective association between habitual intake of flavonoids from fruit and vegetables (FlavFV) during adolescence and risk markers of type 2 diabetes in early adulthood. METHODS: This analysis included participants of the DONALD Study, who had provided a fasting blood sample in adulthood (18-39 years), data on FlavFV-intake during adolescence (females: 9-15 years, males: 10-16 years) and relevant covariates. Habitual FlavFV-intake was either estimated using repeated 3-day weighed dietary records (n = 268), or the validated biomarker hippuric acid (uHA)-excretion in repeated 24-h urine samples (n = 241). Multivariable linear regressions were performed to analyse the prospective associations of FlavFV or uHA with homeostasis model assessment insulin sensitivity (HOMA2-%S), hepatic steatosis index (HSI), fatty liver index (FLI) and a pro-inflammatory score. RESULTS: Higher FlavFV-intake was independently related to higher HOMA2-%S among females (Ptrend = 0.03), but not among males. Both FlavFV-intake and uHA-excretion were inversely associated with HSI (Ptrend < 0.0001 and Ptrend = 0.02, respectively) and the pro-inflammatory score (Ptrend = 0.02 and Ptrend = 0.008, respectively), but not with FLI. CONCLUSIONS: Our data indicate that flavonoid consumption from fruit and vegetables during adolescence is associated with a favourable risk factor profile for type 2 diabetes in early adulthood.

13C-Mixed Triglyceride Breath Test and Fecal Elastase as an Indirect Pancreatic Function Test in Cystic Fibrosis Infants.

BACKGROUND: The 'gold standard' test for the indirect determination of pancreatic function status in infants with cystic fibrosis (CF), the 72-hour fecal fat excretion test, is likely to become obsolete in the near future. Alternative indirect pancreatic function tests with sufficient sensitivity and specificity to determine pancreatic phenotype need further evaluation in CF infants. OBJECTIVE: Evaluation of the clinical utility of both the noninvasive, nonradioactive C-mixed triglyceride (MTG) breath test and fecal elastase-1 (FE1) in comparison with the 72-hour fecal fat assessment in infants with CF. METHODS: C-MTG breath test and the monoclonal and polyclonal FE1 assessment in stool was compared with the 72-hour fecal fat assessment in 24 infants with CF. Oral pancreatic enzyme substitution (PERT; if already commenced) was stopped before the tests. RESULTS: Sensitivity rates between 82% and 100% for CF patients with pancreatic insufficiency assessed by both the C-MTG breath test and the FE1 tests proved to be high and promising. The C-MTG breath test (31%-38%) as well as both FE1 tests assessed by the monoclonal (46%-54%) and the polyclonal (45%) ELISA kits, however, showed unacceptably low-sensitivity rates for the detection of pancreatic-sufficient CF patients in the present study. CONCLUSIONS: The C-MTG breath test with nondispersive infrared spectroscopy (NDIRS) technique, as well as both FE1 tests, are not alternatives to the fecal fat balance test for the evaluation of pancreatic function in CF infants during the first year of life.

Circulating metabolites and general cognitive ability and dementia: Evidence from 11 cohort studies.

INTRODUCTION: Identifying circulating metabolites that are associated with cognition and dementia may improve our understanding of the pathogenesis of dementia and provide crucial readouts for preventive and therapeutic interventions. METHODS: We studied 299 metabolites in relation to cognition (general cognitive ability) in two discovery cohorts (N total = 5658). Metabolites significantly associated with cognition after adjusting for multiple testing were replicated in four independent cohorts (N total = 6652), and the associations with dementia and Alzheimer's disease (N = 25,872) and lifestyle factors (N = 5168) were examined. RESULTS: We discovered and replicated 15 metabolites associated with cognition including subfractions of high-density lipoprotein, docosahexaenoic acid, ornithine, glutamine, and glycoprotein acetyls. These associations were independent of classical risk factors including high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, and apolipoprotein E (APOE) genotypes. Six of the cognition-associated metabolites were related to the risk of dementia and lifestyle factors. DISCUSSION: Circulating metabolites were consistently associated with cognition, dementia, and lifestyle factors, opening new avenues for prevention of cognitive decline and dementia.

Moderate Walking Enhances the Effects of an Energy-Restricted Diet on Fat Mass Loss and Serum Insulin in Overweight and Obese Adults in a 12-Week Randomized Controlled Trial.

BACKGROUND: Increased physical activity may be advantageous for weight loss. OBJECTIVE: We investigated the effects of an energy-restricted diet with and without moderate walking on body weight, body composition, resting energy expenditure (REE), and endocrine and cardiometabolic risk variables in overweight and obese participants. METHODS: A 12-wk, randomized, 2-arm, parallel, controlled, energy-restricted (500-800 kcal/d) dietary intervention study was conducted in 82 men and women [mean baseline characteristics: age, 39.4 y; weight, 99.3 kg; body mass index (in kg/m2), 31.9]. Participants were divided into 2 groups. One group received a hypoenergetic diet (DI) only (n = 44). The second group received the same DI and participated in a regular walking program of 2.5 h/wk (DI + walking; n = 38). RESULTS: After the 12-wk intervention, body weight was significantly decreased in the DI + walking group and the DI group (-8.8 compared with -7.0 kg, P = 0.064 for intergroup differences). The decrease in body weight was accompanied by a significant reduction in total fat mass, which was significantly more pronounced in the DI + walking group than in the DI group (-6.4 ± 3.1 compared with -4.8 ± 3.0 kg; P = 0.020). REE after 12 wk was not significantly different compared with the baseline REE. Diastolic blood pressure, mean arterial pressure, LDL cholesterol, and non-HDL cholesterol were similarly significantly improved by both interventions. In the DI + walking group, insulin and the homeostasis model assessment of insulin resistance index were also significantly reduced. Serum free triiodothyronine was significantly decreased and serum cortisol was significantly increased in both groups. CONCLUSIONS: Participation in a 12-wk weight-loss study resulted in significant reductions in body weight and fat mass and was associated with significant improvements in biomarkers for cardiovascular disease risk. Moderate weight loss was not accompanied by a reduction in REE. Additional moderate walking enhanced the effects of a DI on fat loss and serum insulin. This trial was registered at www.germanctr.de/ and http://apps.who.int/trialsearch/ as DRKS00006827.

Effects of the flavonol quercetin and α-linolenic acid on n-3 PUFA status in metabolically healthy men and women: a randomised, double-blinded, placebo-controlled, crossover trial.

Increased dietary intake and tissue status of the long-chain n-3 PUFA, EPA and DHA, is associated with cardiovascular benefits. Epidemiological and animal studies suggest that concomitant nutritive intake of flavonoids may increase the conversion of α-linolenic acid (ALA) to longer-chain n-3 fatty acids EPA and DHA. We investigated the effects of increased ALA intake on fatty acid composition of serum phospholipids and erythrocytes in metabolically healthy men and women and whether fatty acid profiles and ALA conversion were affected by regular quercetin intake or sex. Subjects (n 74) were randomised to receive at least 3·3 g/d ALA with either 190 mg/d quercetin (ALA+quercetin) or placebo (ALA+placebo) in a double-blinded, placebo-controlled, crossover trial with 8-week intervention periods separated by an 8-week washout period. A total of seven subjects dropped out for personal reasons. Data from the remaining sixty-seven subjects (thirty-four males and thirty-three females) were included in the analysis. Both interventions significantly increased serum phospholipid ALA (ALA+placebo: +69·3 %; ALA+quercetin: +55·8 %) and EPA (ALA+placebo: +37·3 %; ALA+quercetin: +25·5 %). ALA + quercetin slightly decreased DHA concentration by 9·3 %. Erythrocyte ALA and EPA significantly increased with both interventions, whereas DHA decreased. Fatty acid composition did not differ between sexes. We found no effect of quercetin. Intake of 3·6 g/d ALA over an 8-week period resulted in increased ALA and EPA, but not DHA, in serum phospholipids and erythrocytes. Neither quercetin supplementation nor sex affected the increment of ALA and relative proportions of n-3 PUFA in serum phospholipids and erythrocytes.

Acute intake of quercetin from onion skin extract does not influence postprandial blood pressure and endothelial function in overweight-to-obese adults with hypertension: a randomized, double-blind, placebo-controlled, crossover trial.

PURPOSE: To determine whether postprandial metabolic and vascular responses induced by a high-fat and high-carbohydrate meal are attenuated by ingestion of the flavonol quercetin. METHODS: Twenty-two overweight-to-obese hypertensive patients participated in a randomized, double-blind, controlled, crossover meal study. They consumed a test meal (challenge) rich in energy (4754 kJ), fat (61.6 g), saturated fatty acids (53 % of total fatty acids), and carbohydrates (113.3 g) with either placebo or 54 mg quercetin. Blood pressure, reactive hyperemia index (RHI), high-sensitive C-reactive protein (hs-CRP), soluble endothelial-derived adhesion molecules, parameters of lipid and glucose metabolism, and markers of antioxidant status were measured before the meal and at 2 and 4 h postprandially. RESULTS: Systolic and diastolic blood pressure increased significantly over time, but were not affected by treatment (placebo or quercetin). During both treatments, serum endothelin-1, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and plasma asymmetric dimethylarginine slightly decreased over time, whereas RHI increased. Serum triglycerides, total cholesterol, and insulin significantly increased, whereas HDL cholesterol and glucose significantly decreased over time, again with no effect of treatment. Plasma α-tocopherol significantly increased, and plasma Trolox equivalent antioxidative capacity decreased over time. Serum hs-CRP, plasma retinol, and ß-carotene did not significantly change during the trial. CONCLUSION: In hypertensive patients, a high-energy meal did not lead to postprandial impairment of vascular endothelial function. Postprandial metabolic responses induced by the challenge, such as lipemia and insulinemia, were not attenuated by the concomitant ingestion of quercetin. CLINICAL TRIAL: This trial was registered at www.germanctr.de/ and http://apps.who.int/trialsearch/ as DRKS00000555.

Higher plasma quercetin levels following oral administration of an onion skin extract compared with pure quercetin dihydrate in humans.

PURPOSE: To investigate the plasma kinetics of quercetin derived from hard capsules filled with onion skin extract powder or quercetin dihydrate in humans. METHODS: In a randomized, single-blind, diet-controlled crossover study, 12 healthy subjects (six men and six women) aged 21-33 years were administered a single oral supra-nutritional dose of approximately 163 mg quercetin derived from onion skin extract powder (containing 95.3 % of total flavonoids as quercetin aglycone) or quercetin dihydrate (134 mg quercetin aglycone equivalent). Blood samples were collected before and during a 24-h period after quercetin administration. The concentrations of quercetin and its two monomethylated derivatives, isorhamnetin (3'-O-methyl quercetin), and tamarixetin (4'-O-methyl quercetin), were measured using HPLC with fluorescence detection after plasma enzymatic treatment. RESULTS: The systemic availability, determined by comparing the plasma concentration-time curves of quercetin, was 4.8 times higher, and the maximum plasma concentration (C max) was 5.4 times higher after ingestion of the onion skin extract than after ingestion of pure quercetin dihydrate. By contrast, t max did not differ significantly between the two formulations. The C max values for isorhamnetin and tamarixetin were 3.8 and 4.4 times higher, respectively, after administration of onion skin extract than after pure quercetin dihydrate. The plasma kinetics of quercetin were not significantly different in men and women. CONCLUSION: Quercetin aglycone derived from onion skin extract powder is significantly more bioavailable than that from quercetin dihydrate powder filled hard capsules.

No effects of quercetin from onion skin extract on serum leptin and adiponectin concentrations in overweight-to-obese patients with (pre-)hypertension: a randomized double-blinded, placebo-controlled crossover trial.

PURPOSE: Chronic low-level systemic and adipose tissue inflammation has been identified as a major etiologic factor in many chronic diseases, including hypertension and cardiovascular diseases. Evidence from experimental studies suggests anti-inflammatory effects of dietary flavonols such as quercetin. METHODS: We investigated the effects of regular intake of quercetin on leptin, adiponectin, biomarkers of inflammation, glucose and insulin in overweight-to-obese patients with pre- and stage 1 hypertension. Another objective was to assess the safety of daily quercetin supplementation measured by parameters of liver and kidney function and of hematology. Subjects (n = 70) were randomized to receive a supra-nutritional dose of 162 mg/d quercetin or placebo in a double-blinded, placebo-controlled crossover trial with 6-week treatment periods separated by a 6-week washout period. Two subjects dropped out for personal reasons. Only data from the remaining 68 subjects were included in the analysis. RESULTS: Compared to placebo, quercetin did not significantly affect serum concentrations of leptin and adiponectin, HOMA-AD or the ratios of leptin/adiponectin and adiponectin/leptin. Neither quercetin nor placebo significantly changed serum C-reactive protein and plasma tumor necrosis factor alpha. Compared to placebo, quercetin did not significantly affect glucose, insulin, HOMA-IR, blood biomarkers of liver and renal function, hematology and serum electrolytes. CONCLUSION: A supra-nutritional dose of 162 mg/d quercetin from onion skin extract for 6 weeks is safe but without significant effects on parameters of systemic and adipose tissue inflammation as well as glucose and insulin in overweight-to-obese subjects with (pre-)hypertension. This trial was registered at www.germanctr.de/ and http://apps.who.int/trialsearch/ as DRKS00000555.

Nutrients other than carbohydrates: their effects on glucose homeostasis in humans.

Besides carbohydrates, other nutrients, such as dietary protein and amino acids; the supply of fat, vitamin D, and vitamin K; and sodium intake seem to affect glucose homeostasis. Although their effect is less pronounced than that of the amount and composition of carbohydrates, it seems reasonable to consider how nutrient intake habits may be modified to support an improved glucose homeostasis. For instance, taking into account the effect of some nutrients to lower blood glucose concentration on a day-by-day basis might support improvement of glucose homeostasis in the long run. On the other hand, lowering sodium intake too much, as recommended to avoid the development of hypertension, particularly in sodium-sensitive people, might lead to insulin resistance and thereby might risk increasing fasting as well as postprandial blood glucose concentrations. This review summarizes the state of our knowledge of how several nutrients other than carbohydrates, such as protein, fatty acids, vitamin D, vitamin K, magnesium, zinc, chromium, and sodium, affect blood glucose concentrations. Sufficient evidence exists to show that, in prospective studies based on randomized controlled trials, these selected nutrients affect blood glucose regulation. The review describes potential mechanisms leading to the observed effect. As much as is possible from the available data, the extent of the effect, is considered.