Supplemental 25-Hydroxycholecalciferol Is More Effective than Cholecalciferol in Raising Serum 25-Hydroxyvitamin D Concentrations in Older Adults.

BACKGROUND: There are few studies directly comparing the pharmacokinetics of 25-hydroxycholecalciferol [25(OH)D3] to cholecalciferol (D3). OBJECTIVES: The primary objectives were to compare the effectiveness of D3 and 25(OH)D3 in raising 25-hydroxyvitamin D [25(OH)D] serum concentrations and achieving steady state. METHODS: This was a randomized, double-blind, active comparator trial of 91 participants (53 females, 38 males), aged 63.3 ± 7.9 y. 25(OH)D3 (10, 15, and 20 µg) and D3 (20 µg) were dosed daily for 6 mo followed by 6 mo of washout. Frequent measurements of serum 25(OH)D were performed. Pharmacokinetic parameters were fitted for each individual and the treatment average was modeled with linear regression using the individual baseline level, sex, and gender as covariates. RESULTS: Mean baseline 25(OH)D was similar in all groups (47.1-49.5 nmol/L). Increases in 25(OH)D to steady state were higher in the 25(OH)D3 groups than in the D3 group [least squares (LS) means (95% CI): 50.1 (43.3-58.0), 72.5 (64.3-81.7), 97.4 (86.6-109.6) nmol/L in 10, 15, and 20 µg/d and 38.7 (33.1-45.2) nmol/L in the D3 group; P = 0.0173, P < 0.0001, P < 0.0001]. The rate to reach steady state was similar in all groups, but the time to reach 25(OH)D concentrations of 75 nmol/L was faster in the higher-dosed 25(OH)D3 groups than in the D3 group (7 and 10 d compared with 40 d, P < 0.0001 and P < 0.0001 for 15 and 20 µg/d). The rate of elimination was 59-109% higher in the 25(OH)D3 groups than in the D3 group. The area under the curve (AUC)/µg dose demonstrated that 25(OH)D3 was 3 times as effective as D3 at raising 25(OH)D concentrations. CONCLUSIONS: 25(OH)D3 is ∼3 times as effective as D3 at raising 25(OH)D concentrations. Once supplementation is discontinued, the elimination rate of 25(OH)D3 is faster than D3. This trial was registered at clinicaltrials.gov as NCT02333682.

Effects of resveratrol supplementation on liver fat content in overweight and insulin-resistant subjects: A randomized, double-blind, placebo-controlled clinical trial.

We performed the largest randomized, placebo-controlled clinical trial to date (N = 112, 12-week intervention) to investigate the effects and safety of resveratrol supplementation on liver fat content and cardiometabolic risk parameters in overweight and obese and insulin-resistant subjects. At baseline the variability in liver fat content was very large, ranging from 0.09% to 37.55% (median, 7.12%; interquartile range, 3.85%-12.94%). Mean (SD) liver fat content was 9.22 (6.85) % in the placebo group and 9.91 (7.76) % in the resveratrol group. During the study liver fat content decreased in the placebo group (-0.7%) but not in the resveratrol group (-0.03%) (differences between groups: P = .018 for the intention-to-treat [ITT] population; N = 54, resveratrol, N = 54, placebo and P = .0077 for the per protocol [PP] population). No effects of resveratrol supplementation on cardiometabolic risk parameters were observed. Resveratrol supplementation was well tolerated and safe. In conclusion, these data suggest that resveratrol supplementation is safe and that it does not considerably impact liver fat content or cardiometabolic risk parameters in humans.

Resveratrol as Add-on Therapy in Subjects With Well-Controlled Type 2 Diabetes: A Randomized Controlled Trial.

OBJECTIVE: To determine whether resveratrol supplementation can improve insulin sensitivity and promote overall metabolic health on top of standard diabetes care. RESEARCH DESIGN AND METHODS: Seventeen subjects with well-controlled type 2 diabetes (T2D) were treated with placebo and 150 mg/day resveratrol (resVida) in a randomized double-blind crossover study for 30 days. The main outcome measure was insulin sensitivity by the hyperinsulinemic-euglycemic clamp technique. RESULTS: Hepatic and peripheral insulin sensitivity were not affected by resveratrol treatment. Intrahepatic lipid content also remained unaffected by resveratrol; however, the change in intrahepatic lipid content correlated negatively with plasma resveratrol levels (R = -0.68, P = 0.03). Intramyocellular lipid content increased in type 2 muscle fibers (P = 0.03), and systolic blood pressure tended to decrease (P = 0.09) upon resveratrol treatment. In addition, resveratrol significantly improved ex vivo mitochondrial function (state 3 and state U respiration upon malate with octanoyl-carnitine, P < 0.005). Intriguingly, a correlation was found between plasma levels of a metabolite of resveratrol (dihydroresveratrol) and the metformin dose used by the patients (R = 0.66, P = 0.005), suggesting an interaction between metformin and resveratrol. It could be speculated that the lack of a resveratrol-induced insulin-sensitizing effect is caused by this interaction. CONCLUSIONS: Resveratrol supplementation does not improve hepatic or peripheral insulin sensitivity. Our results question the generalized value of resveratrol as an add-on therapy in the treatment of T2D and emphasize the need to perform studies in drug-naive patients with T2D or subjects with prediabetes.

Nutrikinetic modeling reveals order of genistein phase II metabolites appearance in human plasma.

SCOPE: Genistein from foods or supplements is metabolized by the gut microbiota and the human body, thereby releasing many different metabolites into systemic circulation. The order of their appearance in plasma and the possible influence of food format are still unknown. This study compared the nutrikinetic profiles of genistein metabolites. METHODS AND RESULTS: In a randomized cross-over trial, 12 healthy young volunteers were administered a single dose of 30 mg genistein provided as a genistein tablet, a genistein tablet in low fat milk, and soy milk containing genistein glycosides. A high mass resolution LC-LTQ-Orbitrap FTMS platform detected and quantified in human plasma: free genistein, seven of its phase-II metabolites and 15 gut-derived metabolites. Interestingly, a novel metabolite, genistein-4'-glucuronide-7-sulfate (G-4'G-7S) was identified. Nutrikinetic analysis using population-based modeling revealed the order of appearance of five genistein phase II metabolites in plasma: (1) genistein-4',7-diglucuronide, (2) genistein-7-sulfate, (3) genistein-4'-sulfate-7-glucuronide, (4) genistein-4'-glucuronide, and (5) genistein-7-glucuronide, independent of the food matrix. CONCLUSION: The conjugated genistein metabolites appear in a distinct order in human plasma. The specific early appearance of G-4',7-diG suggests a multistep formation process for the mono and hetero genistein conjugates, involving one or two deglucuronidation steps.

Resveratrol, from experimental data to nutritional evidence: the emergence of a new food ingredient.

The polyphenol resveratrol is found notably in grapes and in a variety of medicinal plants. Recently, resveratrol has been suggested to have cardioprotective effects and to improve metabolic health by mimicking the effects of calorie restriction. Numerous animal and in vitro studies suggest that resveratrol could improve cardiovascular and metabolic health in humans. In view of this compelling preclinical evidence, several human studies investigating the effects of resveratrol on vascular and metabolic health have been initiated. Collectively, the animal, human epidemiological, and first human intervention studies support a role of resveratrol in vascular and metabolic health. This has led to the introduction of the first supplement and food products containing resveratrol and its emergence as a promising new health ingredient. Thus, supplementation with resveratrol may be included in nutritional and lifestyle programs aiming to reduce the risk of vascular and obesity-related problems.

Chronic resveratrol consumption improves brachial flow-mediated dilatation in healthy obese adults.

BACKGROUND: We have previously demonstrated acute dose-dependent increases of flow-mediated dilatation (FMD) in the brachial artery after resveratrol consumption in mildly hypertensive, overweight/obese adults. Resveratrol supplementation has also been shown to increase cerebral blood flow acutely, without affecting cognition. OBJECTIVES: To evaluate the effects of chronic resveratrol supplementation on both FMD and cognitive performance. METHOD: Twenty-eight obese but otherwise healthy adults (BMI: 33.3 ± 0.6 kg/m) were randomized to take a single 75 mg capsule of trans-resveratrol (Resvida) or placebo daily for 6 weeks each in a double-blind crossover supplementation trial. Blood pressure, arterial compliance, FMD, and performance on the Stroop Color-Word Test were assessed at the end of each 6-week intervention period while fasted and at least 18 h after taking the last daily capsule. An additional capsule of the same supplement was then taken. FMD assessment was repeated 1 h later. RESULTS: Chronic resveratrol supplementation for 6 weeks was well tolerated and resulted in a 23% increase in FMD compared with placebo (P=0.021, paired t-test). The extent of increase correlated negatively with baseline FMD (r=-0.47, P=0.01). A single dose of resveratrol (75 mg) following chronic resveratrol supplementation resulted in a 35% greater acute FMD response than the equivalent placebo supplementation. These FMD improvements remained significant after adjusting for baseline FMD. Blood pressure, arterial compliance, and all components of the Stroop Color-Word Test were unaffected by chronic resveratrol supplementation. CONCLUSION: Daily resveratrol consumption was well tolerated and has the potential to maintain healthy circulatory function in obese adults.

Effect of a combination of genistein, polyunsaturated fatty acids and vitamins D3 and K1 on bone mineral density in postmenopausal women: a randomized, placebo-controlled, double-blind pilot study.

PURPOSE: Many postmenopausal women desire non-pharmaceutical alternatives to hormone therapy for protection against osteoporosis. Soybean isoflavones, especially genistein, are being studied for this purpose. This study examined the effects of synthetic genistein in combination with other potential bone-protective dietary molecules on bone mineral density (BMD) in early postmenopausal women. METHODS: In this 6-month double-blind pilot study, 70 subjects were randomized to receive daily either calcium only or the geniVida™ bone blend (GBB), which consisted of genistein (30 mg/days), vitamin D3 (800 IU/days), vitamin K1 (150 µg/days) and polyunsaturated fatty acids (1 g polyunsaturated fatty acids as ethyl ester: eicosapentaenoic acid/docosahexaenoic acid ratio = ~2/1). Markers of bone resorption and formation and BMD at the femoral neck, lumbar spine, Ward's triangle, trochanter and intertrochanter, total hip and whole body were assessed. RESULTS: Subjects supplemented with the GBB (n = 30) maintained femoral neck BMD, whereas in the placebo group (n = 28), BMD significantly decreased (p = 0.007). There was also a significant difference (p < 0.05) in BMD between the groups at Ward's triangle in favor of the GBB group. Bone-specific alkaline phosphatase and N-telopeptide significantly increased in the GBB group in comparison with those in baseline and in the placebo group. The GBB was well tolerated, and there were no significant differences in adverse events between groups. CONCLUSIONS: The GBB may help to prevent osteoporosis and reduce fracture risk, at least at the hip, in postmenopausal women. Larger and longer-term clinical trials are warranted.

Resveratrol supplementation does not improve metabolic function in nonobese women with normal glucose tolerance.

Resveratrol has been reported to improve metabolic function in metabolically abnormal rodents and humans, but it has not been studied in nonobese people with normal glucose tolerance. We conducted a randomized, double-blind, placebo-controlled trial to evaluate the metabolic effects of 12 weeks of resveratrol supplementation (75 mg/day) in nonobese, postmenopausal women with normal glucose tolerance. Although resveratrol supplementation increased plasma resveratrol concentration, it did not change body composition, resting metabolic rate, plasma lipids, or inflammatory markers. A two-stage hyperinsulinemic-euglycemic clamp procedure, in conjunction with stable isotopically labeled tracer infusions, demonstrated that resveratrol did not increase liver, skeletal muscle, or adipose tissue insulin sensitivity. Consistent with the absence of in vivo metabolic effects, resveratrol did not affect its putative molecular targets, including AMPK, SIRT1, NAMPT, and PPARGC1A, in either skeletal muscle or adipose tissue. These findings demonstrate that resveratrol supplementation does not have beneficial metabolic effects in nonobese, postmenopausal women with normal glucose tolerance.

Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans.

Resveratrol is a natural compound that affects energy metabolism and mitochondrial function and serves as a calorie restriction mimetic, at least in animal models of obesity. Here, we treated 11 healthy, obese men with placebo and 150 mg/day resveratrol (resVida) in a randomized double-blind crossover study for 30 days. Resveratrol significantly reduced sleeping and resting metabolic rate. In muscle, resveratrol activated AMPK, increased SIRT1 and PGC-1α protein levels, increased citrate synthase activity without change in mitochondrial content, and improved muscle mitochondrial respiration on a fatty acid-derived substrate. Furthermore, resveratrol elevated intramyocellular lipid levels and decreased intrahepatic lipid content, circulating glucose, triglycerides, alanine-aminotransferase, and inflammation markers. Systolic blood pressure dropped and HOMA index improved after resveratrol. In the postprandial state, adipose tissue lipolysis and plasma fatty acid and glycerol decreased. In conclusion, we demonstrate that 30 days of resveratrol supplementation induces metabolic changes in obese humans, mimicking the effects of calorie restriction.

Study on the pharmacokinetics of synthetic genistein after multiple oral intake in post-menopausal women.

Genistein (CAS 446-72-0), an isoflavone and phytoestrogen predominantly found in soy, is considered a promising natural bioactive to prevent post-menopausal bone loss. geniVida (previously Bonistein), a novel product containing of min. 98.5% synthetic genistein aglycone, was investigated in 12 healthy post-menopausal women to assess the safety and tolerability as well as to obtain pharmacokinetic data after 7 days of repeated intakes. 24 h pharmacokinetic profiles were determined after the first oral dose and after 7 days repeated intakes of 30 mg of the test formulation. Plasma genistein (aglycone) and its conjugates were determined by a standardised LC/MS analytical method using D4-genistein as the internal standard. The plasma-concentration time profiles for conjugated genistein showed a fast, monophasic one-peak course until T(max) (5.9 h (first dose), 5.3 h (steady state (SS)); C(max) (456.8 ng/ml (first dose), 498.5 ng/ ml (SS)). Elimination half-lives (t1/2) were calculated to be 10.8 h (first dose) and 8.2 h (SS), respectively. Determination of AUC(0-inf.)) (first dose) was good with a low percentage of extrapolation (3949.1 h ng/ ml). AUC(0-24h) at SS was 5923.3 h ng/ml. Steady state was reached after 4 to 5 days and no relevant accumulation occurred (R = 1.02). The test formulation was safe and very well tolerated.