Long-term effects of an egg-protein hydrolysate on cognitive performance and brain vascular function: a double-blind randomized controlled trial in adults with elevated subjective cognitive failures.

PURPOSE: Short-term intake of the egg-protein hydrolysate Newtricious (NWT)-03 improved executive function, but underlying mechanisms and long-term effects, including other cognitive domains, are unknown. METHODS: A 36-week randomized controlled trial involving 44 overweight/obese individuals experiencing elevated Subjective Cognitive Failures (SCF; aged 60-75 years) assessed the impact of daily consumption of 5.7 g of NWT-03 or placebo powders on cognitive performance (psychomotor speed, executive function, memory) and Cerebral Blood Flow (CBF), a marker of brain vascular function. Cognitive performance was evaluated using a neurophysiological test battery (CANTAB) and CBF was measured using magnetic resonance imaging perfusion method Arterial Spin Labeling (ASL). Serum samples were collected to determine brain-derived neurotrophic factor (BDNF) concentrations. RESULTS: Anthropometrics, and energy and nutrient intakes remained stable throughout the trial. NWT-03 was well tolerated, and compliance was excellent (median: 99%; range: 87-103%). No overall intervention effects were observed on cognitive performance or CBF, but post-hoc analyses revealed significant improvements on executive function in women, but not men. Specifically, a reduction of 74 ms in reaction latency on the multitasking task (95% CI: -134 to -15; p = 0.02), a reduction of 9 between errors (95%CI: -14 to -3; p < 0.001), and a reduction of 9 total errors (95%CI: -15 to -3; p < 0.001) on the spatial working memory task were found in women. No intervention effects were observed on serum BDNF concentrations (p = 0.31). CONCLUSION: Long-term consumption of NWT-03 improved multitasking abilities and working memory in women with elevated SCF. Brain vascular function remained unaffected. Sex differences in executive function require additional clarification.

Short-term Aronia melanocarpa extract supplementation improves cognitive performance: a randomized, double-blind, placebo-controlled cross-over study in healthy young adults.

PURPOSE: Evidence on the potential beneficial effects of anthocyanin-rich foods and supplements on cognitive performance is mainly based on acute or long-term studies in older adults. However, short-term studies focusing on a younger population are lacking. Therefore, short-term effects of Aronia melanocarpa extract (AME) supplementation on cognitive performance were investigated in healthy young adults. Potential underlying mechanisms were also addressed. METHODS: A randomized, double-blind, placebo-controlled cross-over study was performed involving 35 apparently healthy young adults. Participants consumed AME (180 mg anthocyanins/day) or a placebo for 1 week, separated by at least 2 weeks of wash-out. Cognitive performance was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Furthermore, arterial stiffness (carotid-to-femoral pulse wave velocity), retinal microvascular calibers (fundus photography), and serum brain-derived neurotrophic factor (BDNF) concentrations were measured at baseline and after 1 week. RESULTS: Participants had a mean age of 25 ± 4 years and an average BMI of 23.4 ± 2.7 kg/m2. Compliance was excellent and the study product was well-tolerated. As compared to placebo, movement time was significantly reduced by 4.8% within the five-choice reaction time test after 1 week of AME supplementation (intervention effect: - 12 ms; p < 0.05). Memory and executive function did however not change. Serum BDNF concentrations were significantly higher after AME supplementation as compared to placebo (+ 5.7%; intervention effect: 1.8 ng/mL; p < 0.05). However, arterial stiffness and retinal microvascular calibers were not affected. CONCLUSION: Short-term AME supplementation beneficially affected cognitive performance as attention and psychomotor speed improved. Serum BDNF concentrations were increased, but vascular function markers were not affected. CLINICAL TRIAL REGISTRATION: The study was registered on Clinical Trials under NCT03793777 on January 4th, 2019.

Effects of Intermittent Energy Restriction Compared with Those of Continuous Energy Restriction on Body Composition and Cardiometabolic Risk Markers - A Systematic Review and Meta-Analysis of Randomized Controlled Trials in Adults.

The interest in intermittent energy restriction (IER) diets as a weight-loss approach is increasing. Different IER protocols exist, including time-restricted eating (TRE), alternate-day fasting (ADF), and the 5:2 diet. This meta-analysis compared the effects of these IER diets with continuous energy restriction (CER) on anthropometrics and cardiometabolic risk markers in healthy adults. Twenty-eight trials were identified that studied TRE (k = 7), ADF (k = 10), or the 5:2 diet (k = 11) for 2-52 wk. Energy intakes between intervention groups within a study were comparable (17 trials), lower in IER (5 trials), or not reported (6 trials). Weighted mean differences (WMDs) were calculated using fixed- or random-effects models. Changes in body weight [WMD: -0.42 kg; 95% confidence interval (CI): -0.96 to 0.13; P = 0.132] and fat mass (FM) (WMD: -0.31 kg; 95% CI: -0.98 to 0.36; P = 0.362) were comparable when results of the 3 IER diets were combined and compared with those of CER. All IER diets combined reduced fat-free mass (WMD: -0.20 kg; 95% CI: -0.39 to -0.01; P = 0.044) and waist circumference (WMD: -0.91 cm; 95% CI: -1.76 to -0.06; P = 0.036) more than CER. Effects on body mass index [BMI (kg/m2)], glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), serum lipid and lipoprotein concentrations, and blood pressure did not differ. Further, TRE reduced body weight, FM, and fat-free mass more than CER, whereas ADF improved HOMA-IR more. BMI was reduced less in the 5:2 diet compared with CER. In conclusion, the 3 IER diets combined did not lead to superior improvements in anthropometrics and cardiometabolic risk markers compared with CER diets. Slightly greater reductions were, however, observed in fat-free mass and waist circumference. To what extent differences in energy intakes between groups within studies may have influenced these outcomes should be addressed in future studies.

Mixed nut consumption improves brain insulin sensitivity: a randomized, single-blinded, controlled, crossover trial in older adults with overweight or obesity.

BACKGROUND: Improving brain insulin sensitivity, which can be assessed by measuring regional cerebral blood flow (CBF) responses to intranasal insulin, may prevent age-related metabolic and cognitive diseases. OBJECTIVES: This study aimed to investigate longer-term effects of mixed nuts on brain insulin sensitivity in older individuals with overweight/obesity. METHODS: In a randomized, single-blinded, controlled, crossover trial, 28 healthy adults (mean ± standard deviation: 65 ± 3 years; body mass index: 27.9 ± 2.3 kg/m2) received either daily 60-g mixed nuts (15 g of walnuts, pistachio, cashew, and hazelnuts) or no nuts (control) for 16 weeks, separated by an 8-week washout period. Throughout the study, participants were instructed to adhere to the Dutch food-based dietary guidelines. During follow-up, brain insulin action was assessed by quantifying acute effects of intranasal insulin on regional CBF using arterial spin labeling magnetic resonance imaging. Furthermore, effects on peripheral insulin sensitivity (oral glucose tolerance test), intrahepatic lipids, and cardiometabolic risk markers were assessed. RESULTS: Body weight and composition did not change. Compared with control, mixed nut consumption improved regional brain insulin action in 5 clusters located in the left (difference in CBF responses to intranasal insulin: -4.5 ± 4.7 mL/100 g/min; P < 0.001; -4.6 ± 4.8 mL/100 g/min; P < 0.001; and -4.3 ± 3.6 mL/100 g/min; P = 0.007) and right occipital lobes (-4.3 ± 5.6 mL/100 g/min; and -3.9 ± 4.9 mL/100 g/min; P = 0.028). A fifth cluster was part of the left frontal lobe (-5.0 ± 4.6 mL/100 g/min; P < 0.001). Peripheral insulin sensitivity was not affected. Intrahepatic lipid content (-0.7%-point; 95% CI: -1.3%-point to -0.1%-point; P = 0.027), serum low-density lipoprotein cholesterol concentration (-0.24 mmol/L; 95% CI: -0.44 to -0.04 mmol/L; P = 0.019), and systolic blood pressure (-5 mm Hg; 95% CI: -8 to -1 mm Hg; P = 0.006) were lower after the mixed nut intervention. CONCLUSIONS: Longer-term mixed nut consumption affected insulin action in brain regions involved in the modulation of metabolic and cognitive processes in older adults with overweight/obesity. Intrahepatic lipid content and different cardiometabolic risk markers also improved, but peripheral insulin sensitivity was not affected. This trial was registered at clinicaltrials.gov as NCT04210869.

The tissue-specific metabolic effects of the PPARα agonist ciprofibrate in insulin-resistant male individuals: a double-blind, randomized, placebo-controlled crossover study.

OBJECTIVE: Insulin resistance is characterized by ectopic fat accumulation leading to cardiac diastolic dysfunction and nonalcoholic fatty liver disease. The objective of this study was to determine whether treatment with the peroxisome proliferator-activated receptor-α (PPARα) agonist ciprofibrate has direct effects on cardiac and hepatic metabolism and can improve insulin sensitivity and cardiac function in insulin-resistant volunteers. METHODS: Ten insulin-resistant male volunteers received 100 mg/d of ciprofibrate and placebo for 5 weeks in a randomized double-blind crossover study. Insulin-stimulated metabolic rate of glucose (MRgluc) was measured using dynamic 18 F-fluorodeoxyglucose-positron emission tomography (18 F-FDG-PET). Additionally, cardiac function, whole-body insulin sensitivity, intrahepatic lipid content, skeletal muscle gene expression, 24-hour blood pressure, and substrate metabolism were measured. RESULTS: Whole-body insulin sensitivity, energy metabolism, and body composition were unchanged after ciprofibrate treatment. Ciprofibrate treatment decreased insulin-stimulated hepatic MRgluc and increased hepatic lipid content. Myocardial net MRgluc tended to decrease after ciprofibrate treatment, but ciprofibrate treatment had no effect on cardiac function and cardiac energy status. In addition, no changes in PPAR-related gene expression in muscle were found. CONCLUSIONS: Ciprofibrate treatment increased hepatic lipid accumulation and lowered MRgluc, without affecting whole-body insulin sensitivity. Furthermore, parameters of cardiac function or cardiac energy status were not altered upon ciprofibrate treatment.

Longer-term effects of the egg-protein hydrolysate NWT-03 on arterial stiffness and cardiometabolic risk markers in adults with metabolic syndrome: a randomized, double-blind, placebo-controlled, crossover trial.

BACKGROUND: Short-term intake of egg-derived protein hydrolysates, such as NWT-03, suggest improvements in arterial stiffness and metabolic profiles, but longer-term trials are lacking. This study therefore examined the longer-term effects of NWT-03 on arterial stiffness and cardiometabolic markers in men and women with metabolic syndrome. METHODS: Seventy-six adults with metabolic syndrome (age 61 ± 10 years; BMI 31.7 ± 4.0 kg/m2) participated in a randomized, controlled, double-blind, cross-over trial with a 27-day intervention (5 g/day NWT-03) or placebo period, separated by two-to-eight weeks of washout. At the start and end of both periods, measurements were performed in the fasting state and 2 h following acute NWT-03 intake. Arterial stiffness was assessed by carotid-to-radial (PWVc-r), carotid-to-femoral pulse wave velocity (PWVc-f), and central augmentation index (CAIxHR75). Moreover, cardiometabolic markers were assessed. RESULTS: Compared with control, longer-term NWT-03 supplementation did not affect fasting PWVc-r (0.1 m/s; -0.2 to 0.3; P = 0.715) or PWVc-f (-0.2 m/s; -0.5 to 0.1; P = 0.216). Fasting pulse pressure (PP) was however reduced by 2 mmHg (95% CI: -4 to 0; P = 0.043), but other fasting cardiometabolic markers were not affected. No effects were observed following acute NWT-03 intake at baseline. However, acute intake of NWT-03 after the intervention significantly lowered CAIxHR75 (-1.3%-point; -2.6 to -0.1; P = 0.037) and diastolic BP (-2 mmHg; -3 to 0; P = 0.036), but other cardiometabolic markers did not change. CONCLUSION: Longer-term NWT-03 supplementation did not affect arterial stiffness, but modestly improved fasting PP in adults with metabolic syndrome. Acute intake of NWT-03 after the intervention also improved CAIxHR75 and diastolic BP. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov as NCT02561663.

Longer-term mixed nut consumption improves brain vascular function and memory: A randomized, controlled crossover trial in older adults.

BACKGROUND: Nut consumption may reduce age-related cognitive decline, but underlying mechanisms are unclear. OBJECTIVE: To investigate in older adults longer-term effects of mixed nut consumption on brain vascular function, which may underlie improvements in cognitive performance. METHODS: Twenty-eight healthy individuals (age [mean ± SD]: 65 ± 3 years; BMI: 27.9 ± 2.3 kg/m2) were included in a randomized, single-blinded, cross-over trial with a 16-week intervention (60 g/d mixed nuts: walnuts, pistachio, cashew, and hazelnuts) and control period (no nuts), separated by 8 weeks of washout. Participants followed the Dutch food-based dietary guidelines. At the end of each period, cerebral blood flow (CBF), a marker of brain vascular function, was quantified using arterial spin labeling magnetic resonance imaging. Effects on endothelial function, arterial stiffness, and the retinal microvasculature were also assessed. Cognitive performance was measured using the Cambridge Neuropsychological Test Automated Battery. RESULTS: Body weight remained stable during the study. As compared to the control period, the mixed nut intervention resulted in a higher regional CBF in the right frontal and parietal lobes (treatment effect: 5.0 ± 6.5 mL/100 g/min; P < 0.001), left frontal lobe (5.4 ± 7.1 mL/100 g/min; P < 0.001), and bilateral prefrontal cortex (5.6 ± 6.6 mL/100 g/min; P < 0.001). Carotid artery reactivity (0.7 PP; 95%CI: 0.2 to 1.2; P = 0.007), brachial flow-mediated vasodilation (1.6 PP; 95%CI: 1.0 to 2.2; P < 0.001) and retinal arteriolar calibers were higher (2 µm; 95%CI: 0 to 3; P = 0.037), and carotid-to-femoral pulse wave velocity lower (-0.6 m/s; 95%CI: -1.1 to -0.1; P = 0.032). Further, visuospatial memory (-4 errors [16%]; 95%CI: -8 to 0; P = 0.045) and verbal memory (+1 correct [16%]; 0 to 2; P = 0.035) improved, but executive function and psychomotor speed did not change. CONCLUSIONS: Longer-term mixed nut consumption as part of a healthy diet beneficially affected brain vascular function, which may relate to the observed beneficial effects on memory in older adults. Moreover, different characteristics of the peripheral vascular tree also improved.

Effect of ß2-agonist treatment on insulin-stimulated peripheral glucose disposal in healthy men in a randomised placebo-controlled trial.

ß2-agonist treatment improves skeletal muscle glucose uptake and whole-body glucose homeostasis in rodents, likely via mTORC2-mediated signalling. However, human data on this topic is virtually absent. We here investigate the effects of two-weeks treatment with the ß2-agonist clenbuterol (40 µg/day) on glucose control as well as energy- and substrate metabolism in healthy young men (age: 18-30 years, BMI: 20-25 kg/m2) in a randomised, placebo-controlled, double-blinded, cross-over study (ClinicalTrials.gov-identifier: NCT03800290). Randomisation occurred by controlled randomisation and the final allocation sequence was seven (period 1: clenbuterol, period 2: placebo) to four (period 1: placebo, period 2: clenbuterol). The primary and secondary outcome were peripheral insulin-stimulated glucose disposal and skeletal muscle GLUT4 translocation, respectively. Primary analyses were performed on eleven participants. No serious adverse events were reported. The study was performed at Maastricht University, Maastricht, The Netherlands, between August 2019 and April 2021. Clenbuterol treatment improved peripheral insulin-stimulated glucose disposal by 13% (46.6 ± 3.5 versus 41.2 ± 2.7 µmol/kg/min, p = 0.032), whereas skeletal muscle GLUT4 translocation assessed in overnight fasted muscle biopsies remained unaffected. These results highlight the potential of ß2-agonist treatment in improving skeletal muscle glucose uptake and underscore the therapeutic value of this pathway for the treatment of type 2 diabetes. However, given the well-known (cardiovascular) side-effects of systemic ß2-agonist treatment, further exploration on the underlying mechanisms is needed to identify viable therapeutic targets.

Effects of Intranasal Insulin Administration on Cerebral Blood Flow and Cognitive Performance in Adults: A Systematic Review of Randomized, Placebo-Controlled Intervention Studies.

INTRODUCTION: Brain insulin resistance is an important hallmark of age-related conditions, including type 2 diabetes (T2D) and dementia. This systematic review summarized effects of cerebral blood flow (CBF) responses to intranasal insulin to assess brain insulin sensitivity in healthy and diseased populations. We also explored relationships between changes in brain insulin sensitivity and cognitive performance. METHODS: A systemic literature search (PROSPERO: CRD42022309770) identified 58 randomized, placebo-controlled trials (RCTs) that investigated effects of intranasal insulin on (regional) CBF, cognitive performance, and systemic spill-over in adults. RESULTS: Acute intranasal insulin did not affect whole-brain CBF in healthy adults, but increased regional CBF of the inferior frontal gyrus, dorsal striatum, and insular cortex, and reduced CBF around the middle frontal gyrus and hypothalamus. Obese adults showed increased CBF responses following internasal insulin for the middle frontal gyrus but decreased CBF for hypothalamic and cortico-limbic regions. Furthermore, increased CBF responses were reported for the insular cortex in T2D patients and for occipital and thalamic regions in older adults. The spray also improved memory and executive function, but a causal relation with regional CBF still needs to be established. Finally, intranasal insulin resulted in only a small amount of systemic spill-over, which is unlikely to have an impact on the observed findings. CONCLUSIONS: Region-specific changes in CBF after intranasal insulin administration were affected by obesity, T2D, and normal aging, indicating altered brain insulin sensitivity. Future RCTs should investigate longer-term effects of intranasal insulin and explore potential associations between effects on CBF and cognitive performance.

Effects of Physical Exercise Training on Cerebral Blood Flow Measurements: A Systematic Review of Human Intervention Studies.

The aim of this systematic review was to examine the effects of physical exercise training on cerebral blood flow (CBF), which is a physiological marker of cerebrovascular function. Relationships between training-induced effects on CBF with changes in cognitive performance were also discussed. A systematic search was performed up to July 2022. Forty-five intervention studies with experimental, quasi-experimental, or pre-post designs were included. Sixteen studies (median duration: 14 weeks) investigated effects of physical exercise training on CBF markers using magnetic resonance imaging, 20 studies (median duration: 14 weeks) used transcranial Doppler ultrasound, and eight studies (median duration: 8 weeks) used near-infrared spectroscopy. Studies using magnetic resonance imaging observed consistent increases in CBF in the anterior cingulate cortex and hippocampus, but not in whole-brain CBF. Effects on resting CBF-measured with transcranial Doppler ultrasound and near-infrared spectroscopy-were variable, while middle cerebral artery blood flow velocity increased in some studies following exercise or hypercapnic stimuli. Interestingly, concomitant changes in physical fitness and regional CBF were observed, while a relation between training-induced effects on CBF and cognitive performance was evident. In conclusion, exercise training improved cerebrovascular function because regional CBF was changed. Studies are however still needed to establish whether exercise-induced improvements in CBF are sustained over longer periods of time and underlie the observed beneficial effects on cognitive performance.

Acute Effects of Inorganic Nitrate Intake on Brachial and Femoral Flow-Mediated Vasodilation, and on Carotid Artery Reactivity Responses: Results of a Randomized, Double-Blinded, Placebo-Controlled Cross-Over Study in Abdominally Obese Men.

Most trials on the effects of inorganic nitrate intake have focused on only one specific aspect of the endothelial cell response to a stimulus, thereby possibly missing other important effects. The aim of the present randomized, double-blinded, placebo-controlled cross-over study was therefore to investigate in eighteen healthy abdominally obese men (18-60 years, waist circumference ≥ 102 cm) acute effects of potassium nitrate on brachial and femoral flow-mediated vasodilation (FMD), and on carotid artery reactivity (CAR) to a cold pressure test. Participants received in random order a drink providing 10 mmol potassium nitrate (i.e., 625 mg of nitrate) or an iso-molar placebo drink with potassium chloride. Fasted and 4 h post-drink FMD and blood pressure measurements were performed. CAR responses were assessed at 4 h. Circulating nitrate plus nitrite concentration increased following nitrate intake (p = 0.003). Compared with placebo, potassium nitrate did not affect brachial (mean [95% confidence interval]: -0.2% [-2.5, 2.1], p = 0.86) and femoral FMD responses (-0.6% [-3.0; 1.7], p = 0.54). CAR responses were also not different (-0.8% [-2.5, 0.9], p = 0.32). Finally, changes in blood pressure and heart rate did not differ. No adverse events were observed. In conclusion, this trial did not provide evidence for effects of a single dose of inorganic nitrate on 4 h vascular endothelial function in abdominally obese men.

Aerobic exercise training improves not only brachial artery flow-mediated vasodilatation but also carotid artery reactivity: A randomized controlled, cross-over trial in older men.

It is well-known that aerobic exercise training beneficially affects endothelial function as measured by brachial artery flow-mediated vasodilation (FMD). This trial with older sedentary overweight and obese men, therefore, examined the effects of aerobic training on other non-invasive markers of the vasculature, which have been studied in less detail. Seventeen men (67 ± 2 years, BMI: 30.3 ± 2.8 kg/m2 ) participated in this controlled cross-over study. Study participants followed in random order a fully supervised, progressive, aerobic exercise training (three 50-min sessions each week at 70% maximal power) and a no-exercise control period for 8 weeks, separated by a 12-week wash-out period. At the end of each period, endothelial function was assessed by the carotid artery reactivity (CAR) response to a cold pressor test and FMD, and local carotid and regional aortic stiffness by the carotid-to-femoral pulse wave velocity (PWVc-f ). The retinal microvasculature, the serum lipid profile, 24-h ambulatory blood pressure, and 96-h continuous glucose concentrations were also determined. Aerobic training increased CAR from 1.78% to 4.01% (Δ2.23 percentage point [pp]; 95% CI: 0.58, 3.89 pp; p = 0.012) and FMD from 3.88% to 6.87% (Δ2.99 pp; 95% CI: 0.58, 5.41 pp; p = 0.019). The stiffness index ß0 increased by 1.1 (95% CI: 0.3, 1.9; p = 0.012), while PWVc-f did not change. Retinal arteriolar width increased by 4 µm (95% CI: 0, 7 µm; p = 0.041). Office blood pressure decreased, but ambulatory blood pressure, and serum lipid and continuous glucose concentrations did not change. Aerobic exercise training improved endothelial function and retinal arteriolar width in older sedentary overweight and obese men, which may reduce cardiovascular risk.

A randomized diet-induced weight-loss intervention reduces plasma complement C3: Possible implication for endothelial dysfunction.

OBJECTIVE: Complement C3 and other components of the alternative pathway are higher in individuals with obesity. Moreover, C3 has been identified as a risk factor for cardiovascular disease. This study investigated whether, and how, a weight-loss intervention reduced plasma C3, activated C3 (C3a), and factor D and explored potential biological effects of such a reduction. METHODS: The study measured plasma C3, C3a, and factor D by ELISA and measured visceral adipose tissue, subcutaneous adipose tissue, and intrahepatic lipid by magnetic resonance imaging in lean men (n = 25) and men with abdominal obesity (n = 52). The men with obesity were randomized to habitual diet or an 8-week dietary weight-loss intervention. RESULTS: The intervention significantly reduced C3 (-0.15 g/L [95% CI: -0.23 to -0.07]), but not C3a or factor D. The C3 reduction was mainly explained by reduction in visceral adipose tissue but not subcutaneous adipose tissue or intrahepatic lipid. This reduction in C3 explained a part of the weight-loss-induced improvement of markers of endothelial dysfunction, particularly the reduction in soluble endothelial selectin and soluble intercellular adhesion molecule. CONCLUSIONS: Diet-induced weight loss in men with abdominal obesity could be a way to lower plasma C3 and thereby improve endothelial dysfunction. C3 reduction may be part of the mechanism via which diet-induced weight loss could ameliorate the risk of cardiovascular disease in men with abdominal obesity.

Acute inorganic nitrate intake increases regional insulin action in the brain: Results of a double-blind, randomized, controlled cross-over trial with abdominally obese men.

AIMS: Improving brain insulin sensitivity may be a promising approach in the prevention and treatment of metabolic and cognitive diseases. Our aim was to investigate acute effects of inorganic nitrate on regional cerebral blood flow (CBF) responses to intranasal insulin in abdominally obese men. METHODS: Eighteen apparently healthy men, aged 18-60 years and with a waist circumference ≥ 102 cm, participated in a randomized, double-blind, placebo-controlled cross-over trial. The study consisted of two test days separated by at least one week. Men received in random order a drink providing 10 mmol (i.e., 625 mg nitrate) potassium nitrate or an isomolar placebo drink with potassium chloride. Brain insulin action was assessed 120-150 min after the drinks by quantifying acute effects of nasal insulin on regional CBF using arterial spin labeling Magnetic Resonance Imaging. Glucose and insulin concentrations were measured at regular intervals, while blood pressure was determined fasted and at 240 min. RESULTS: Inorganic nitrate intake increased regional insulin action in five brain clusters. The two largest clusters were located in the right temporal lobe (ΔCBF: 7.0 ± 3.8 mL/100 g/min, volume: 5296 mm3, P < 0.001; and ΔCBF: 6.5 ± 4.3 mL/100 g/min, volume: 3592 mm3, P < 0.001), while two other cortical clusters were part of the right frontal (ΔCBF: 9.0 ± 6.0 mL/100 g/min, volume: 1096 mm3, P = 0.007) and the left parietal lobe (ΔCBF: 6.1 ± 4.3 mL/100 g/min, volume: 1024 mm3, P = 0.012). One subcortical cluster was located in the striatum (ΔCBF: 5.9 ± 3.2 mL/100 g/min, volume: 1792 mm3, P < 0.001). No effects of nitrate were observed on CBF before administration. Following nitrate intake, circulating nitrate plus nitrite concentrations increased over time (P = 0.003), but insulin and glucose concentrations and blood pressure did not change. CONCLUSION: Acute inorganic nitrate intake may improve regional brain insulin action in abdominally obese men. These regions are involved in the regulation of different metabolic and cognitive processes. The trial was registered on January 6th, 2021 at ClinicalTrials.gov as NCT04700241.

Effects of Diet-Induced Weight Loss on Plasma Markers for Cholesterol Absorption and Synthesis: Secondary Analysis of a Randomized Trial in Abdominally Obese Men.

Cross-sectional studies have shown that obesity is associated with lower intestinal cholesterol absorption and higher endogenous cholesterol synthesis. These metabolic characteristics have also been observed in patients with type 2 diabetes, metabolic syndrome, steatosis or cholestasis. The number of intervention studies evaluating the effect of weight loss on these metabolic characteristics is, however, limited, while the role of the different fat compartments has not been studied into detail. In a randomized trial, abdominally obese men (N = 54) followed a 6-week very low caloric (VLCD) diet, followed by a 2 week weight-maintenance period. Non-cholesterol sterols were measured at baseline and after 8 weeks, and compared to levels in lean participants (N = 25). After weight loss, total cholesterol (TC)-standardized cholestanol levels increased by 0.18 µmol/mmol (p < 0.001), while those of campesterol and lathosterol decreased by 0.25 µmol/mmol (p < 0.05) and 0.39 µmol/mmol (p < 0.001), respectively. Moreover, after weight loss, TC-standardized lathosterol and cholestanol levels were comparable to those of lean men. Increases in TC-standardized cholestanol after weight loss were significantly associated with changes in waist circumference (p < 0.01), weight (p < 0.001), BMI (p < 0.001) and visceral fat (p < 0.01), but not with subcutaneous and intrahepatic lipids. In addition, cross-sectional analysis showed that visceral fat fully mediated the association between BMI and TC-standardized cholestanol levels. Intrahepatic lipid content was a partial mediator for the association between BMI and TC-standardized lathosterol levels. In conclusion, diet-induced weight loss decreased cholesterol synthesis and increased cholesterol absorption. The increase in TC-standardized cholestanol levels was not only related to weight loss, but also to a decrease in visceral fat volume. Whether these metabolic changes ameliorate other metabolic risk factors needs further study.

Longer-term soy nut consumption improves vascular function and cardiometabolic risk markers in older adults: Results of a randomized, controlled cross-over trial.

BACKGROUND: Soy foods may contribute to the beneficial health effects of healthy plant-based diets on the risk to develop cardiovascular disease (CVD). However, their effects on vascular function have hardly been studied. OBJECTIVE: To investigate longer-term effects of soy nut consumption on vascular function and cardiometabolic risk markers in healthy older men and women. DESIGN: Twenty-three healthy participants (age: 60-70 years; BMI: 20-30 kg/m2) participated in a randomized, controlled, single-blinded cross-over trial with an intervention (67 g/day of soy nuts providing 25.5 g protein and 174 mg isoflavones) and control period (no nuts) of 16 weeks, separated by eight weeks wash-out. Adults followed the Dutch food-based dietary guidelines. RESULTS: No serious adverse events were reported and the soy nut regime was well tolerated. Body weights remained stable during the whole study. A higher protein (3.1 energy percent [En%]) and a lower carbohydrate intake (2.0 En%) was observed during the intervention period. Total fat intake was comparable, but that of saturated (-1.3 En%), cis-monounsaturated (-1.5 En%) and cis-polyunsaturated fatty acids (+1.9 En%) differed. Serum isoflavone concentrations were higher after the intervention as compared with the control period (daidzein: 127.8 ng/mL; 95% CI: 74.3-181.3 ng/mL; p < 0.001 and genistein: 454.2 ng/mL; 95% CI: 266.6-641.8 ng/mL; p < 0.001). Brachial artery flow-mediated vasodilation was 1.48 percent points (pp; 95% CI: 0.08-2.89 pp; p = 0.040) higher following soy nut intake. The carotid artery reactivity response and arterial stiffness did not differ. Serum LDL-cholesterol was lower (0.17 mmol/L; 95% CI: 0.02-0.32 mmol/L; p = 0.027), while HDL-cholesterol and triacylglycerol concentrations were comparable. Mean arterial pressure (MAP) was lower (3 mmHg; 95% CI: 0-6 mmHg; p = 0.035). CONCLUSIONS: Longer-term soy nut intake as part of a healthy diet improved endothelial function, LDL-cholesterol concentrations and MAP levels, suggesting mechanisms by which an increased soy food intake beneficially affects CVD risk in older adults. Registered under ClinicalTrials.gov Identifier no. NCT03627637.

Effects of Magnesium Citrate, Magnesium Oxide, and Magnesium Sulfate Supplementation on Arterial Stiffness: A Randomized, Double-Blind, Placebo-Controlled Intervention Trial.

Background Magnesium supplements may have beneficial effects on arterial stiffness. Yet, to our knowledge, no head-to-head comparison between various magnesium formulations in terms of effects on arterial stiffness has been performed. We assessed the effects of magnesium citrate supplementation on arterial stiffness and blood pressure and explored whether other formulations of magnesium have similar effects. Methods and Results In this randomized trial, subjects who were overweight and slightly obese received either magnesium citrate, magnesium oxide, magnesium sulfate, or placebo for 24 weeks. The total daily dose of magnesium was 450 mg/d. The primary outcome was carotid-to-femoral pulse wave velocity, which is the gold standard method for measuring arterial stiffness. Secondary outcomes included blood pressure and plasma and urine magnesium. Overall, 164 participants (mean±SD age, 63.2±6.8 years; 104 [63.4%] women) were included. In the intention-to-treat analysis, neither magnesium citrate nor the other formulations had an effect on carotid-to-femoral pulse wave velocity or blood pressure at 24 weeks compared with placebo. Magnesium citrate increased plasma (+0.04 mmol/L; 95% CI, +0.02 to +0.06 mmol/L) and urine magnesium (+3.12 mmol/24 h; 95% CI, +2.23 to +4.01 mmol/24 h) compared with placebo. Effects on plasma magnesium were similar among the magnesium supplementation groups, but magnesium citrate led to a more pronounced increase in 24-hour urinary magnesium excretion than magnesium oxide or magnesium sulfate. One serious adverse event was reported, which was considered unrelated to the study treatment. Conclusions Oral magnesium citrate supplementation for 24 weeks did not significantly change arterial stiffness or blood pressure. Magnesium oxide and magnesium sulfate had similar nonsignificant effects. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03632590.

Impact of Replacement of Individual Dietary SFAs on Circulating Lipids and Other Biomarkers of Cardiometabolic Health: A Systematic Review and Meta-Analysis of Randomized Controlled Trials in Humans.

Little is known of the impact of individual SFAs and their isoenergetic substitution with other SFAs or unsaturated fatty acids (UFAs) on the prevention of cardiometabolic disease (CMD). This systematic literature review assessed the impact of such dietary substitutions on a range of fasting CMD risk markers, including lipid profile, markers of glycemic control and inflammation, and metabolic hormone concentrations. Eligible randomized controlled trials (RCTs) investigated the effect of isoenergetic replacements of individual dietary SFAs for ≥14 d on ≥1 CMD risk markers in humans. Searches of the PubMed, Embase, Scopus, and Cochrane CENTRAL databases on 14 February, 2021 identified 44 RCTs conducted in participants with a mean ± SD age of 39.9 ± 15.2 y. Studies' risk of bias was assessed using the Cochrane Risk of Bias tool 2.0 for RCTs. Random-effect meta-analyses assessed the effect of ≥3 similar dietary substitutions on the same CMD risk marker. Other dietary interventions were described in qualitative syntheses. We observed reductions in LDL-cholesterol concentrations after the replacement of palmitic acid (16:0) with UFAs (-0.36 mmol/L; 95% CI: -0.50, -0.21 mmol/L; I2 = 96.0%, n = 18 RCTs) or oleic acid (18:1n-9) (-0.16 mmol/L; 95% CI: -0.28, -0.03 mmol/L; I2 = 89.6%, n = 9 RCTs), with a similar impact on total cholesterol and apoB concentrations. No effects on other CMD risk markers, including HDL-cholesterol, triacylglycerol, glucose, insulin, or C-reactive protein concentrations, were evident. Similarly, we found no evidence of a benefit from replacing dietary stearic acid (18:0) with UFAs on CMD risk markers (n = 4 RCTs). In conclusion, the impact of replacing dietary palmitic acid with UFAs on lipid biomarkers is aligned with current public health recommendations. However, owing to the high heterogeneity and limited studies, relations between all individual SFAs and biomarkers of cardiometabolic health need further confirmation from RCTs. This systematic review was registered at www.crd.york.ac.uk/prospero/ as CRD42020084241.

Effects of L-citrulline supplementation and watermelon consumption on longer-term and postprandial vascular function and cardiometabolic risk markers: A meta-analysis of randomized controlled trials in adults.

L-citrulline may improve non-invasive vascular function and cardiometabolic risk markers through increases in L-arginine bioavailability and nitric oxide synthesis. A meta-analysis of randomized controlled trials (RCTs) was performed to examine longer-term and postprandial effects of L-citrulline supplementation and watermelon consumption on these markers for cardiovascular disease in adults. Summary estimates of weighted mean differences (WMDs) in vascular function and cardiometabolic risk markers with accompanying 95% confidence intervals (CIs) were calculated using random or fixed-effect meta-analyses. Seventeen RCTs were included involving an L-citrulline intervention, of which six studied postprandial and twelve longer-term effects. Five studies investigated longer-term effects of watermelon consumption and five assessed effects during the postprandial phase. Longer-term L-citrulline supplementation improved brachial artery flow-mediated vasodilation (FMD) by 0.9 %-point (95 % CI: 0.7 to 1.1, P < 0.001). Longer-term watermelon consumption improved pulse wave velocity by 0.9 m/s (95% CI: 0.1 to 1.5, P < 0.001), while effects on FMD were not studied. No postprandial effects on vascular function markers were found. Postprandial glucose concentrations decreased by 0.6 mmol/L (95% CI: 0.4 to 0.7, P < 0.001) following watermelon consumption, but no other longer-term or postprandial effects were observed on cardiometabolic risk markers. To conclude, longer-term L-citrulline supplementation and watermelon consumption may improve vascular function, suggesting a potential mechanism by which increased L-citrulline intake beneficially affects cardiovascular health outcomes in adults. No effects on postprandial vascular function markers were found, while more research is needed to investigate effects of L-citrulline and watermelon on risk markers related to cardiometabolic health.

Longer-term soy nut consumption improves cerebral blood flow and psychomotor speed: results of a randomized, controlled crossover trial in older men and women.

BACKGROUND: Effects of soy foods on cerebral blood flow (CBF)-a marker of cerebrovascular function-may contribute to the beneficial effects of plant-based diets on cognitive performance. OBJECTIVES: We aimed to investigate longer-term effects of soy nut consumption on CBF in older adults. Changes in 3 different domains of cognitive performance were also studied. METHODS: Twenty-three healthy participants (age: 60-70 y; BMI: 20-30 kg/m2) participated in a randomized, controlled, single-blinded crossover trial with an intervention (67 g/d of soy nuts providing ∼25.5 g protein and 174 mg isoflavones) and control period (no nuts) of 16 wk, separated by an 8-wk washout period. Adults followed the Dutch food-based dietary guidelines. At the end of each period, CBF was assessed with arterial spin labeling MRI. Psychomotor speed, executive function, and memory were assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). RESULTS: No serious adverse events were reported, and soy nut intake was well tolerated. Body weights remained stable during the study. Serum isoflavone concentrations increased (daidzein mean difference ± SD: 128 ± 113 ng/mL, P < 0.001; genistein: 454 ± 256 ng/mL, P < 0.001), indicating excellent compliance. Regional CBF increased in 4 brain clusters located in the left occipital and temporal lobes (mean ± SD increase: 11.1 ± 12.4 mL · 100 g-1 · min-1, volume: 11,296 mm3, P < 0.001), bilateral occipital lobe (12.1 ± 15.0 mL · 100 g-1 · min-1, volume: 2632 mm3, P = 0.002), right occipital and parietal lobes (12.7 ± 14.3 mL · 100 g-1 · min-1, volume: 2280 mm3, P = 0.005), and left frontal lobe (12.4 ± 14.5 mL · 100 g-1 · min-1, volume: 2120 mm3, P = 0.009) which is part of the ventral network. These 4 regions are involved in psychomotor speed performance, which improved as the movement time reduced by (mean ± SD) 20 ± 37 ms (P = 0.005). Executive function and memory did not change. CONCLUSIONS: Longer-term soy nut consumption may improve cerebrovascular function of older adults, because regional CBF increased. Effects may underlie observed improvements in psychomotor speed.This trial was registered at clinicaltrials.gov as NCT03627637.