Therapeutic brain modulation with targeted large neutral amino acid supplements in the Pah-enu2 phenylketonuria mouse model.
Am J Clin Nutr. 2016 Sep 21;
Authors: van Vliet D, Bruinenberg VM, Mazzola PN, van Faassen MH, de Blaauw P, Pascucci T, Puglisi-Allegra S, Kema IP, Heiner-Fokkema MR, van der Zee EA, van Spronsen FJ
BACKGROUND: Phenylketonuria treatment consists mainly of a Phe-restricted diet, which leads to suboptimal neurocognitive and psychosocial outcomes. Supplementation of large neutral amino acids (LNAAs) has been suggested as an alternative dietary treatment strategy to optimize neurocognitive outcome in phenylketonuria and has been shown to influence 3 brain pathobiochemical mechanisms in phenylketonuria, but its optimal composition has not been established.
OBJECTIVE: In order to provide additional pathobiochemical insight and develop optimal LNAA treatment, several targeted LNAA supplements were investigated with respect to all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria.
DESIGN: Pah-enu2 (PKU) mice received 1 of 5 different LNAA-supplemented diets beginning at postnatal day 45. Control groups included phenylketonuria mice receiving an isonitrogenic and isocaloric high-protein diet or the AIN-93M diet, and wild-type mice receiving the AIN-93M diet. After 6 wk, brain and plasma amino acid profiles and brain monoaminergic neurotransmitter concentrations were measured.
RESULTS: Brain Phe concentrations were most effectively reduced by supplementation of LNAAs, such as Leu and Ile, with a strong affinity for the LNAA transporter type 1. Brain non-Phe LNAAs could be restored on supplementation, but unbalanced LNAA supplementation further reduced brain concentrations of those LNAAs that were not (sufficiently) included in the LNAA supplement. To optimally ameliorate brain monoaminergic neurotransmitter concentrations, LNAA supplementation should include Tyr and Trp together with LNAAs that effectively reduce brain Phe concentrations. The requirement for Tyr supplementation is higher than it is for Trp, and the relative effect of brain Phe reduction is higher for serotonin than it is for dopamine and norepinephrine.
CONCLUSION: The study shows that all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria can be targeted by specific LNAA supplements. The study thus provides essential information for the development of optimal LNAA supplementation as an alternative dietary treatment strategy to optimize neurocognitive outcome in patients with phenylketonuria.
PMID: 27655443 [PubMed - as supplied by publisher]
Prospective associations of maternal betaine status with offspring weight and body composition at birth: the GUSTO (Growing Up in Singapore Toward healthy Outcomes) cohort study.
Am J Clin Nutr. 2016 Sep 21;
Authors: van Lee L, Tint MT, Aris IM, Quah PL, Fortier MV, Lee YS, Yap FK, Saw SM, Godfrey KM, Gluckman PD, Chong YS, Kramer MS, Chong MF
BACKGROUND: Betaine supplementation results in lower body weight and fat mass and higher lean mass in animals and adult humans. However, the relation between maternal betaine status and offspring birth weight and body composition is less known.
OBJECTIVE: The aim was to examine the association between maternal betaine status and neonatal birth size and adiposity in an Asian mother-offspring cohort.
DESIGN: We included 955 pregnant women whose plasma betaine concentrations were measured at 26-28 wk of gestation. Neonatal anthropometric values were measured at birth, and abdominal adipose tissue compartments were assessed by MRI in a subset of infants (n = 307) in the first 14 d after birth. Multivariate general linear models were used to adjust for gestational age; fetal sex; and maternal age, height, education, ethnicity, prepregnancy body mass index, and plasma folate, vitamin B-12, and choline concentrations.
RESULTS: The mean ± SD plasma concentration of betaine was 13.2 ± 2.7 μmol/L (range: 5.3-25.0 μmol/L). After adjustment for covariates, higher maternal plasma betaine was associated with lower birth weight (β: -57.6 g; 95% CI: -109.9, -5.3 g), shorter birth length (β: -0.29 cm per 5-μmol/L increment; 95% CI: -0.55, -0.03 cm), smaller head circumference (-0.20 cm; 95% CI: -0.38, -0.02 cm), smaller midupper arm circumference (-0.16 cm; 95% CI: -0.30, -0.03 cm), lower volumes of abdominal superficial subcutaneous adipose tissue (-4.53 mL; 95% CI: -8.70, -0.36 mL), and a higher risk of small-for-gestational-age birth (OR: 1.57; 95% CI: 1.05, 2.35).
CONCLUSIONS: Higher maternal betaine status was generally associated with smaller infant birth size and less abdominal fat mass. Further studies are needed to replicate these findings and to understand their biological mechanisms. This study was registered at clinicaltrials.gov as NCT01174875.
PMID: 27655442 [PubMed - as supplied by publisher]
Mortality in children with complicated severe acute malnutrition is related to intestinal and systemic inflammation: an observational cohort study.
Am J Clin Nutr. 2016 Sep 21;
Authors: Attia S, Versloot CJ, Voskuijl W, van Vliet SJ, Di Giovanni V, Zhang L, Richardson S, Bourdon C, Netea MG, Berkley JA, van Rheenen PF, Bandsma RH
BACKGROUND: Diarrhea affects a large proportion of children with severe acute malnutrition (SAM). However, its etiology and clinical consequences remain unclear.
OBJECTIVE: We investigated diarrhea, enteropathogens, and systemic and intestinal inflammation for their interrelation and their associations with mortality in children with SAM.
DESIGN: Intestinal pathogens (n = 15), cytokines (n = 29), fecal calprotectin, and the short-chain fatty acids (SCFAs) butyrate and propionate were determined in children aged 6-59 mo (n = 79) hospitalized in Malawi for complicated SAM. The relation between variables, diarrhea, and death was assessed with partial least squares (PLS) path modeling.
RESULTS: Fatal subjects (n = 14; 18%) were younger (mean ± SD age: 17 ± 11 compared with 25 ± 11 mo; P = 0.01) with higher prevalence of diarrhea (46% compared with 18%, P = 0.03). Intestinal pathogens Shigella (36%), Giardia (33%), and Campylobacter (30%) predominated, but their presence was not associated with death or diarrhea. Calprotectin was significantly higher in children who died [median (IQR): 1360 mg/kg feces (2443-535 mg/kg feces) compared with 698 mg/kg feces (1438-244 mg/kg feces), P = 0.03]. Butyrate [median (IQR): 31 ng/mL (112-22 ng/mL) compared with 2036 ng/mL (5800-149 ng/mL), P = 0.02] and propionate [median (IQR): 167 ng/mL (831-131 ng/mL) compared with 3174 ng/mL (5819-357 ng/mL), P = 0.04] were lower in those who died. Mortality was directly related to high systemic inflammation (path coefficient = 0.49), whereas diarrhea, high calprotectin, and low SCFA production related to death indirectly via their more direct association with systemic inflammation.
CONCLUSIONS: Diarrhea, high intestinal inflammation, low concentrations of fecal SCFAs, and high systemic inflammation are significantly related to mortality in SAM. However, these relations were not mediated by the presence of intestinal pathogens. These findings offer an important understanding of inflammatory changes in SAM, which may lead to improved therapies. This trial was registered at www.controlled-trials.com as ISRCTN13916953.
PMID: 27655441 [PubMed - as supplied by publisher]
Intragastric administration of leucine or isoleucine lowers the blood glucose response to a mixed-nutrient drink by different mechanisms in healthy, lean volunteers.
Am J Clin Nutr. 2016 Sep 21;
Authors: Ullrich SS, Fitzgerald PC, Schober G, Steinert RE, Horowitz M, Feinle-Bisset C
BACKGROUND: The branched-chain amino acids leucine and isoleucine lower blood glucose after oral glucose ingestion, and the intraduodenal infusion of leucine decreases energy intake in healthy, lean men.
OBJECTIVE: We investigated the effects of the intragastric administration of leucine and isoleucine on the gastric emptying of, and blood glucose responses to, a physiologic mixed-macronutrient drink and subsequent energy intake.
DESIGN: In 2 separate studies, 12 healthy, lean subjects received on 3 separate occasions an intragastric infusion of 5 g leucine (leucine-5g) or an intragastric infusion of 10 g leucine (leucine-10g), an intragastric infusion of 5 g isoleucine (isoleucine-5g) or an intragastric infusion of 10 g isoleucine (isoleucine-10g), or a control. Fifteen minutes later, subjects consumed a mixed-nutrient drink (400 kcal, 56 g carbohydrates, 15 g protein, and 12 g fat), and gastric emptying ((13)C-acetate breath test) and blood glucose, plasma insulin, C-peptide, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and cholecystokinin (leucine study only) were measured for 60 min. Immediately afterward, energy intake from a cold, buffet-style meal was assessed.
RESULTS: Compared with the control, leucine-10g decreased the blood glucose area under the curve (AUC) (P < 0.05) and tended to reduce peak blood glucose (P = 0.07), whereas effects of leucine-5g were NS. Leucine-10g, but not leucine-5g, increased plasma insulin and C-peptide AUCs (P < 0.01 for both), but neither dose affected glucagon, GLP-1, GIP, cholecystokinin, gastric emptying, or energy intake. Compared with the control, isoleucine-10g reduced the blood glucose AUC and peak blood glucose (P < 0.01), whereas effects of isoleucine-5g were NS. Neither load affected insulin, C-peptide, glucagon, GLP-1, or GIP. Isoleucine-10g, but not isoleucine-5g, slowed gastric emptying (P < 0.05), but gastric emptying was not correlated with the blood glucose AUC. Isoleucine did not affect energy intake.
CONCLUSIONS: In healthy subjects, both leucine and isoleucine reduced blood glucose in response to a mixed-nutrient drink but did not affect subsequent energy intake. The mechanisms underlying glucose lowering appear to differ; leucine stimulated insulin, whereas isoleucine acted insulin independently. These trials were registered at www.anzctr.org.au as 12613000899741 and 12614000837628.
PMID: 27655440 [PubMed - as supplied by publisher]
Dietary flavonoid intake and incident coronary heart disease: the REasons for Geographic and Racial Differences in Stroke (REGARDS) study.
Am J Clin Nutr. 2016 Sep 21;
Authors: Goetz ME, Judd SE, Safford MM, Hartman TJ, McClellan WM, Vaccarino V
BACKGROUND: Flavonoids are dietary polyphenolic compounds with a variety of proposed beneficial cardiovascular effects, but rigorous prospective studies that examine the association between flavonoid intake and incident coronary heart disease (CHD) in geographically and racially diverse US samples are limited.
OBJECTIVE: With the use of the new, expanded USDA flavonoid database, we assessed the association between total flavonoid and flavonoid subclass intakes with incident CHD in a biracial and geographically diverse cohort, as well as effect modification by age, sex, race, and region of residence.
DESIGN: Participants were 16,678 black and white men and women enrolled in the REGARDS (REasons for Geographic and Racial Differences in Stroke) study, a national prospective cohort study. All participants were without CHD at baseline, and all completed a Block98 food-frequency questionnaire. Flavonoid intakes were estimated from USDA flavonoid databases, which were recently improved to address missing values for cooked foods and to adjust for flavonoid losses due to processing. Incident CHD events were participant reported and adjudicated by experts. Quintiles of flavonoid intake were examined as predictors of incident CHD by using Cox proportional hazards regression to obtain HRs. Tests for trend used the quintile medians.
RESULTS: Over a mean ± SD follow-up of 6.0 ± 1.9 y, there were 589 CHD events. High flavonoid intake was associated with self-identified white race, exercise, not smoking, more education, and higher income. In models that adjusted for sociodemographic, health behavior, and dietary factors, there was an inverse association between anthocyanidin and proanthocyanidin intakes and incident CHD (HRs for quintile 5 compared with quintile 1-anthocyanidins: 0.71; 95% CI: 0.52, 0.98; P-trend = 0.04; proanthocyanidins: 0.63; 95% CI: 0.47, 0.84; P-trend = 0.02). There was no association between total flavonoid or other flavonoid subclass intakes and incident CHD.
CONCLUSIONS: Reported anthocyanidin and proanthocyanidin intakes were inversely associated with incident CHD. There was no significant effect modification by age, sex, race, or region of residence.
PMID: 27655439 [PubMed - as supplied by publisher]
Estimation of the dietary requirement for vitamin D in adolescents aged 14-18 y: a dose-response, double-blind, randomized placebo-controlled trial.
Am J Clin Nutr. 2016 Sep 21;
Authors: Smith TJ, Tripkovic L, Damsgaard CT, Mølgaard C, Ritz C, Wilson-Barnes SL, Dowling KG, Hennessy Á, Cashman KD, Kiely M, Lanham-New SA, Hart KH
BACKGROUND: Adolescents are a population group at high risk of low vitamin D status, yet the evidence base for establishing dietary vitamin D requirements remains weak.
OBJECTIVE: The aim was to establish the distribution of vitamin D intakes required to maintain serum 25-hydroxyvitamin D [25(OH)D] concentrations above proposed cutoffs (25, 30, 40, and 50 nmol/L) during winter in white males and females (14-18 y of age) in the United Kingdom (51°N).
DESIGN: In a dose-response trial, 110 adolescents (aged 15.9 ± 1.4 y; 43% males) were randomly assigned to receive 0, 10, or 20 μg vitamin D3 supplements/d for 20 wk during winter. A nonlinear regression model was fit to total vitamin D intake and postintervention serum 25(OH)D concentrations, and regression-predicted values estimated the vitamin D intakes required to maintain serum 25(OH)D concentrations above specific cutoffs.
RESULTS: Mean ± SD serum 25(OH)D concentrations increased from 49.2 ± 12.0 to 56.6 ± 12.4 nmol/L and from 51.7 ± 13.4 to 63.9 ± 10.6 nmol/L in the 10- and 20-μg/d groups, respectively, and decreased in the placebo group from 46.8 ± 11.4 to 30.7 ± 8.6 nmol/L (all P ≤ 0.001). Vitamin D intakes required to maintain 25(OH)D concentrations >25 and >30 nmol/L in 97.5% of adolescents were estimated to be 10.1 and 13.1 μg/d, respectively, and 6.6 μg/d to maintain 50% of adolescents at concentrations >40 nmol/L. Because the response of 25(OH)D reached a plateau at 46 nmol/L, there is uncertainty in estimating the vitamin D intake required to maintain 25(OH)D concentrations >50 nmol/L in 97.5% of adolescents, but it exceeded 30 μg/d.
CONCLUSION: Vitamin D intakes between 10 and ∼30 μg/d are required by white adolescents during winter to maintain serum 25(OH)D concentrations >25-50 nmol/L, depending on the serum 25(OH)D threshold chosen. This trial was registered at clinicaltrials.gov as NCT02150122 and as International Standard Randomized Controlled Trial Number ISRCTN40736890.
PMID: 27655438 [PubMed - as supplied by publisher]