Abstract Impaired post-prandial skeletal muscle glucose uptake plays a pivotal role in the development of type 2 diabetes mellitus (T2DM), yet pharmacological strategies to enhance muscle glucose uptake are limited. Previous (pre)clinical research revealed that β2-adrenergic receptor (β2-AR) stimulation enhances glucose uptake, but its clinical relevance in individuals susceptible to developing T2DM is unknown. Here we determined in a double-blinded, placebo-controlled, crossover study (ClinicalTrials.gov-identifier: NCT04921306), the effects of a 4-week treatment with the β2-adrenergic agonist clenbuterol (40 μg/day) on insulin-stimulated glucose uptake in the quadriceps muscle (primary outcome) and brown adipose tissue (BAT) (secondary outcome) using 18F-FDG PET-MRI during a hyperinsulinemic-euglycemic clamp in individuals with overweight or obesity (age: 40-70 years, BMI: 25-35 kg/m2). A total of 14 participants were recruited and randomized. Insulin-stimulated glucose uptake tended to improve in vastus lateralis (15%, p = 0.072) and increased significantly in the hamstring (13%, p = 0.039) muscle, while BAT uptake (p = 0.720) remained unaffected. These findings suggest potential therapeutic benefits of β2-AR stimulation for improving muscle-specific glucose uptake in individuals with or at risk for developing diabetes.

INTRODUCTION:Nutritional ketosis may prevent age-related cognitive decline, but underlying mechanisms remain unclear. This study investigated acute ketone monoester (KME) supplementation on brain insulin responsiveness and cognitive performance in older men with overweight. METHODS:In a randomized, double-blind, placebo-controlled crossover trial, 18 men (age: 70.2 ± 3.5 years, BMI: 27.2 ± 1.5 kg/m2) consumed KME (395 mg/kg body weight) or a taste-matched placebo. Brain insulin responsiveness (primary outcome) was assessed using pseudo-continuous arterial spin labeling (pCASL)-MRI by measuring cerebral blood flow (CBF) responses to intranasal insulin. Cognitive performance (CANTAB, secondary outcome), resting CBF, cerebral perfusion, and cardiometabolic risk markers were also assessed. RESULTS:KME was well tolerated and rapidly induced nutritional ketosis (peak β-hydroxybutyrate: 2.9 ± 0.4 mmol/L; P < 0.001). Compared with placebo, KME lowered insulin-induced CBF responses in ten brain clusters (all P ≤ 0.05), including five frontal gyri, three parietal/occipital regions, and two subcortical clusters, a pattern opposite to that typically observed in adults with peripheral insulin resistance. KME modestly improved attention and psychomotor speed (reaction time: -9 ms; 95%CI: -18 to -1; P = 0.029), but did not affect memory or executive function. KME ingestion also lowered resting whole-brain CBF (-4.7 mL/100 g/min; 95%CI: -6.4 to -3.0; P < 0.001) and cerebral perfusion (middle cerebral artery velocity: -5.1 cm/s; 95%CI: -9.6 to -0.7; P = 0.028), and induced changes in cardiometabolic markers, including blood pressure, circulating insulin, and glucose. CONCLUSIONS:Acute nutritional ketosis differentially modulates brain insulin responsiveness, reflected by lower insulin-induced CBF responses in insulin-sensitive brain regions, and is accompanied by modest improvements in attention and psychomotor speed in older men with overweight.

Background Both physical inactivity and prolonged sedentary behaviour are risk factors for the development of cardiometabolic disease, yet the long-term benefits of reducing sedentary behaviour in addition to increasing physical activity remain unclear. This study investigated whether increasing physical activity combined with reducing sedentary behaviour additionally improves insulin sensitivity in sedentary and inactive adults, compared to increasing physical activity alone. Methods Sedentary, physically inactive adults (18–65 years) were randomised to an 8-week intervention of either increased physical activity alone (PA) or physical activity combined with reduced sedentary behaviour by installing sit-to-stand workstations (PA-SB) to evaluate the effect on insulin sensitivity. Body composition, anthropometrics, activity behaviour, cardiorespiratory fitness, blood pressure, vascular endothelial function, blood parameters and health-related questionnaires were also assessed before and after the intervention periods. Linear mixed-effects models were used to explore effects. Results Twenty-nine participants (18 female), aged 47.4 ± 12.3 years were included. Insulin sensitivity improved after the intervention, with significantly greater improvements in the PA group than in the PA-SB group group (-11948 [-23142 to -754] pmol/L*120min; group x time effect p = 0.038). Participants in both groups improved cardiorespiratory fitness, body composition and quality of life. Vascular endothelial function and blood pressure remained unchanged. Conclusions Guideline-based physical activity improved insulin sensitivity and induced favourable cardiometabolic adaptations in sedentary adults. Adding a sedentary behaviour reduction component did not result in additional improvements in insulin sensitivity or other cardiometabolic outcomes. More effective strategies to reduce prolonged sedentary behaviour in free-living settings should be explored in future research. Trial registration The study was registered at clinicaltrials.gov as NCT07363499.

Wild blueberries (Vaccinium angustifolium Ait.) are North American perennial plants rich in polyphenols, including flavonoids, beneficial to human health. This article provides a summary of the evidence and perspectives presented at an expert symposium that focused on wild blueberries and cardiometabolic health. Topics covered include historical perspectives, food matrix and bioavailability, clinical and translational evidence on blueberries and cardiometabolic health, mechanisms of action, the role of the gut microbiome, knowledge gaps, and future research. Overall, data support that acute and chronic wild blueberry consumption can favorably affect measures of cardiometabolic health and related health outcomes such as the gut microbiota and cognitive function. Mechanistically, data suggest wild blueberry polyphenols, particularly anthocyanins, mediate the cardiometabolic benefits of dietary blueberries by acting on multiple targets. However, the cardiometabolic health benefits of wild blueberry consumption are equivocal, and future research should aim to understand factors and mechanisms contributing to individual and subgroup responses. Future studies should also investigate comprehensive biomarkers of cardiometabolic health and explore standardized methodological and precision nutrition approaches. Finally, evaluation and confirmation of wild blueberry phytochemicals, dosing strategies and food matrix interactions are needed to strengthen clinical trial designs and extend dietary recommendations to broader public health benefits.

BACKGROUND AND OBJECTIVE:The genetic background of hypertriglyceridemia is complex. In this systematic review and meta-analysis, we determined genetic variants associated with fasting triglyceride (TG) and very-low-density lipoprotein-TG (VLDL-TG) concentrations in European adults. METHODS:We searched PubMed and the National Human Genome Research Institute-European Bioinformatics Institute (NHGRI-EBI) genome-wide association studies catalog for studies on genetic variants associated with fasting TG and VLDL-TG concentrations. We performed the meta-analysis on 23 variants from studies that met our criteria. A fixed-effects model was applied, with a random-effects model used when significant heterogeneity was detected. The Ensembl Variant Effect Predictor was used to annotate these variants. RESULTS:Overall, 157 studies were included, of which 130 were used for meta-analysis. Overall, 1837 variants were related to fasting TG and/or VLDL-TG (P ≤ 0.05). Our meta-analysis revealed 11 genetic variants associated with fasting TG: rs58542926 in the transmembrane 6 superfamily member 2 (TM6SF2) gene, rs738409 in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, rs7903146 in the transcription factor 7-like 2 (TCF7L2) gene, rs320 and rs328 in the lipoprotein lipase (LPL) gene, and rs1801282 in the peroxisome proliferator-activated receptor γ2 (PPARγ2) gene were associated with lower TG concentrations, while rs693 in the apolipoprotein-B (APOB) gene, rs5128 in the apolipoprotein-c3 (APOC3) gene, rs662799 in the apolipoprotein A-V (APOA5) gene, rs662 in the paraoxonase 1 (PON1) gene, and rs1800588 in the hepatic lipase C (LIPC) gene were associated with higher TG concentrations. Five of those (rs58542926, rs738409, rs320, rs328, and rs1801282) were predicted to be deleterious to the protein function. CONCLUSION:This study identified variants associated with fasting TG and/or VLDL-TG concentrations in European adults, which may help in identifying genetically susceptible individuals and strengthening the accuracy of genetic risk prediction for TG-related outcomes.

BACKGROUND:Previous almond intervention studies involving relatively healthy populations did not demonstrate improvements in cognitive performance. However, a long-term study with participants at risk of cognitive decline, such as those with prediabetes, may be necessary. Potential changes in cognitive performance could be related to changes in brain vascular function. METHODS:A randomized, single-blinded, controlled crossover trial including 43 overweight/obese men and women with prediabetes. Participants were assigned to a 5-month almond (50 g/day) intervention and a 5-month control period, separated by a 2-month washout. Cognitive performance (psychomotor speed, executive function and memory) was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) at the beginning and at the end of each period. Cerebral blood flow (CBF), a marker of brain vascular function, was measured using the non-invasive magnetic resonance imaging (MRI) perfusion method, pseudo-continuous Arterial Spin Labeling (pCASL) at the end of each study period. Data were analyzed using linear mixed models. RESULTS:Participants had a median age (interquartile range [IQR]) of 66 years (IQR: 59-69 years), and their median BMI was 28.3 kg/m2 (IQR: 26.7-33.1 kg/m2). Thirty-four prediabetic adults (22 men and 12 women) completed the study. No significant intervention effects were observed on any cognitive performance outcomes (n = 33). Compared to the control period, long-term almond consumption also had no significant impact on whole-brain or regional CBF (n = 26). CONCLUSION:In line with earlier observations in relatively healthy populations, long-term almond consumption (50 g/day) did not enhance cognitive performance in overweight/obese individuals with prediabetes. Moreover, brain vascular function was unaffected.

In vitro and animal studies have shown promising effects of collagen hydrolysate on blood pressure (BP), serum lipid profiles, and plasma concentrations of endothelial and inflammatory markers. Therefore, we evaluated in humans the effects of a porcine-derived collagen hydrolysates on office and ambulatory blood pressure (ABP) profiles, retinal microvascular calibers, serum lipids, markers for endothelial dysfunction and low-grade inflammation. Given a possible link between peripheral vascular and brain vascular function, effects on cognitive performance were also explored. Therefore, in this randomized, placebo-controlled parallel trial, 56 middle-aged and older adults with overweight/obesity consumed 10 g porcine-derived collagen hydrolysates or placebo (erythritol) daily for four weeks after a 2-week run-in period. Measurements were performed at the end of the run-in and intervention periods. Collagen hydrolysates consumption did not significantly affect office systolic BP (SBP) (-1 mmHg, 95% CI: -3, 2; p = 0.529), or diastolic BP (DBP) (-1 mmHg, 95% CI: -2, 1; p = 0.449), nor 24-hour SBP (0 mmHg, 95% CI: -4, 4; p = 0.884) or DBP (-2 mmHg, 95% CI: -5, 1; p = 0.195). No significant changes were observed in mean arterial pressure, pulse pressure, nocturnal BP dipping, retinal microvascular calibers, serum lipids, and markers for endothelial dysfunction and low-grade inflammation. Cognitive performance remained unaffected, except for an unexpected increase in movement reaction time (29 ms, 95% CI: 553; p = 0.019). In conclusion, four-week porcine-derived collagen hydrolysate supplementation did not improve cardiometabolic risk markers and cognitive performance in middle-aged and older adults with overweight or obesity. This clinical trial was registered in November 2021 at ClinicalTrials.gov as NCT05282641.

BACKGROUND:Interesterified (IE) fats rich in palmitic acid (16:0) and stearic acid (18:0) are widely used hard fats. Comparative effects of commercially relevant palmitic or stearic acid-rich IE fat blends on cardiometabolic disease (CMD) risk markers remain unclear. It was hypothesized that functionally matched palmitic and stearic acid-rich fats would have equivalent effects on plasma total:high-density lipoprotein (HDL) cholesterol ratio within a predefined equivalence margin of ±0.09. OBJECTIVES:This study aimed to compare the effects of diets enriched in palmitic or stearic acid, delivered as commercially relevant IE fats and incorporated at realistic levels of dietary intake, on plasma lipid concentrations and other CMD risk markers in healthy participants. METHODS:In a randomized, crossover trial at 2 centers, 51 healthy participants (aged 35-65 y) consumed diets with either palmitic acid-rich or stearic acid-rich IE fats (10% energy intake) for 6 wk per arm, with a 4-wk washout. IE fats were incorporated into muffins and margarine spreads. The primary outcome was total:HDL cholesterol ratio; secondary outcomes included HDL and low-density lipoprotein cholesterol and fasting and postprandial triacylglycerol, lipoproteins, apolipoproteins, insulin sensitivity, vascular endothelial function, inflammation markers, and fasting liver fat (via proton magnetic resonance spectroscopy, subgroup). Linear mixed models were used to assess intervention effects. RESULTS:Forty-seven participants (51% female, mean age 52 ± 8 y; body mass index 25.2 ± 2.8 kg/m2) completed the study. No significant differences were observed in total:HDL cholesterol ratio between interventions (stearic compared with palmitic mean difference: 0.05; 95% confidence interval [CI]: -0.08, 0.18). Interleukin-10 concentration decreased after consuming palmitic relative to stearic acid-rich IE fats (-0.14 ng/L; 95% CI: -0.23, -0.06 ng/L). No effects were observed on other outcomes. CONCLUSIONS:Commercially relevant palmitic acid-rich IE fats consumed at 10% energy for a 6-wk period do not adversely affect total:HDL cholesterol ratio or other CMD risk markers compared with stearic acid-rich fats. Long-term effects could not be determined from this trial. This trial was registered at clinicaltrials.gov as NCT04418102.

CONTEXT:Coffee contains various bioactive compounds, including chlorogenic acids (CGAs), caffeine, and hydroxyhydroquinone (HHQ), which may differently affect endothelial function. OBJECTIVE:This meta-analysis of randomized controlled trials (RCTs) examined both longer-term and acute effects of coffee-related bioactive components on endothelial function in adults, measured by brachial artery flow-mediated vasodilation (FMD), a validated marker of cardiovascular disease (CVD) risk. DATA SOURCES:A systematic literature search was conducted in Ovid Medline, Embase, Cochrane, and Web of Science up to July 2025. DATA EXTRACTION:Relevant data were extracted from 19 eligible RCTs. Fixed or random-effects meta-analyses were conducted to estimate weighted mean differences (WMDs) with 95% CIs. DATA ANALYSIS:Four RCTs investigating longer-term CGA intake (median dose: 300 mg/day) showed a significant increase in fasting FMD of 2.52 percentage points (PP; 95% CI: 1.19, 3.85, P < .001; I2 = 0.0%). Ten RCTs evaluating acute CGA intake also reported a significant FMD increase of 1.51 PP (95% CI: 0.91, 2.96; P < .001; I2 = 68.0%). These effects were more pronounced for studies using CGA-rich coffee beverages compared with those using isolated CGA supplements (ΔWMD: 1.41 PP; 95% CI: 0.27, 2.55; P = .016). Caffeine showed no significant effect on FMD across 6 acute studies (WMD: -0.05 PP; 95% CI: -2.78, 2.68, P = .971; I2 = 95.3%), while FMD was significantly reduced by 1.04 PP (95% CI: 0.20, 1.88; P = .015; I2 = 0.0%) in the 2 acute studies that examined HHQ. CONCLUSIONS:This meta-analysis provides evidence that both longer-term and acute CGA intake significantly improve endothelial function, especially when consumed as part of coffee beverages. These findings support the potential role of moderate coffee consumption in reducing CVD risk.

PURPOSE OF REVIEW:As global life expectancy increases, age-related neurodegenerative conditions such as dementia impose an increasing public health and socioeconomic burden. Maintaining a healthy lifestyle, particularly through a healthy diet, may reduce cognitive decline and support cognitive performance in aging populations. Despite increasing interest in dietary interventions as a strategy to enhance cognitive performance, research findings remain inconclusive. This narrative review aims to synthesize evidence on the longer-term effects (published February 2023-October 2024) and underlying mechanisms of dietary intervention strategies on cognitive performance in adults with preexisting cognitive impairment. RECENT FINDINGS:Recent evidence from randomized controlled trials suggests that both single- and multifactor dietary interventions may improve one or more cognitive domains in aging adults with preexisting cognitive impairment. However, variability in intervention types, durations, and participant characteristics limits the ability to draw definitive conclusions. SUMMARY:This review highlights the potential benefits of longer-term dietary interventions on cognitive performance in adults with cognitive impairment. It further integrates emerging mechanistic insights, suggesting that specific dietary components may exert neuroprotective effects primarily by reducing oxidative stress and neuroinflammation, and by enhancing brain vascular function. These mechanisms may promote neuroplasticity through the modulation of neurotrophic signaling pathways. Future research should focus on replicating these findings to validate their efficacy and the underlying mechanisms involved. This is essential for integrating dietary approaches into evidence-based guidelines for promoting long-term cognitive health.

The aim of this study was to investigate the long-term effects of almond consumption on peripheral vascular function, ambulant blood pressure profiles (ABP), and serum/plasma markers reflecting endothelial dysfunction and inflammation in participants with overweight/obesity and prediabetes. Thirty-four participants completed this single-blinded, randomized, cross-over trial with 5-month intervention and control periods, separated by a 2-month wash-out. During the intervention period, participants consumed 50 g of whole almonds daily. At the end of each intervention period, peripheral vascular function was assessed by measuring the carotid-to-femoral and carotid-to-radial pulse wave velocities (PWVc-f and PWVc-r, respectively) and retinal microvascular calibers. Serum/plasma concentrations of soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), interleukin-6 (IL-6), IL-8, tumor necrosis factor-alpha (TNFα), serum amyloid A protein (SAA) and high-sensitivity C-reactive protein (hs-CRP) and 24-hour ABP were also analyzed. Almond consumption did not significantly affect arterial stiffness (PWVc−f and PWVc−r), while central retinal venular equivalent (CRVE) was minimally increased by 2 μm (P = 0.019). Central retinal arteriolar equivalent (CRAE), the arteriolar-to-venular ratio (AVR), and endothelial and inflammatory serum/plasma markers showed no significant changes after almond consumption. Almond consumption reduced systolic blood pressure (SBP; -3 mmHg 24-hour P = 0.035, -4 mmHg daytime P = 0.046, and − 4 mmHg during nighttime P = 0.029), SBP variability during 24-hour, daytime, and nighttime (P = 0.005, P = 0.019, and P = 0.003, respectively), and diastolic blood pressure variability during nighttime (P ≤ 0.001). Almond consumption did not affect arterial stiffness, retinal microvasculature calibers, or serum and plasma markers for endothelial dysfunction and inflammation in participants with prediabetics, while BP and BP variability were improved. This clinical trial was registered in February 2018 as NCT03419702.

Changes in cerebral blood flow (CBF) - a marker of brain vascular function - may improve cognitive performance, and enhancing CBF through a healthy lifestyle could mitigate cognitive decline. Protein hydrolysates have shown potential to improve brain health. This systematic review analyzed randomized controlled trials on the effects of protein hydrolysates on cognitive performance and CBF in healthy adults and specific target populations. 4747 studies were identified, yielding 13 papers investigating cognitive performance, with four of those also evaluating CBF. Two egg-protein hydrolysates out of five studies on inhibitory control reported cognitive performance improvements. Three out of six studies from various protein sources observed enhancements in visuospatial memory. A link between CBF and cognitive performance was not observed. In conclusion, some studies have indicated that certain protein hydrolysates may benefit cognitive performance, but further research is needed to clarify contradictory findings and to identify beneficial bioactive peptides.

Background and Aims Dietary anthocyanins are recognized for their potential beneficial effects on cognitive performance. It remains unclear which mechanisms underlie these effects. This study aimed to investigate the effects of anthocyanin-rich Aronia Melanocarpa extract (AME) on (brain) vascular function and cognitive performance in adults at increased risk of cognitive impairment. Methods Thirty healthy older adults (age: 65 ± 6 years old) with overweight or obesity (BMI: 28.3 ± 2.7 kg/m2) were included in a randomized, double-blind, placebo-controlled cross-over study of 6 weeks (40 mg anthocyanins/day). At the end of each study period, cerebral blood flow (CBF), a marker of brain vascular function, was assessed using arterial spin labeling magnetic resonance imaging (ASL-MRI). Additionally, cognitive performance was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB), cerebral perfusion with transcranial Doppler ultrasound, and peripheral vascular function through endothelial function and retinal microvascular caliber measurements. Results AME supplementation did not affect CBF in predefined brain regions, but regional CBF decreased in one cluster located in the right insular cortex (treatment effect 4.4 ± 3.6 mL/100 g/min; p=0.004), compared to placebo. Furthermore, cognitive performance was improved on the spatial working memory test, reflecting the executive function domain as the between errors and total errors were reduced by 20% (-3; 95% CI: -5 to -1; p=0.006). Memory and psychomotor speed did not change, while cerebral perfusion and peripheral vascular function measurements were also not affected. Conclusions Six weeks of AME supplementation improved executive functioning in older adults with overweight or obesity. Although CBF decreased in the right insular cortex, the relevance remains unclear. CBF in predefined brain regions and other potential underlying mechanisms were not affected. Clinical Trial Registry This trial was registered at clinicaltrial.gov as NCT 05268133.

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. 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. 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

The dietary egg-protein hydrolysate Newtricious (NWT)-03 has previously demonstrated improvements in blood pressure and metabolic profiles. However, the long-term effects on vascular function and cardiometabolic risk markers are unknown. Forty-four older (aged 60–75) adults with overweight/obesity experiencing elevated Subjective Cognitive Failures (SCF) were randomized into a 36-week, double-blind, placebo-controlled trial. Participants either consumed 5.7 g of an egg-protein hydrolysate (NWT-03) or maltodextrin placebo. Endothelial function (brachial artery flow-mediated vasodilation [FMD] and carotid artery reactivity [CAR] responses after a cold pressor test), arterial stiffness (carotid-to-femoral pulse wave velocity [PWVc-f]), retinal microvascular calibers, and cardiometabolic risk markers (insulin sensitivity using a 7-point oral glucose tolerance test, serum lipid profiles, and blood pressure) were evaluated. FMD observed a non-significant trend towards a 0.3 percentage point (pp) increase in the intervention compared to the placebo group (95 https://clinicaltrials.gov/study/NCT04831203