Effect of a diet based on the dietary guidelines for americans on inflammation markers in women at risk for cardiometabolic disease: results of a randomized, controlled trial.

OBJECTIVE: To evaluate the effect of a diet pattern based on Dietary Guidelines for Americans (DGA), in a controlled feeding setting, on plasma markers of inflammation and on cytokine production by peripheral blood mononuclear cells (PBMC). DESIGN: Women (n = 44) with one or more risk factors of metabolic syndrome (and BMI: 25.2-39.8 kg/m2) completed an 8-wk controlled feeding study. They were randomized to either a group following a diet based on DGA 2010 (DGA), or a group given a 'typical American diet' (TAD), based largely on a Western diet pattern. By design, women maintained their body weight. Fasting plasma and PBMC were collected at wk. 0 (baseline) and at wk. 8 (post-intervention). Sixteen plasma markers of inflammation and eight PBMC cytokines were measured at both time points, to evaluate if the diet had a significant effect on concentrations of these inflammatory markers. Data were analyzed using ANCOVA, followed by multiple-comparison adjustment using Benjamini-Hochberg method. RESULTS: Significant changes observed in Serum Amyloid A (SAA) and Matrix Metalloproteinase 3 (MMP3) in plasma did not retain significance upon multiple comparison adjustment. SAA: p = 0.044, adj p = 0.450; DGA mean change [95% CI] = - 12.6[- 32.3 to 7.04]; TAD mean change [95% CI] = - 2.24 [- 9.99 to 5.51]. MMP3: p = 0.014, adj p = 0.35; DGA mean change [95% CI] = 2.72[- 4.16 to 9.59]; TAD mean change [95% CI] = - 0.98[- 16.7 to 14.7]). Other inflammation markers were not differently altered by DGA relative to TAD. Effect size of change (Cohens d) indicated a large/medium-large effect of intervention on MMP3 and CRP, and medium effect on IL-6. CONCLUSIONS: No statistically significant changes were observed in the immune markers examined in this study. The biological roles and magnitude of the non-significant differences seen with two variables, CRP and MMP3, suggest that they be examined in future studies. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02298725.

SNPs in apolipoproteins contribute to sex-dependent differences in blood lipids before and after a high-fat dietary challenge in healthy U.S. adults.

BACKGROUND: The effect of genetic polymorphisms on fasting blood lipid levels have been widely studied but the effects of these within the context of a high-fat meal challenge remain less characterized. The current study aimed to investigate the association of SNPs in lipoprotein-related genes with blood lipid profiles in healthy adults in the U.S. METHODS: Subjects (n = 393) between 18-66 years of age with BMIs ranging from 18.5-45 kg/m2 were enrolled the cross-sectional Nutritional Phenotyping Study. Among them, 349 subjects (men: 48%; women: 52%) gave consent for genotyping. SNPs in APOA5, APOB, APOC3, APOE, and LDLR were assessed. The association between lipid markers and genotypes was tested separately for each SNP with analysis of variance (ANOVA), adjusted for sex, age, and BMI. We also examined two-factor interactions between SNPs and sex, age, or BMI. RESULTS: Women carrying the C allele of rs3135506 in APOA5 or men carrying the C allele of rs429358 in APOE had reduced HDL-cholesterol levels during fasting and postprandially. The C allele in APOE was also correlated to increased LDL-C levels. The TT genotype of rs2854116 in APOC3 was associated with elevated total cholesterol. Additive effect of the risk alleles of APOA5 and APOE or APOC3 and APOE was detected. Nevertheless, the tested SNPs had little impact on the postprandial triglyceride responses to the high-fat challenge meal. We found no significant effects of SNPs in APOB (rs1042034) or LDLR (rs2228671) on triglycerides, cholesterol, or free fatty acid levels. CONCLUSIONS: In healthy adults, fasting and postprandial cholesterol levels are strongly correlated with the tested APOA5, APOE, and APOC3 genotypes. Sex contributes to the genetic impact of the tested SNPs on lipid profiles. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02367287. Registered February 20, 2015, https://clinicaltrials.gov/ct2/show/NCT02367287 .

Resistant starch wheat increases PYY and decreases GIP but has no effect on self-reported perceptions of satiety.

Dietary fiber has numerous health benefits, such as increasing satiety, and is regularly included in healthy dietary recommendations. However, different types and sources of fiber vary in their chemical properties and biological effects. This double-blind, randomized, placebo-controlled, crossover study investigated the effects of resistant starch type 2 (RS2) from wheat on self-reported perceptions of satiety and associated gut hormones in 30 healthy adults ages 40-65 years of age. Participants consumed rolls made using either RS2-enriched wheat flour or a wild-type flour for one week before a test day during which they ate a mixed meal containing the same roll type. Both self-reported perceptions of satiety and plasma concentrations of gut hormones were measured following the meal to assess whether the RS2-enriched wheat enhanced satiety and suppressed hunger for a longer period than the control wheat. Exploratory analysis indicated that fasting and peak concentration of peptide YY3-36 (PYY3-36; qfast = 0.02, qpeak = 0.02) increased, while peak concentration and iAUC of glucose-dependent insulinotropic peptide (GIP; qpeak < 0.001, qiAUC < 0.001) decreased after ingesting RS2-enriched wheat. However, self-reported perceptions of hunger or fullness using visual analog scales (VAS) did not differ following the test meal.

Technician-Scored Stool Consistency Spans the Full Range of the Bristol Scale in a Healthy US Population and Differs by Diet and Chronic Stress Load.

BACKGROUND: Prior studies of adults with constipation or diarrhea suggest that dietary intake, physical activity, and stress may affect stool consistency. However, the influence of these factors is unresolved and has not been investigated in healthy adults. OBJECTIVES: We assessed the relations of technician-scored stool consistency in healthy adults with self-reported diet, objectively monitored physical activity, and quantifiable markers of stress. METHODS: Stool consistency was scored by an independent technician using the Bristol Stool Form Scale (BSFS) to analyze samples provided by healthy adults, aged 18-65 y, BMI 18-44 kg/m2, in the USDA Nutritional Phenotyping Study (n = 364). A subset of participants (n = 109) were also asked to rate their sample using the BSFS. Dietary intake was assessed with two to three 24-h recalls completed at home and energy expenditure from physical activity was monitored using an accelerometer in the 7-d period preceding the stool collection. Stress was measured using the Wheaton Chronic Stress Inventory and allostatic load (AL). Statistical and machine learning analyses were conducted to determine which dietary, physiological, lifestyle, and stress factors differed by stool form. RESULTS: Technician-scored BSFS scores were significantly further (P = 0.003) from the central score (mean ± SEM distance: 1.41 ± 0.089) than the self-reported score (1.06 ± 0.086). Hard stool was associated with higher (P = 0.005) intake of saturated fat (13.8 ± 0.40 g/1000 kcal) than was normal stool (12.5 ± 0.30 g/1000 kcal). AL scores were lower for normal stool (2.49 ± 0.15) than for hard (3.07 ± 0.18) (P = 0.009) or soft stool (2.89 ± 0.18) (P = 0.049). Machine learning analyses revealed that various dietary components, physiological characteristics, and stress hormones predicted stool consistency. CONCLUSIONS: Technician-scored stool consistency differed by dietary intake and stress hormones, but not by physical activity, in healthy adults.This trial was registered at clincialtrials.gov as NCT02367287.

Weight Loss, but Not Dairy Composition of Diet, Moderately Affects Satiety and Postprandial Gut Hormone Patterns in Adults.

BACKGROUND: Inclusion of dairy in diet patterns has been shown to have mixed effects on weight loss. A prevailing hypothesis is that dairy improves weight loss by influencing endocrine systems associated with satiety and food intake regulation. OBJECTIVES: The objective of the current study was to evaluate the effect of weight loss with or without adequate dietary dairy on subjective and objective appetitive measures. METHODS: Men and women who were habitual low dairy consumers (n = 65, 20-50 y) participated in a 12-wk randomized controlled feeding weight loss trial. During the 12-wk intervention, a low-dairy (<1 serving dairy/d) was compared with an adequate-dairy (3-4 servings dairy/d) diet, both with a 500-kcal deficit/d. Test days, before and at the end of the intervention, began with 2 fasting blood draws and visual analog scale (VAS) measures, followed by a standard breakfast (25% of prescribed restricted calories), 5 postbreakfast blood draws and VASs, a standard lunch (40% of restricted energy amount), and 12 postlunch blood draws and VASs. Blood samples were used for satiety hormone measurements. On a separate day when matching standard meals were consumed, an ad libitum buffet meal was provided as dinner, at a self-selected time. Meal duration and intermeal interval were recorded. RESULTS: Weight loss (-6.1 kg), irrespective of dairy, resulted in reduced fasting insulin (-20%) and leptin (-25%), and increased fasting acylated ghrelin (+25%) and VAS desire to eat (+18%) (P < 0.05). There were no effects of dairy on objective or subjective satiety measures. Weight loss marginally reduced the intermeal interval (289 min compared with 276 min, P = 0.059) between lunch and the ad libitum buffet. CONCLUSIONS: These results do not support the hypothesis that inclusion of dairy in long-term dietary patterns influences appetite during weight loss. Weight loss per se has a modest impact on select systems that regulate hunger and satiety.This trial was registered at clinicaltrials.gov as NCT00858312.

Effect of exogenous phytase added to small-quantity lipid-based nutrient supplements (SQ-LNS) on the fractional and total absorption of zinc from a millet-based porridge consumed with SQ-LNS in young Gambian children: a randomized controlled trial.

BACKGROUND: Dietary phytate inhibits zinc absorption from composite meals in adults. OBJECTIVE: The objective of this study was to investigate the effect of adding exogenous phytase to a small-quantity lipid-based nutrient supplement (SQ-LNS) on zinc absorption among young children. METHODS: In a double-blind randomized controlled trial, intraindividual differences in fractional and total absorption of zinc (FAZ and TAZ, respectively) from a millet-based porridge containing SQ-LNS with and without phytase were measured in 30 asymptomatic children 18-23 mo of age in the Kiang West district of The Gambia. Using a crossover design, children received for 1 d each porridge test meals with 20 g SQ-LNS containing 8 mg zinc and either 1) exogenous phytase or 2) no exogenous phytase. The test meals were provided on consecutive days in randomized order. FAZ was measured using a triple stable isotope tracer ratio technique with Zn-67 and Zn-70 as oral tracers and Zn-68 as the intravenous tracer. RESULTS: Twenty-six participants completed the study. The prevalence of stunting and wasting were 20% and 13%, respectively; no children had low plasma zinc concentrations (<65 µg/dL). Total mean ± SD dietary zinc intake from the test meals was 7.3 ± 2.2 mg (phytate:zinc molar ratio = 3.1 ± 0.3, not accounting for phytase activity). Mean FAZ increased from 8.6% ± 1.3% to 16.0% ± 1.3% when exogenous phytase was added to the SQ-LNS product (P < 0.001). Mean TAZ from test meals containing SQ-LNS with phytase was more than double that from test meals containing SQ-LNS without phytase (1.1 ± 0.1 mg and 0.5 ± 0.1 mg, respectively; P < 0.001). CONCLUSIONS: The addition of exogenous phytase to SQ-LNS increased both FAZ and TAZ. These results suggest that phytate reduction may be an important strategy to increase zinc absorption among young children. This trial was registered at clinicaltrials.gov as NCT02668133.

Vitamin D3 Supplementation Increases Spine Bone Mineral Density in Adolescents and Young Adults With Human Immunodeficiency Virus Infection Being Treated With Tenofovir Disoproxil Fumarate: A Randomized, Placebo-Controlled Trial.

Background: Tenofovir disoproxil fumarate (TDF) decreases bone mineral density (BMD). We hypothesized that vitamin D3 (VITD3) would increase BMD in youth receiving TDF. Methods: This was a randomized, double-blind, placebo-controlled trial of directly observed VITD3 vs placebo every 4 weeks for 48 weeks in youth aged 16-24 years with HIV, RNA load <200 copies/mL, taking TDF-containing combination antiretroviral therapy (TDF-cART) for ≥180 days. Participants (N = 214) received a daily multivitamin containing VITD3 400 IU and calcium 162 mg, plus monthly randomized VITD3 50000 IU (n = 109) or placebo (n = 105). Outcome was change from baseline to week 48 in lumbar spine BMD (LSBMD). Data presented are median (Q1, Q3). Results: Participants were aged 22.0 (21.0, 23.0) years, 84% were male, and 74% were black/African American. At baseline, 62% had 25-hydroxy vitamin D (25-OHD) <20 ng/mL. Multivitamin adherence was 49% (29%, 69%), and VITD3/placebo adherence 100% (100%, 100%). Vitamin D intake was 2020 (1914, 2168) and 284 (179, 394) IU/day, and serum 25-OHD concentration was 36.9 (30.5, 42.4) and 20.6 (14.4, 25.8) ng/mL at 48 weeks in VITD3 and placebo groups, respectively (P < .001). From baseline to week 48, LSBMD increased by 1.15% (-0.75% to 2.74%) in the VITD3 group (n = 99; P < .001) and 0.09% (-1.49% to 2.61%) in the placebo group (n = 89; P = .25), without between-group difference (P = .12). VITD3 group changes occurred with baseline 25-OHD <20 ng/mL (1.17% [-.82% to 2.90%]; P = .004) and ≥20 ng/mL (0.93% [-.26% to 2.15%]; P = .033). Conclusions: For youth taking TDF-cART, LSBMD increased through 48 weeks with VITD3 plus multivitamin, but not with placebo plus multivitamin, independent of baseline vitamin D status. Clinical Trials Registration: NCT01751646.

Design and implementation of a cross-sectional nutritional phenotyping study in healthy US adults.

BACKGROUND: Metabolic imbalance is a key determinant of risk of chronic diseases. Metabolic health cannot be assessed solely by body mass calculations or by static, fasted state biochemical readouts. Although previous studies have described temporal responses to dietary challenges, these studies fail to assess the environmental factors associated with certain metabolic phenotypes and therefore, provide little scientific rationale for potentially effective intervention strategies. METHODS/DESIGN: In this phenotyping study of healthy US adults, we are evaluating lifestyle, biological and environmental factors in addition to metabolic parameters to determine the factors associated with variations in metabolic health. A series of practical fitness, dietary, and emotional challenges are introduced and temporal responses in various areas of specialization, including immunology, metabolomics, and endocrinology, are monitored. We expect that this study will identify key factors related to healthy or unhealthy metabolic phenotypes (metabotypes) that may be modifiable targets for the prevention of chronic diseases in an individual. DISCUSSION: This study will provide novel insights into metabolic variability among healthy adults in balanced strata defined by sex, age and body mass index. Usual dietary intake and physical activity will be evaluated across these strata to determine how diet is associated with health status defined using many indicators including immune function, metabolism, body composition, physiology, response to exercise andmeal challenges and neuroendocrine assessment. A principal study goal is to identify dietary and other personal factors that will differentiate different levels of "health" among study participants. TRIAL REGISTRATION: ClinicalTrials.gov NCT02367287.

Decline in Bone Mass With Tenofovir Disoproxil Fumarate/Emtricitabine Is Associated With Hormonal Changes in the Absence of Renal Impairment When Used by HIV-Uninfected Adolescent Boys and Young Men for HIV Preexposure Prophylaxis.

BACKGROUND: We aimed to define the relative importance of renal and endocrine changes in tenofovir disoproxil fumarate (TDF)-related bone toxicity. METHODS: In a study of daily TDF/emtricitabine (FTC) preexposure prophylaxis (PrEP) in human immunodeficiency virus (HIV)-uninfected young men who have sex with men, we measured changes from baseline in blood and urine markers of the parathyroid hormone (PTH)-vitamin D-fibroblast growth factor 23 (FGF23) axis, creatinine, and renal tubular reabsorption of phosphate (TRP). We explored the relationship of those variables to changes in bone mineral density (BMD). Tenofovir-diphosphate (TFV-DP) in red blood cells was used to categorize participants into high and low drug exposure groups. RESULTS: There were 101 participants, median age 20 years (range 15 to 22). Compared with low drug exposure, high-exposure participants showed increase from baseline in PTH and decline in FGF23 by study week 4, with no differences in creatinine, phosphate, or TRP. At 48 weeks, the median (interquartile range) percent decline in total hip BMD was greater in those with high- compared to low- exposure (-1.59 [2.77] vs +1.54 [3.34] %, respectively; P = .001); in high-exposure participants, this correlated with week 4 TFV-DP (inversely; r = -0.60, P = .002) and FGF23 (directly; r = 0.42; P = .039) but not other variables. CONCLUSIONS: These findings support the short-term renal safety of TDF/FTC PrEP in HIV-seronegative young men and suggest that endocrine disruption (PTH-FGF23) is a primary contributor to TDF-associated BMD decline in this age group. CLINICAL TRIALS REGISTRATION: NCT01769469.

Postprandial Inflammatory Responses and Free Fatty Acids in Plasma of Adults Who Consumed a Moderately High-Fat Breakfast with and without Blueberry Powder in a Randomized Placebo-Controlled Trial.

BACKGROUND: Saturated fatty acids (FAs) released from triglyceride-rich lipoproteins (TGRLs) activate Toll-like receptor 2 (TLR-2) and induce the expression of proinflammatory cytokines in monocytes. Certain plant polyphenols inhibit TLR-mediated signaling pathways. OBJECTIVE: We determined whether plasma free FAs (FFAs) after a moderately high-fat (MHF, 40% kcal from fat) breakfast modulate the inflammatory status of postprandial blood, and whether blueberry intake suppresses FFA-induced inflammatory responses in healthy humans. METHODS: Twenty-three volunteers with a mean ± SEM age and body mass index (in kg/m(2)) of 30 ± 3 y and 21.9 ± 0.4, respectively, consumed an MHF breakfast with either a placebo powder or 2 or 4 servings of blueberry powder in a randomized crossover design. The placebo powder was provided on the first test day and the blueberry powder doses were randomized with a 2-wk washout period. Plasma concentrations of lipids, glucose, and cytokines were determined. To determine whether FFAs derived from TGRL stimulate monocyte activation, and whether this is inhibited by blueberry intake, whole blood was treated with lipoprotein lipase (LPL). RESULTS: The median concentrations of FFAs and cytokines [tumor necrosis factor-α, interleukin (IL)-6 and IL-8] in postprandial plasma (3.5 h) decreased compared with fasting plasma regardless of the blueberry intake (P < 0.001 for FFAs and P < 0.05 for cytokines). However, concentrations of FFAs and cytokines including IL-1ß increased in LPL-treated whole blood compared with untreated blood samples from participants who consumed the placebo powder. Blueberry intake suppressed IL-1ß and IL-6 production in LPL-treated postprandial blood compared with the placebo control when fasting changes were used as a covariate. CONCLUSIONS: The plasma FFA concentration may be an important determinant affecting inflammatory cytokine production in blood. Supplementation with blueberry powder did not affect plasma FFA and cytokine concentrations; however, it attenuated the cytokine production induced by ex vivo treatment of whole blood with LPL. This trial was registered at clinicaltrials.gov as NCT01594008.

Dietary supplementation with purified citrus limonin glucoside does not alter ex vivo functions of circulating T lymphocytes or monocytes in overweight/obese human adults.

Overweight/obesity is associated with chronic inflammation and impairs both innate and adaptive immune responses. Limonoids found in citrus fruits decreased cell proliferation and inflammation in animal studies. We hypothesized that limonin glucoside (LG) supplementation in vivo will decrease the ex vivo proliferation of T cells and the production of inflammatory cytokines by monocytes and T cells. In a double-blind, randomized, cross-over study, 10 overweight/obese human subjects were served purified LG or placebo drinks for 56 days each to determine the effects of LG on immune cell functions. The percentage of CD14+CD36+ cells in whole blood was analyzed by flow cytometry. Peripheral blood mononuclear cells were isolated and activated with CD3 plus CD28 antibodies (T-lymphocyte activation) or lipopolysaccharide (monocyte activation). Interferon γ, tumor necrosis factor α, interleukin (IL) 2, IL-4, and IL-10 were measured in supernatants from activated T cells. Supernatants from activated monocytes were analyzed for the production of tumor necrosis factor α, IL-1ß, and IL-6. Peripheral blood mononuclear cells were prestained with PKH dye and activated with CD3 plus CD28 antibodies to determine the proliferative responses of CD4+ and CD8+ T lymphocytes by flow cytometry. No differences were observed for CD14+CD36+ monocyte populations, T-cell proliferation, or the production of T cell and monocyte cytokines between the 2 treatments. Thus, LG supplementation in vivo did not affect ex vivo functions of T cells and monocytes, whereas it decreased several circulating markers of hepatic inflammation as we previously reported.

Dietary grape powder increases IL-1ß and IL-6 production by lipopolysaccharide-activated monocytes and reduces plasma concentrations of large LDL and large LDL-cholesterol particles in obese humans.

Obese individuals are at an increased risk of developing CVD, hypertension, type 2 diabetes, and bacterial and viral infections when compared with the normal-weight population. In a 9-week randomised, double-blind, cross-over study, twenty-four obese subjects aged between 20 and 60 years and with a BMI between 30 and 45 kg/m2 were fed grape or placebo powder for 3-week intervals to determine the effects of dietary grapes on blood lipid profiles, plasma inflammatory marker concentrations and immune cell function. Blood samples were collected on days 1 and 8 for obtaining baseline information and at weeks 3, 4, 8 and 9. Comprehensive chemistry panels, lipid profile analyses by NMR, measurement of plasma inflammatory marker concentrations, and analyses of cytokine production by activated T lymphocytes and monocytes were performed for each blood draw. Dietary grape powder reduced the plasma concentrations of large LDL-cholesterol and large LDL particles compared with the placebo powder (P< 0·05). The concentrations of interferon-γ, TNF-α, IL-4 and IL-10 were measured in supernatants from peripheral blood mononuclear cells (PBMC) activated with anti-CD3/CD28 antibodies and those of TNF-α, IL-1ß, IL-6 and IL-8 were measured in supernatants from PBMC activated with lipopolysaccharide (LPS). No difference in the production of T-cell cytokines was observed between the two intervention groups. The production of IL-1ß and IL-6 was increased in supernatants from LPS-activated PBMC in the grape powder group compared with the placebo powder group (P< 0·05). These data suggest that dietary grapes may decrease atherogenic lipid fractions in obese individuals and increase the sensitivity of monocytes in a population at a greater risk of developing infections.

Associations among endocrine, inflammatory, and bone markers, body composition and weight loss induced bone loss.

INTRODUCTION: Weight loss reduces co-morbidities of obesity, but decreases bone mass. PURPOSE: Our aims were to (1) determine if adequate dairy intake attenuates weight loss-induced bone loss; (2) evaluate the associations of endocrine, inflammatory and bone markers, anthropometric and other parameters to bone mineral density and content (BMD, BMC) pre- and post-weight loss; and (3) model the contribution of these variables to post weight-loss BMD and BMC. METHODS: Overweight/obese women (BMI: 28-37 kg/m2) were enrolled in an energy reduced (-500 kcal/d; -2092 kJ/d) diet with adequate dairy (AD: 3-4 servings/d; n=25, 32.2±8.8 years) or low dairy (LD: ≤1 serving/d; n=26, 31.7±8.4 years). BMD, BMC and body composition were measured by DXA. Bone markers (CTX, PYD, BAP, OC), endocrine (PTH, vitamin D, leptin, adiponectin, ghrelin, amylin, insulin, GLP-1, PAI-1, HOMA) and inflammatory markers (CRP, IL1-ß, IL-6, IL-8, TNF-α, cortisol) were measured in serum or plasma. PA was assessed by accelerometry. RESULTS: Following weight loss, AD intake resulted in significantly greater (p=0.004) lumbar spine BMD and serum osteocalcin (p=0.004) concentration compared to LD. Pre- and post-body fat was negatively associated with hip and lumbar spine BMC (r=-0.28, p=0.04 to -0.45, p=0.001). Of note were the significant negative associations among bone markers and IL-1ß, TNFα and CRP ranging from r = -0.29 (p=0.04) to r = -0.34 (p=0.01); magnitude of associations did not change with weight loss. Adiponectin was negatively related to change in osteocalcin. Factor analysis resulted in 8 pre- and post-weight loss factors. Pre-weight loss factors accounted for 13.7% of the total variance in pre-weight loss hip BMD; post-weight loss factors explained 19.6% of the total variance in post-weight loss hip BMD. None of the factors contributed to the variance in lumbar spine BMD. CONCLUSION: AD during weight loss resulted in higher lumbar spine BMD and osteocalcin compared to LD. Significant negative associations were observed between bone and inflammatory markers suggesting that inflammation suppresses bone metabolism. Using factor analysis, 19.6% of total variance in post-weight loss hip BMD could be explained by endocrine, immune, and anthropometric variables, but not lumbar spine BMD.

Vitamin D3 supplementation increases fibroblast growth factor-23 in HIV-infected youths treated with tenofovir disoproxil fumarate.

BACKGROUND: Tenofovir (TDF) is associated with phosphaturia and elevated 1,25 dihydroxy vitamin D (1,25-OH(2)D). Fibroblast growth factor 23 (FGF23) causes phosphaturia and increases in response to elevated 1,25-OH(2)D. Vitamin D-binding protein (VDBP) binds to 1,25-OH(2)D, decreasing its biological activity, and is elevated in individuals with higher plasma tenofovir concentrations. We compared FGF23 and VDBP before and after vitamin D3 (VITD) supplementation in youths treated with combination antiretroviral therapy (cART) containing or not containing TDF. METHODS: A randomized controlled trial in HIV-positive youths aged 18-25 years enrolled participants based on cART treatment with TDF (TDF; n=118) or without TDF (no-TDF; n=85), and randomized within those groups to VITD (50,000 IU every 4 weeks) or placebo (PL). We measured FGF23 and VDBP and calculated free 1,25-OH(2)D at baseline and week 12, and compared changes by TDF treatment and VITD randomized group. RESULTS: At baseline, serum FGF23 concentration showed a quadratic relationship with 1,25-OH(2)D most pronounced in the TDF group. At week 12, total and free 1,25-OH(2)D increased in the VITD but not PL groups, independent of TDF use. FGF23 increased in the TDF group receiving VITD, but there was no FGF23 change in the no-TDF group receiving VITD or the PL groups. The adjusted mean change in FGF23 from baseline to week 12 was 7.7 pg/ml in the TDF/VITD group, compared with -1.7 (no-TDF/VITD, P=0.010), -1.3 (TDF/PL, P=0.006) and 1.1 (no-TDF/PL, P=0.035). CONCLUSIONS: These results suggest that TDF-containing cART may alter the FGF23 response to vitamin D supplementation in HIV-infected youths. Clinical trials number: NCT00490412.

Association between subcutaneous white adipose tissue and serum 25-hydroxyvitamin D in overweight and obese adults.

Cholecalciferol is known to be deposited in human adipose tissue, but it is not known whether 25-hydroxyvitamin D (25(OH)D) is found in detectable concentrations. Therefore, our objective was to determine whether 25(OH)D is detectable in subcutaneous white adipose tissue (SWAT) in overweight and obese persons enrolled in a twelve week energy restricted diet. Baseline and post-intervention gluteal SWAT biopsies were collected from 20 subjects participating in a larger clinical weight loss intervention. LC-MS/MS was utilized to determine SWAT 25(OH)D concentrations. Serum 25(OH)D and 1,25(OH)2D were measured by RIA. Body composition was assessed by dual energy x-ray absorptiometry. SWAT 25(OH)D concentrations were 5.8 ± 2.6 nmol/kg tissue and 6.2 ± 2.7 nmol/kg tissue pre- and post-intervention SWAT, respectively. There was a significant positive association between SWAT 25(OH)D concentration and serum 25(OH)D concentration (r = 0.52, P < 0.01). Both SWAT and serum 25(OH)D concentrations did not significantly change after a twelve-week period of energy restriction with approximately 5 kg of fat loss. In conclusion, we have demonstrated our LC-MS/MS method can detect 25(OH)D3 in human subcutaneous fat tissue from overweight and obese individuals and is consistent with previously reported concentrations in swine. Additionally, our findings of no significant changes in SWAT 25(OH)D3 or serum 25(OH)D after a 6% loss of total body weight and 13% reduction in total fat provides the first human evidence that adipose 25(OH)D does not likely contribute to serum 25(OH)D with moderate weight loss; whether this is also the case with larger amounts of weight loss is unknown. Weight loss alone is not sufficient to increase serum 25(OH)D and increases in dietary or dermal biosynthesis of vitamin D appear to be the most critical contributors to in vitamin D status.

Association of higher plasma vitamin D binding protein and lower free calcitriol levels with tenofovir disoproxil fumarate use and plasma and intracellular tenofovir pharmacokinetics: cause of a functional vitamin D deficiency?

Tenofovir disoproxil fumarate (TDF) causes bone, endocrine, and renal changes by an unknown mechanism(s). Data are limited on tenofovir pharmacokinetics and these effects. Using baseline data from a multicenter study of HIV-infected youth on stable treatment with regimens containing TDF (n = 118) or lacking TDF (n = 85), we measured cross-sectional associations of TDF use with markers of renal function, vitamin D-calcium-parathyroid hormone balance, phosphate metabolism (tubular reabsorption of phosphate and fibroblast growth factor 23 [FGF23]), and bone turnover. Pharmacokinetic-pharmacodynamic associations with plasma tenofovir and intracellular tenofovir diphosphate concentrations were explored among those receiving TDF. The mean age was 20.9 (standard deviation [SD], 2.0) years; 63% were male; and 52% were African American. Compared to the no-TDF group, the TDF group showed lower mean estimated glomerular filtration rates and tubular reabsorption of phosphate, as well as higher parathyroid hormone and 1,25-dihydroxy vitamin D [1,25-OH(2)D] levels. The highest quintile of plasma tenofovir concentrations was associated with higher vitamin D binding protein, lower free 1,25-OH(2)D, higher 25-OH vitamin D, and higher serum calcium. The highest quintile of intracellular tenofovir diphosphate concentration was associated with lower FGF23. Higher plasma tenofovir concentrations were associated with higher vitamin D binding protein and lower free 1,25-OH(2)D, suggesting a functional vitamin D deficiency explaining TDF-associated increased parathyroid hormone. The finding of lower FGF23 accompanying higher intracellular tenofovir diphosphate suggests that different mechanisms mediate TDF-associated changes in phosphate handling. Separate pharmacokinetic properties may be associated with distinct TDF toxicities: tenofovir with parathyroid hormone and altered calcium balance and tenofovir diphosphate with hypophosphatemia and FGF23 regulation. (The clinical trial registration number for this study is NCT00490412 and is available online at http://clinicaltrials.gov/ct2/show/NCT00490412.).

Total zinc absorption from a diet containing either conventional rice or higher-zinc rice does not differ among Bangladeshi preschool children.

Information is needed on zinc absorption from grain cultivars having higher zinc content. Total absorbed zinc (TAZ) from mixed diets containing high-zinc rice (HZnR), conventional rice (CR), or CR plus zinc fortificant (CR+Zn) was measured. Forty-two nonmalnourished preschool-aged children were enrolled in 1 of 2 groups. Using a crossover design, children in group A (n = 22) received for 1 d each a mixed diet containing 150 g CR or HZnR. Children in group B (n = 20) received HZnR on 1 d and CR+Zn on the other day. Fractional zinc absorption (FZA) was measured during each dietary period by using a dual-isotope tracer ratio technique; TAZ was calculated as the product of zinc intake [total dietary zinc (TDZ)] and FZA. TDZ was 3.83, 4.83, and 6.03 mg/d when the children were fed the CR, HZnR, and CR+Zn-containing diets, respectively. Mean FZA from the CR diet was greater than from the HZnR diet (25.1 vs. 20.1%, P < 0.001), and the mean FZA from the CR+Zn diet (18.8%) was less than from both the CR diet (P < 0.001) and the HZnR diet (P = 0.014). The mean TAZ was 0.96 ± 0.16, 0.97 ± 0.18, and 1.13 ± 0.20 mg/d from the CR, HZnR and CR +Zn diets, respectively. TAZ was not different for the CR and HZnR diets (P = 0.99) but was significantly greater from the CR+Zn diet compared with the other 2 diets (P < 0.001). Rice cultivars with higher zinc and/or lower phytate content are needed to increase TAZ by young children consuming this amount of rice.

Biofortified cassava increases ß-carotene and vitamin A concentrations in the TAG-rich plasma layer of American women.

Biofortification of cassava with the provitamin A carotenoid ß-carotene is a potential mechanism for alleviating vitamin A deficiency. Cassava is a staple food in the African diet, but data regarding the human bioavailability of ß-carotene from this food are scarce. The objective of the present study was to evaluate provitamin A-enhanced cassava as a source of ß-carotene and vitamin A for healthy adult women. The study was a randomised, cross-over trial of ten American women. The subjects consumed three different porridges separated by 2 week washout periods. Treatment meals (containing 100 g cassava) included: biofortified cassava (2 mg ß-carotene) porridge with added oil (15 ml peanut or rapeseed oil, 20 g total fat); biofortified cassava porridge without added oil (6 g total fat); unfortified white cassava porridge with a 0·3 mg retinyl palmitate reference dose and added oil (20 g total fat). Blood was collected six times from - 0·5 to 9·5 h post-feeding. TAG-rich lipoprotein (TRL) plasma was separated by ultracentrifugation and analysed using HPLC with coulometric array electrochemical detection. The AUC for retinyl palmitate increased after the biofortified cassava meals were fed (P< 0·05). Vitamin A conversion was 4·2 (sd 3·1) and 4·5 (sd 3·1) µg ß-carotene:1 µg retinol, with and without added oil, respectively. These results show that biofortified cassava increases ß-carotene and retinyl palmitate TRL plasma concentrations in healthy well-nourished adult women, suggesting that it is a viable intervention food for preventing vitamin A deficiency.

Sweet bing cherries lower circulating concentrations of markers for chronic inflammatory diseases in healthy humans.

A limited number of studies have demonstrated that some modulators of inflammation can be altered by the consumption of sweet cherries. We have taken a proteomics approach to determine the effects of dietary cherries on targeted gene expression. The purpose was then to determine changes caused by cherry consumption in the plasma concentrations of multiple biomarkers for several chronic inflammatory diseases in healthy humans with modestly elevated C-reactive protein (CRP; range, 1-14 mg/L; mean, 3.5 mg/L; normal, <1.0 mg/L). Eighteen men and women (45-61 y) supplemented their diets with Bing sweet cherries (280 g/d) for 28 d. Fasting blood samples were taken before the start of consuming the cherries (study d 7), 28 d after the initiation of cherry supplementation (d 35), and 28 d after the discontinuation (d 63). Of the 89 biomarkers assessed, cherry consumption for 28 d altered concentrations of 9, did not change those of 67, and the other 13 were below the detection limits. Cherry consumption decreased (P < 0.05) plasma concentrations of extracellular newly identified ligand for the receptor for advanced glycation end products (29.0%), CRP (20.1%), ferritin (20.3%), plasminogen activator inhibitor-1 (19.9%), endothelin-1 (13.7%), epidermal growth factor (13.2%), and IL-18 (8.1%) and increased that of IL-1 receptor antagonist (27.9%) compared with corresponding values on study d 7. The ferritin concentration continued to decrease between d 35 and 63 and it was significantly lower on d 63 than on d 7. Because the participants in this study were healthy, no clinical pathology end points were measured. However, results from the present study demonstrate that cherry consumption selectively reduced several biomarkers associated with inflammatory diseases.

Vitamin D3 decreases parathyroid hormone in HIV-infected youth being treated with tenofovir: a randomized, placebo-controlled trial.

BACKGROUND: The study goal was to determine the effect of vitamin D (VITD) supplementation on tubular reabsorption of phosphate (TRP), parathyroid hormone (PTH), bone alkaline phosphatase (BAP), and C-telopeptide (CTX) in youth infected with human immunodeficiency virus (HIV) receiving and not receiving combination antiretroviral therapy (cART) containing tenofovir disoproxil fumarate (TDF). METHODS: This randomized, double-blind, placebo-controlled multicenter trial enrolled HIV-infected youth 18-25 years based on stable treatment with cART containing TDF (n = 118) or no TDF (noTDF; n = 85), and randomized within those groups to vitamin D3, 50 000 IU (n = 102) or placebo (n = 101), administered at 0, 4, and 8 weeks. Outcomes included change in TRP, PTH, BAP, and CTX from baseline to week 12 by TDF/noTDF; and VITD/placebo. RESULTS: At baseline, VITD and placebo groups were similar except those on TDF had lower TRP and higher PTH and CTX. At week 12, 95% in the VITD group had sufficient serum 25-hydroxy vitamin D (25-OHD; ≥20 ng/mL), increased from 48% at baseline, without change in placebo (P < .001). PTH decreased in the TDF group receiving VITD (P = .031) but not in the noTDF group receiving VITD, or either placebo group. The decrease in PTH with VITD in those on TDF occurred with insufficient and sufficient baseline 25-OHD (mean PTH change, -7.9 and -6.2 pg/mL; P = .031 and .053, respectively). CONCLUSIONS: In youth on TDF, vitamin D3 supplementation decreased PTH, regardless of baseline 25-OHD concentration. CLINICAL TRIALS REGISTRATION: NCT00490412.