Publications by authors named "Adrian McCann"

46 Publications

Cobalamin and folate status in women during early pregnancy in Bhaktapur, Nepal.

J Nutr Sci 2021;10:e57. Epub 2021 Aug 9.

Centre for Intervention Science in Maternal and Child Health, Centre for International Health, Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.

The demand for cobalamin (vitamin B12) and folate is increased during pregnancy, and deficiency during pregnancy may lead to complications and adverse outcomes. Yet, the status of these micronutrients is unknown in many populations. We assessed the concentration of cobalamin, folate and their functional biomarkers, total homocysteine (tHcy) and methylmalonic acid (MMA), in 561 pregnant women enrolled in a community-based randomised controlled trial in Bhaktapur, Nepal. Plasma concentrations of cobalamin, folate, tHcy and MMA were measured and a combined indicator of vitamin B12 status (3cB12) was calculated. We report mean or median concentrations and the prevalence of deficiency according to commonly used cut-offs, and assessed their association with indicators of socio-economic status, and maternal and dietary characteristics by linear regression. Among the women at gestational week less than 15, deficiencies of cobalamin and folate were seen in 24 and 1 %, respectively. Being a vegetarian was associated with lower plasma cobalamin, and a higher socio-economic status was associated with a better micronutrient status. We conclude that cobalamin deficiency defined by commonly used cut-offs was common in Nepalese women in early pregnancy. In contrast, folate deficiency was rare. As there is no consensus on cut-off points for vitamin B12 deficiency during pregnancy, future studies are needed to assess the potential functional consequences of these low values.
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http://dx.doi.org/10.1017/jns.2021.53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358842PMC
August 2021

Baked cod consumption delayed the development of kidney and liver dysfunction and affected plasma amino acid concentrations, but did not affect blood pressure, blood glucose or liver triacylglycerol concentrations in obese fa/fa Zucker rats.

Nutr Res 2021 08 12;92:72-83. Epub 2021 Jun 12.

Dietary Protein Research Group, Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway. Electronic address:

Obesity is associated with changes in amino acid metabolism, and studies show that ingestion of fish proteins influence amino acid composition in plasma and urine, in addition to affecting risk factors for metabolic syndrome. Since the majority of fish proteins consumed by humans are as fish fillet, it is of interest to investigate if cod fillet intake affects amino acid composition and metabolic disorders. We hypothesized that a modified AIN-93G diet containing cod fillet would affect amino acid compositions in plasma and urine in obese rats, and also affect risk factors for metabolic syndrome when compared to rats fed a regular AIN-93G diet with casein as the protein source. Obese Zucker fa/fa rats, a rat model of metabolic syndrome, received diets containing 25% protein from lyophilized baked cod fillet and 75% protein from casein (Baked cod diet), or a Control diet with casein for four weeks. The Baked cod diet affected the amino acid composition in plasma, with e.g., lower glycine, histidine, homoarginine, homocysteine, methionine, proline and tyrosine concentrations, but did not affect amino acid concentrations in urine. The concentrations of markers for kidney and liver dysfunction were lower in the Baked cod group, however blood pressure development, fasting and postprandial glucose, and hepatic triacylglycerol concentrations were similar to the Control group. To conclude, substituting 25% of dietary protein with baked cod fillet affected concentrations of some amino acids in plasma and delayed development of kidney and liver dysfunction, but did not affect blood pressure, glucose concentration or fatty liver.
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http://dx.doi.org/10.1016/j.nutres.2021.05.009DOI Listing
August 2021

Quantifying Precision Loss in Targeted Metabolomics Based on Mass Spectrometry and Nonmatching Internal Standards.

Anal Chem 2021 06 20;93(21):7616-7624. Epub 2021 May 20.

Bevital, Laboratoriebygget, 9 etg., Jonas Lies veg 87, 5021 Bergen, Norway.

In mass spectrometry, reliable quantification requires correction for variations in ionization efficiency between samples. The preferred method is the addition of a stable isotope-labeled internal standard (SIL-IS). In targeted metabolomics, a dedicated SIL-IS for each metabolite of interest may not always be realized due to high cost or limited availability. We recently completed the analysis of more than 70 biomarkers, each with a matching SIL-IS, across four mass spectrometry-based platforms (one GC-MS/MS and three LC-MS/MS). Using data from calibrator and quality control samples added to 60 96-well trays (analytical runs), we calculated analytical precision (CV) retrospectively. The use of integrated peak areas for all metabolites and internal standards allowed us to calculate precision for all matching analyte (A)/SIL-IS (IS) pairs as well as for all nonmatching A/IS pairs within each platform (total = 1442). The median between-run precision for matching A/IS across the four platforms was 2.7-5.9%. The median CV for nonmatching A/IS (corresponding to pairing analytes with a non-SIL-IS) was 2.9-10.7 percentage points higher. Across all platforms, CVs for nonmatching A/IS increased with increasing difference in retention time (Spearman's rho of 0.17-0.93). The CV difference for nonmatching vs matching A/IS was often, but not always, smaller when analytes and internal standards were close structural analogs.
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http://dx.doi.org/10.1021/acs.analchem.1c00119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611570PMC
June 2021

Biomarkers and Fatty Fish Intake: A Randomized Controlled Trial in Norwegian Preschool Children.

J Nutr 2021 Aug;151(8):2134-2141

Innlandet Hospital Trust, Lillehammer, Norway.

Background: Biomarkers such as omega-3 (n-3) PUFAs, urinary iodine concentration (UIC), 1-methylhistidine (1-MH), and trimethylamine N-oxide (TMAO) have been associated with fish intake in observational studies, but data from children in randomized controlled trials are limited.

Objectives: The objective of this exploratory analysis was to investigate the effects of fatty fish intake compared with meat intake on various biomarkers in preschool children.

Methods: We randomly allocated (1:1) 232 children, aged 4 to 6 y, from 13 kindergartens. The children received lunch meals of either fatty fish (herring/mackerel) or meat (chicken/lamb/beef) 3 times a week for 16 wk. We analyzed 86 biomarkers in plasma (n = 207), serum (n = 195), RBCs (n = 211), urine (n = 200), and hair samples (n = 210). We measured the effects of the intervention on the normalized biomarker concentrations in linear mixed-effect regression models taking the clustering within the kindergartens into account. The results are presented as standardized effect sizes.

Results: We found significant effects of the intervention on the following biomarkers: RBC EPA (20:5n-3), 0.61 (95% CI: 0.36, 0.86); DHA (22:6n-3), 0.43 (95% CI: 0.21, 0.66); total n-3 PUFAs, 0.41 (95% CI: 0.20, 0.64); n-3/n-6 ratio, 0.48 (95% CI: 0.24, 0.71); adrenic acid (22:4n-6, -0.65 (95% CI: -0.91, -0.40), arachidonic acid (20:4n-6), -0.54 (95% CI: -0.79, -0.28); total n-6 PUFAs, -0.31 (95% CI: -0.56, -0.06); UIC, 0.32 (95% CI: 0.052, 0.59); hair mercury, 0.83 (95% CI: 0.05, 1.05); and plasma 1-MH, -0.35 (95% CI: -0.61, -0.094).

Conclusions: Of the 86 biomarkers, the strongest effect of fatty fish intake was on n-3 PUFAs, UIC, hair mercury, and plasma 1-MH. We observed no or limited effects on biomarkers related to micronutrient status, inflammation, or essential amino acid, choline oxidation, and tryptophan pathways.The trial was registered at clinicaltrials.gov (NCT02331667).
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http://dx.doi.org/10.1093/jn/nxab112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349119PMC
August 2021

Pre-diagnostic circulating concentrations of fat-soluble vitamins and risk of glioma in three cohort studies.

Sci Rep 2021 Apr 29;11(1):9318. Epub 2021 Apr 29.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Few prospective studies have evaluated the relation between fat-soluble vitamins and glioma risk. Using three cohorts-UK Biobank (UKB), Nurses' Health Study (NHS), and Health Professionals Follow-Up Study (HPFS), we investigated associations of pre-diagnostic concentrations of fat-soluble vitamins D, A, and E with incident glioma. In 346,785 participants (444 cases) in UKB, associations with vitamin D (25-hydroxyvitamin D [25(OH)D]) were evaluated by Cox proportional hazards regression. In NHS (52 cases, 104 controls) and HPFS (32 cases, 64 controls), associations with 25(OH)D, vitamin A (retinol), and vitamin E (α- and γ-tocopherol) were assessed using conditional logistic regression. Our results suggested plasma concentrations of 25(OH)D and retinol were not associated with glioma risk. Comparing the highest to lowest tertile, the multivariable hazard ratio (MVHR) for 25(OH)D was 0.87 (95% confidence interval [CI] 0.68-1.11) in UKB and the multivariable risk ratio (MVRR) was 0.97 (95% CI 0.51-1.85) in NHS and HPFS. In NHS and HPFS, the MVRR for the same comparison for retinol was 1.16 (95% CI 0.56-2.38). Nonsignificant associations were observed for α-tocopherol (MVRR = 0.61, 95% CI 0.29-1.32) and γ-tocopherol (MVRR  = 1.30, 95% CI 0.63-2.69) that became stronger in 4-year lagged analyses. Further investigation is warranted on a potential association between α- and γ-tocopherol and glioma risk.
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http://dx.doi.org/10.1038/s41598-021-88485-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084971PMC
April 2021

Serum tyrosine is associated with better cognition in Lewy body dementia.

Brain Res 2021 08 16;1765:147481. Epub 2021 Apr 16.

Department of Internal Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway.

Amino acids' neuroactivity, and roles in excitotoxity and oxidative stress are linked to dementia. We aimed to investigate whether circulating amino acid concentrations were associated with cognitive decline in patients with mild Alzheimer's disease (AD) and Lewy body dementia (LBD). Baseline serum amino acid concentrations were measured in 89 patients with AD and 65 with LBD (13 with Parkinson's disease dementia and 52 with dementia with Lewy bodies). The Mini-Mental State Examination (MMSE) was administered at baseline and annually for five years. Associations between baseline amino acid concentrations and longitudinal MMSE score were assessed using a linear-mixed effects model stratified by diagnosis with adjustment for multiple comparisons. The results of the study indicated that serum tyrosine was positively associated with MMSE performance during the five-year follow-up period in patients with LBD (q-value = 0.012), but not AD. In conclusion, higher baseline serum concentrations of tyrosine, the precursor amino acid in dopamine and norepinephrine synthesis, was associated with better cognitive performance in patients with LBD, but not AD, throughout the 5-year follow-up period.
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http://dx.doi.org/10.1016/j.brainres.2021.147481DOI Listing
August 2021

The Pah-R261Q mouse reveals oxidative stress associated with amyloid-like hepatic aggregation of mutant phenylalanine hydroxylase.

Nat Commun 2021 04 6;12(1):2073. Epub 2021 Apr 6.

Department of Biomedicine, University of Bergen, Bergen, Norway.

Phenylketonuria (PKU) is caused by autosomal recessive variants in phenylalanine hydroxylase (PAH), leading to systemic accumulation of L-phenylalanine (L-Phe) that may reach neurotoxic levels. A homozygous Pah-R261Q mouse, with a highly prevalent misfolding variant in humans, reveals the expected hepatic PAH activity decrease, systemic L-Phe increase, L-tyrosine and L-tryptophan decrease, and tetrahydrobiopterin-responsive hyperphenylalaninemia. Pah-R261Q mice also present unexpected traits, including altered lipid metabolism, reduction of liver tetrahydrobiopterin content, and a metabolic profile indicative of oxidative stress. Pah-R261Q hepatic tissue exhibits large ubiquitin-positive, amyloid-like oligomeric aggregates of mutant PAH that colocalize with selective autophagy markers. Together, these findings reveal that PKU, customarily considered a loss-of-function disorder, can also have toxic gain-of-function contribution from protein misfolding and aggregation. The proteostasis defect and concomitant oxidative stress may explain the prevalence of comorbid conditions in adult PKU patients, placing this mouse model in an advantageous position for the discovery of mutation-specific biomarkers and therapies.
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http://dx.doi.org/10.1038/s41467-021-22107-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024259PMC
April 2021

The Role of the Transsulfuration Pathway in Non-Alcoholic Fatty Liver Disease.

J Clin Med 2021 Mar 5;10(5). Epub 2021 Mar 5.

Gastro Unit, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and approximately 25% of the global population may have NAFLD. NAFLD is associated with obesity and metabolic syndrome, but its pathophysiology is complex and only partly understood. The transsulfuration pathway (TSP) is a metabolic pathway regulating homocysteine and cysteine metabolism and is vital in controlling sulfur balance in the organism. Precise control of this pathway is critical for maintenance of optimal cellular function. The TSP is closely linked to other pathways such as the folate and methionine cycles, hydrogen sulfide (HS) and glutathione (GSH) production. Impaired activity of the TSP will cause an increase in homocysteine and a decrease in cysteine levels. Homocysteine will also be increased due to impairment of the folate and methionine cycles. The key enzymes of the TSP, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), are highly expressed in the liver and deficient CBS and CSE expression causes hepatic steatosis, inflammation, and fibrosis in animal models. A causative link between the TSP and NAFLD has not been established. However, dysfunctions in the TSP and related pathways, in terms of enzyme expression and the plasma levels of the metabolites (e.g., homocysteine, cystathionine, and cysteine), have been reported in NAFLD and liver cirrhosis in both animal models and humans. Further investigation of the TSP in relation to NAFLD may reveal mechanisms involved in the development and progression of NAFLD.
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http://dx.doi.org/10.3390/jcm10051081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961611PMC
March 2021

One-Carbon Metabolism in Nepalese Infant-Mother Pairs and Child Cognition at 5 Years Old.

J Nutr 2021 04;151(4):883-891

Center for International Health, University of Bergen, Bergen, Norway.

Background: One-carbon metabolism (OCM) refers to the transfer of methyl groups central to DNA methylation and histone modification. Insufficient access to methyl donors and B-vitamin cofactors affects epigenetic maintenance and stability, and when occurring in early life may impact future health and neurodevelopment.

Objective: The objective of this study was to examine the relative associations between one-carbon metabolites in Nepalese mother-infant pairs and child cognition measured at 5 y of age.

Methods: This is a cross-sectional study from Bhaktapur, Nepal, in a population at high risk of subclinical B-vitamin deficiencies and cumulative infection burden. Venous blood samples from 500 mother-infant pairs were collected when the infants were 2 to 12 mo old, and metabolite concentrations measured by microbiological assays and GC-tandem MS. We re-enrolled 321 of these children at 5 y and assessed cognition by the Ages and Stages Questionnaire, 3rd edition, and subtests from the Developmental Neuropsychological Assessment, 2nd edition (NEPSY-II). The associations of the independent metabolites or unobserved metabolic phenotypes (identified by latent class analysis) with the cognitive outcomes were estimated by seemingly unrelated regression. We explored direct and indirect relations between the OCM pathway and the cognitive outcomes using path analysis.

Results: Infant cystathionine concentration was inversely associated with 4 cognitive outcomes (standardized βs ranging from -0.22 to -0.11, P values from <0.001 to 0.034). Infants with a metabolic phenotype indicating impaired OCM and low vitamin B-12 status had poorer cognitive outcomes compared with infants with normal OCM activity and adequate vitamin B-12 status (standardized βs ranging from -0.80 to -0.40, P < 0.001 and 0.05). In the path analysis, we found several OCM biomarkers were associated with affect recognition through infant plasma cystathionine.

Conclusions: Elevated plasma cystathionine during infancy reflects a metabolic phenotype of impaired OCM and low vitamin B-12 status and is associated with poorer cognitive function when the children are 5 y old.
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http://dx.doi.org/10.1093/jn/nxaa403DOI Listing
April 2021

Role of the Neutral Amino Acid Transporter SLC7A10 in Adipocyte Lipid Storage, Obesity, and Insulin Resistance.

Diabetes 2021 03 6;70(3):680-695. Epub 2021 Jan 6.

Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway

Elucidation of mechanisms that govern lipid storage, oxidative stress, and insulin resistance may lead to improved therapeutic options for type 2 diabetes and other obesity-related diseases. Here, we find that adipose expression of the small neutral amino acid transporter SLC7A10, also known as alanine-serine-cysteine transporter-1 (ASC-1), shows strong inverse correlates with visceral adiposity, insulin resistance, and adipocyte hypertrophy across multiple cohorts. Concordantly, loss of Slc7a10 function in zebrafish in vivo accelerates diet-induced body weight gain and adipocyte enlargement. Mechanistically, SLC7A10 inhibition in human and murine adipocytes decreases adipocyte serine uptake and total glutathione levels and promotes reactive oxygen species (ROS) generation. Conversely, SLC7A10 overexpression decreases ROS generation and increases mitochondrial respiratory capacity. RNA sequencing revealed consistent changes in gene expression between human adipocytes and zebrafish visceral adipose tissue following loss of SLC7A10, e.g., upregulation of (lipid storage) and downregulation of (lipid oxidation). Interestingly, ROS scavenger reduced lipid accumulation and attenuated the lipid-storing effect of SLC7A10 inhibition. These data uncover adipocyte SLC7A10 as a novel important regulator of adipocyte resilience to nutrient and oxidative stress, in part by enhancing glutathione levels and mitochondrial respiration, conducive to decreased ROS generation, lipid accumulation, adipocyte hypertrophy, insulin resistance, and type 2 diabetes.
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http://dx.doi.org/10.2337/db20-0096DOI Listing
March 2021

Altered Gut Microbial Metabolism of Essential Nutrients in Primary Sclerosing Cholangitis.

Gastroenterology 2021 04 31;160(5):1784-1798.e0. Epub 2020 Dec 31.

Norwegian Primary Sclerosing Cholangitis Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway. Electronic address:

Background & Aims: To influence host and disease phenotype, compositional microbiome changes, which have been demonstrated in patients with primary sclerosing cholangitis (PSC), must be accompanied by functional changes. We therefore aimed to characterize the genetic potential of the gut microbiome in patients with PSC compared with healthy controls (HCs) and patients with inflammatory bowel disease (IBD).

Methods: Fecal DNA from 2 cohorts (1 Norwegian and 1 German), in total comprising 136 patients with PSC (58% with IBD), 158 HCs, and 93 patients with IBD without PSC, were subjected to metagenomic shotgun sequencing, generating 17 billion paired-end sequences, which were processed using HUMAnN2 and MetaPhlAn2, and analyzed using generalized linear models and random effects meta-analyses.

Results: Patients with PSC had fewer microbial genes compared with HCs (P < .0001). Compared with HCs, patients with PSC showed enrichment and increased prevalence of Clostridium species and a depletion of, for example, Eubacterium spp and Ruminococcus obeum. Patients with PSC showed marked differences in the abundance of genes related to vitamin B6 synthesis and branched-chain amino acid synthesis (Q < .05). Targeted metabolomics of plasma from an independent set of patients with PSC and controls found reduced concentrations of vitamin B6 and branched-chain amino acids in PSC (P < .0001), which strongly associated with reduced liver transplantation-free survival (log-rank P < .001). No taxonomic or functional differences were detected between patients with PSC with and without IBD.

Conclusions: The gut microbiome in patients with PSC exhibits large functional differences compared with that in HCs, including microbial metabolism of essential nutrients. Alterations in related circulating metabolites associated with disease course, suggesting that microbial functions may be relevant for the disease process in PSC.
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http://dx.doi.org/10.1053/j.gastro.2020.12.058DOI Listing
April 2021

Microheterogeneity and preanalytical stability of protein biomarkers of inflammation and renal function.

Talanta 2021 Feb 14;223(Pt 1):121774. Epub 2020 Oct 14.

Bevital AS, Jonas Lies veg 87, Laboratory building, 5021, Bergen, Norway.

Protein biomarker microheterogeneity has attracted increasing attention in epidemiological and clinical research studies. Knowledge concerning the preanalytical stability of proteins is paramount to assess the biological significance of their proteoforms. We investigated the stability of the inflammatory markers C-reactive protein (CRP), serum amyloid A (SAA), and calprotectin (S100A8/9), and the renal function marker, cystatin C (CnC). In total 16 proteoforms were quantified by immuno-MALDI-TOF MS in EDTA plasma and serum samples from 15 healthy volunteers. Prior to analysis blood samples were stored at either room temperature from 1 h up to 8 days, or underwent up to 9 consecutive freeze/thaw cycles. Pearson's correlation coefficient and t-test, intra-class correlation coefficient (ICC), and Autoregressive Integrated Moving-Average (ARIMA) models were used to investigate the stability of proteoform concentrations and distributions in blood. Plasma and serum concentrations of CRP and SAA proteoforms were highly stable during room temperature exposure and repeated freeze/thaw cycles, demonstrating excellent reproducibility (ICC > 0.75), no serial dependency in ARIMA models, and stable distribution of proteoforms. Stability analyses for proteoforms of S100A8/9 and CnC identified only minor preanalytical changes in concentrations and distributions, and none of the proteoforms were produced during prolonged exposure to room temperature or repeated freezing/thawing. The four proteins and their proteoforms are stable during sub-optimal sample handling, and represent robust biomarker candidates for future biobank studies aimed at investigating the microheterogeneity of SAA, S100A8/9, and CnC in relation to inflammation, renal dysfunction and various clinical outcomes.
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http://dx.doi.org/10.1016/j.talanta.2020.121774DOI Listing
February 2021

Effects of vitamin B12 supplementation on neurodevelopment and growth in Nepalese Infants: A randomized controlled trial.

PLoS Med 2020 12 1;17(12):e1003430. Epub 2020 Dec 1.

Department of Community Medicine, Kathmandu Medical College, Kathmandu, Nepal.

Background: Vitamin B12 deficiency is common and affects cell division and differentiation, erythropoiesis, and the central nervous system. Several observational studies have demonstrated associations between biomarkers of vitamin B12 status with growth, neurodevelopment, and anemia. The objective of this study was to measure the effects of daily supplementation of vitamin B12 for 1 year on neurodevelopment, growth, and hemoglobin concentration in infants at risk of deficiency.

Methods And Findings: This is a community-based, individually randomized, double-blind placebo-controlled trial conducted in low- to middle-income neighborhoods in Bhaktapur, Nepal. We enrolled 600 marginally stunted, 6- to 11-month-old infants between April 2015 and February 2017. Children were randomized in a 1:1 ratio to 2 μg of vitamin B12, corresponding to approximately 2 to 3 recommended daily allowances (RDAs) or a placebo daily for 12 months. Both groups were also given 15 other vitamins and minerals at around 1 RDA. The primary outcomes were neurodevelopment measured by the Bayley Scales of Infant and Toddler Development 3rd ed. (Bayley-III), attained growth, and hemoglobin concentration. Secondary outcomes included the metabolic response measured by plasma total homocysteine (tHcy) and methylmalonic acid (MMA). A total of 16 children (2.7%) in the vitamin B12 group and 10 children (1.7%) in the placebo group were lost to follow-up. Of note, 94% of the scheduled daily doses of vitamin B12 or placebo were reported to have been consumed (in part or completely). In this study, we observed that there were no effects of the intervention on the Bayley-III scores, growth, or hemoglobin concentration. Children in both groups grew on an average 12.5 cm (SD: 1.8), and the mean difference was 0.20 cm (95% confidence interval (CI): -0.23 to 0.63, P = 0.354). Furthermore, at the end of the study, the mean difference in hemoglobin concentration was 0.02 g/dL (95% CI: -1.33 to 1.37, P = 0.978), and the difference in the cognitive scaled scores was 0.16 (95% CI: -0.54 to 0.87, P = 0.648). The tHcy and MMA concentrations were 23% (95% CI: 17 to 30, P < 0.001) and 30% (95% CI: 15 to 46, P < 0.001) higher in the placebo group than in the vitamin B12 group, respectively. We observed 43 adverse events in 36 children, and these events were not associated with the intervention. In addition, 20 in the vitamin B12 group and 16 in the placebo group were hospitalized during the supplementation period. Important limitations of the study are that the strict inclusion criteria could limit the external validity and that the period of vitamin B12 supplementation might not have covered a critical window for infant growth or brain development.

Conclusions: In this study, we observed that vitamin B12 supplementation in young children at risk of vitamin B12 deficiency resulted in an improved metabolic response but did not affect neurodevelopment, growth, or hemoglobin concentration. Our results do not support widespread vitamin B12 supplementation in marginalized infants from low-income countries.

Trial Registration: ClinicalTrials.gov NCT02272842 Universal Trial Number: U1111-1161-5187 (September 8, 2014) Trial Protocol: Original trial protocol: PMID: 28431557 (reference [18]; study protocols and plan of analysis included as Supporting information).
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http://dx.doi.org/10.1371/journal.pmed.1003430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707571PMC
December 2020

Impact of the common MTHFR 677C→T polymorphism on blood pressure in adulthood and role of riboflavin in modifying the genetic risk of hypertension: evidence from the JINGO project.

BMC Med 2020 11 11;18(1):318. Epub 2020 Nov 11.

The Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK.

Background: Genome-wide and clinical studies have linked the 677C→T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) with hypertension, whilst limited evidence shows that intervention with riboflavin (i.e. the MTHFR co-factor) can lower blood pressure (BP) in hypertensive patients with the variant MTHFR 677TT genotype. We investigated the impact of this common polymorphism on BP throughout adulthood and hypothesised that riboflavin status would modulate the genetic risk of hypertension.

Methods: Observational data on 6076 adults of 18-102 years were drawn from the Joint Irish Nutrigenomics Organisation project, comprising the Trinity-Ulster Department of Agriculture (TUDA; volunteer sample) and the National Adult Nutrition Survey (NANS; population-based sample) cohorts. Participants were recruited from the Republic of Ireland and Northern Ireland (UK) in 2008-2012 using standardised methods.

Results: The variant MTHFR 677TT genotype was identified in 12% of adults. From 18 to 70 years, this genotype was associated with an increased risk of hypertension (i.e. systolic BP ≥ 140 and/or a diastolic BP ≥ 90 mmHg): odds ratio (OR) 1.42, 95% confidence interval (CI) 1.07 to 1.90; P = 0.016, after adjustment for antihypertensive drug use and other significant factors, namely, age, male sex, BMI, alcohol and total cholesterol. Low or deficient biomarker status of riboflavin (observed in 30.2% and 30.0% of participants, respectively) exacerbated the genetic risk of hypertension, with a 3-fold increased risk for the TT genotype in combination with deficient riboflavin status (OR 3.00, 95% CI, 1.34-6.68; P = 0.007) relative to the CC genotype combined with normal riboflavin status. Up to 65 years, we observed poorer BP control rates on antihypertensive treatment in participants with the TT genotype (30%) compared to those without this variant, CT (37%) and CC (45%) genotypes (P < 0.027).

Conclusions: The MTHFR 677TT genotype is associated with higher BP independently of homocysteine and predisposes adults to an increased risk of hypertension and poorer BP control with antihypertensive treatment, whilst better riboflavin status is associated with a reduced genetic risk. Riboflavin intervention may thus offer a personalised approach to prevent the onset of hypertension in adults with the TT genotype; however, this requires confirmation in a randomised trial in non-hypertensive adults.
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http://dx.doi.org/10.1186/s12916-020-01780-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656675PMC
November 2020

3-Hydroxyisobutyrate, A Strong Marker of Insulin Resistance in Type 2 Diabetes and Obesity That Modulates White and Brown Adipocyte Metabolism.

Diabetes 2020 09 25;69(9):1903-1916. Epub 2020 Jun 25.

Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway

Circulating branched-chain amino acids (BCAAs) associate with insulin resistance and type 2 diabetes. 3-Hydroxyisobutyrate (3-HIB) is a catabolic intermediate of the BCAA valine. In this study, we show that in a cohort of 4,942 men and women, circulating 3-HIB is elevated according to levels of hyperglycemia and established type 2 diabetes. In complementary cohorts with measures of insulin resistance, we found positive correlates for circulating 3-HIB concentrations with HOMA2 of insulin resistance, as well as a transient increase in 3-HIB followed by a marked decrease after bariatric surgery and weight loss. During differentiation, both white and brown adipocytes upregulate BCAA utilization and release increasing amounts of 3-HIB. Knockdown of the 3-HIB-forming enzyme 3-hydroxyisobutyryl-CoA hydrolase decreases release of 3-HIB and lipid accumulation in both cell types. Conversely, addition of 3-HIB to white and brown adipocyte cultures increases fatty acid uptake and modulated insulin-stimulated glucose uptake in a time-dependent manner. Finally, 3-HIB treatment decreases mitochondrial oxygen consumption and generation of reactive oxygen species in white adipocytes, while increasing these measures in brown adipocytes. Our data establish 3-HIB as a novel adipocyte-derived regulator of adipocyte subtype-specific functions strongly linked to obesity, insulin resistance, and type 2 diabetes.
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http://dx.doi.org/10.2337/db19-1174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968520PMC
September 2020

Effect of Cod Residual Protein Supplementation on Markers of Glucose Regulation in Lean Adults: A Randomized Double-Blind Study.

Nutrients 2020 May 16;12(5). Epub 2020 May 16.

Dietary Protein Research Group, Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway.

Large quantities of protein-rich cod residuals, which are currently discarded, could be utilized for human consumption. Although fish fillet intake is related to beneficial health effects, little is known about the potential health effects of consuming cod residual protein powder. Fifty lean adults were randomized to consume capsules with 8.1 g/day of cod residual protein (Cod-RP) or placebo capsules (Control group) for eight weeks, in this randomized, double-blind study. The intervention was completed by 40 participants. Fasting glucose and insulin concentrations were unaffected by Cod-RP supplementation, whereas plasma concentrations of α-hydroxybutyrate, β-hydroxybutyrate and acetoacetate all were decreased compared with the Control group. Trimethylamine N-oxide concentration in plasma and urine were increased in the Cod-RP group compared with the Control group. To conclude, the reduction in these potential early markers of impaired glucose metabolism following Cod-RP supplementation may indicate beneficial glucoregulatory effects of cod residual proteins. Trimethylamine N-oxide appears to be an appropriate biomarker of cod residual protein intake in lean adults.
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http://dx.doi.org/10.3390/nu12051445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285039PMC
May 2020

Dietary Intake and Biomarkers of Folate and Cobalamin Status in Norwegian Preschool Children: The FINS-KIDS Study.

J Nutr 2020 07;150(7):1852-1858

Institute of Marine Research, Bergen, Norway.

Background: Folate and cobalamin (vitamin B-12) are essential for growth and development. However, few population-based studies have investigated B-vitamin status in children.

Objectives: This study aimed to assess biomarkers of folate and vitamin B-12 status and to explore their dietary determinants in healthy Norwegian children.

Methods: Using baseline data obtained from a randomized controlled trial on the effect of fish intake on neurodevelopment in children aged 4-6 y, we measured the plasma concentrations of folate, cobalamin, total plasma homocysteine (tHcy), and methylmalonic acid (MMA). Food-frequency questionnaires (FFQs) were used to assess dietary intake. We used unadjusted and multiple linear regression models to explore the determinants of biomarker concentrations.

Results: The median (IQR) of plasma folate (n = 197) and plasma cobalamin (n = 195) concentrations were 15.2 (12.2-21.1) nmol/L and 785 (632-905) pmol/L, respectively. Plasma folate concentrations of <10 nmol/L were observed in 13% of the children. No child had a cobalamin concentration <148 pmol/L. Two children were identified with elevated plasma MMA concentrations (>0.26 μmol/L) and 8 children had elevated tHcy concentrations (>6.5 μmol/L). Plasma folate concentration was inversely correlated with tHcy (ρ = -0.24, P < 0.001); we found no correlation between tHcy and cobalamin (ρ = -0.075, P = 0.30). Children who consumed vitamin supplements had 51% higher plasma folate concentrations (P < 0.0001) than those who did not. Consumption of red meat for dinner more than twice a week was associated with 23% lower plasma folate (P < 0.01). No other significant associations between dietary intake and the biomarkers were observed.

Conclusions: The Norwegian preschool children from this cohort had adequate vitamin B-12 status. Poor folate status was common and associated with elevated tHcy. The implications of poor folate status during childhood should be a prioritized research question. This trial was registered at ClinicalTrials.gov as NCT02331667.
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http://dx.doi.org/10.1093/jn/nxaa111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330454PMC
July 2020

Impact of the MTHFR C677T polymorphism on one-carbon metabolites: Evidence from a randomised trial of riboflavin supplementation.

Biochimie 2020 Jun 21;173:91-99. Epub 2020 Apr 21.

Nutrition Innovation Centre for Food and Health (NICHE), Ulster University, Cromore Rd, Coleraine, BT52 1SA, Northern Ireland, UK. Electronic address:

Homozygosity for the C677T polymorphism in MTHFR (TT genotype) is associated with a 24-87% increased risk of hypertension. Blood pressure (BP) lowering was previously reported in adults with the TT genotype, in response to supplementation with the MTHFR cofactor, riboflavin. Whether the BP phenotype associated with the polymorphism is related to perturbed one-carbon metabolism is unknown. This study investigated one-carbon metabolites and their responsiveness to riboflavin in adults with the TT genotype. Plasma samples from adults (n 115) screened for the MTHFR genotype, who previously participated in RCTs to lower BP, were analysed for methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), betaine, choline and cystathionine by liquid chromatography tandem mass spectrometry (LC-MS/MS). The one-carbon metabolite response to riboflavin (1.6 mg/d; n 24) or placebo (n 23) for 16 weeks in adults with the TT genotype was also investigated. Plasma SAM (74.7 ± 21.0 vs 85.2 ± 22.6 nmol/L, P = 0.013) and SAM:SAH ratio (1.66 ± 0.55 vs 1.85 ± 0.51, P = 0.043) were lower and plasma homocysteine was higher (P = 0.043) in TT, compared to CC individuals. In response to riboflavin, SAM (P = 0.008) and cystathionine (P = 0.045) concentrations increased, with no responses in other one-carbon metabolites observed. These findings confirm perturbed one-carbon metabolism in individuals with the MTHFR 677TT genotype, and for the first time demonstrate that SAM, and cystathionine, increase in response to riboflavin supplementation in this genotype group. The genotype-specific, one-carbon metabolite responses to riboflavin intervention observed could offer some insight into the role of this gene-nutrient interaction in blood pressure.
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http://dx.doi.org/10.1016/j.biochi.2020.04.004DOI Listing
June 2020

The Associations Between Cognitive Prognosis and Kynurenines Are Modified by the Apolipoprotein ε4 Allele Variant in Patients With Dementia.

Int J Tryptophan Res 2019 15;12:1178646919885637. Epub 2019 Nov 15.

Department of Clinical Science, University of Bergen, Bergen, Norway.

Background: The apolipoprotein E ε4 gene variant (APOEε4) confers considerable risk for dementia and affects neuroinflammation, brain metabolism, and synaptic function. The kynurenine pathway (KP) gives rise to neuroactive metabolites, which have inflammatory, redox, and excitotoxic effects in the brain.

Aim: To assess whether the presence of at least one APOEε4 allele modifies the association between kynurenines and the cognitive prognosis.

Methods: A total of 152 patients with sera for metabolite measurements and APOE genotype were included from the Dementia of Western Norway. The participants had mild Alzheimer disease and Lewy body dementia. Apolipoprotein E ε4 gene variant allele status was classified as one or more ε4 versus any other. Mini-Mental State Examination (MMSE) was measured at baseline and for 5 consecutive years. Mann-Whitney tests and linear mixed-effects models were used for statistical analysis.

Results: There were no significant differences in serum concentrations of tryptophan and kynurenine according to the presence or absence of APOEε4. High serum concentrations of kynurenic acid, quinolinic acid, and picolinic acid, and a higher kynurenine-to-tryptophan ratio, were all associated with more cognitive decline in patients without APOEε4 compared to those with the APOEε4 allele (-value of the interactions < .05).

Conclusions: Kynurenic acid, quinolinic acid, picolinic acid, and the kynurenine-to-tryptophan ratio were associated with a significant increase in cognitive decline when the APOEε4 variant was absent, whereas there was a relatively less decline when the APOEε4 variant was present.
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http://dx.doi.org/10.1177/1178646919885637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859685PMC
November 2019

Components of the choline oxidation pathway modify the association between the apolipoprotein ε4 gene variant and cognitive decline in patients with dementia.

Brain Res 2020 01 22;1726:146519. Epub 2019 Oct 22.

Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Internal Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway. Electronic address:

Background: Metabolites involved in one-carbon metabolism (OCM) may predict cognitive prognosis in dementia. The link between OCM, apolipoprotein E (APOE), and DNA methylation creates a biologically plausible mechanism of interaction.

Aim: To assess OCM metabolites as predictors of 5-year cognitive prognosis in patients with mild dementia, and in subgroups defined by the APOEε4 allele variant.

Methods: We followed one-hundred and fifty-two patients with mild dementia (86 with Alzheimer's disease, 66 with Lewy body dementia, including 90 with at least one APOEε4 allele) for 5 years with annual Mini-Mental State Examinations (MMSE). Total homocysteine, methionine, choline, betaine, dimethylglycine, sarcosine, folate, cobalamin and pyridoxal 5'-phoshate were measured in serum at baseline. We used linear mixed models to assess metabolite-MMSE associations, including 3-way interactions between metabolites, time, and APOEε4. False-discovery rate adjusted p-values (Q-values) are reported.

Results: Metabolite concentrations were not different in patients with dementia according to the presence of APOEε4. Overall, serum concentration of total homocysteine was inversely associated with MMSE performance, while betaine was positively associated with MMSE (Q < 0.05), but neither was associated with MMSE decline. Serum concentrations of betaine, dimethylglycine and sarcosine, however, were associated with slower MMSE decline in patients with APOEε4, but with faster MMSE decline in patients without the allele (all 3-way interactions: Q < 0.05).

Conclusion: Components of the choline oxidation pathway are associated with a better cognitive prognosis in APOEε4 carriers and a worse cognitive prognosis in non-carriers. Further research investigating targeted metabolic interventions according to APOE allele status is warranted.
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http://dx.doi.org/10.1016/j.brainres.2019.146519DOI Listing
January 2020

Kynurenines, Neuropsychiatric Symptoms, and Cognitive Prognosis in Patients with Mild Dementia.

Int J Tryptophan Res 2019 29;12:1178646919877883. Epub 2019 Sep 29.

Department of Internal Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway.

Introduction: Circulating tryptophan (Trp) and its downstream metabolites, the kynurenines, are potentially neuroactive. Consequently, they could be associated with neuropsychiatric symptoms and cognitive prognosis in patients with dementia.

Objective: The objective of this study was to assess associations between circulating kynurenines, cognitive prognosis, and neuropsychiatric symptoms.

Methods: We measured baseline serum Trp, neopterin, pyridoxal 5'-phosphate (PLP), and 9 kynurenines in 155 patients with mild dementia (90 with Alzheimer's disease, 65 with Lewy body dementia). The ratios between kynurenine and Trp and kynurenic acid (KA) to kynurenine (KKR) were calculated. The Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI) were administered at baseline and annually over 5 years. Associations between baseline metabolite concentrations with MMSE and the NPI total score were assessed using a generalized structural equation model (mixed-effects multiprocess model), adjusted for age, sex, current smoking, glomerular filtration rate, and PLP. Post hoc associations between KKRs and individual NPI items were assessed using logistic mixed-effects models. False discovery rate (0.05)-adjusted values ( values) are reported.

Results: Kynurenine had a nonlinear quadratic relationship with the intercept of the MMSE scores over 5 years ( < 0.05), but not with the slope of MMSE decline. Kynurenine was associated with a higher NPI total score over time ( < 0.001). Post hoc, both KKR and KA were associated with more hallucinations ( < 0.05).

Conclusions: Kynurenine has a complex relationship with cognition, where both low and high levels were associated with poor cognitive performance. A higher KKR indicated risk for neuropsychiatric symptoms, especially hallucinations.
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http://dx.doi.org/10.1177/1178646919877883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769202PMC
September 2019

Tryptophan catabolites as metabolic markers of vitamin B-6 status evaluated in cohorts of healthy adults and cardiovascular patients.

Am J Clin Nutr 2020 01;111(1):178-186

Department of Clinical Science, University of Bergen, Bergen, Norway.

Background: Vitamin B-6 status is routinely measured as pyridoxal 5'-phosphate (PLP) in plasma. Low concentrations of PLP are associated with rheumatic, cardiovascular, and neoplastic diseases. We have previously shown that vitamin B-6 status affects the kynurenine (Kyn) pathway of tryptophan (Trp) catabolism.

Objective: This study aimed to comprehensively evaluate the use of Kyns as potential markers of functional vitamin B-6 status across 2 large cohorts.

Methods: We measured circulating concentrations of the first 6 metabolites in the Trp catabolic pathway by LC-MS-MS in the community-based Hordaland Health Study (HUSK; n = 7017) and cardiovascular patient-based Western Norway Coronary Angiography Cohort (WECAC; n = 4161). Cross-sectional and longitudinal associations of plasma PLP with Kyns were estimated using linear and nonlinear regression-based methods.

Results: 3'-Hydroxykynurenine (HK), a substrate, and all 4 products formed directly by the PLP-dependent enzymes kynurenine transaminase and kynureninase contributed to the explanation of circulating PLP in multivariable-adjusted regression models. The construct HK:(kynurenic acid + xanthurenic acid + 3'-hydroxyanthranilic acid + anthranilic acid), termed HK ratio (HKr), was related to plasma PLP with standardized regression coefficients (95% CIs) of -0.47 (-0.49, -0.45) and -0.46 (-0.49, -0.43) in HUSK and WECAC, respectively. Across strata of cohort and sex, HKr was 1.3- to 2.7-fold more sensitive, but also 1.7- to 2.9-fold more specific to changes in PLP than a previously proposed marker, HK:xanthurenic acid. Notably, the association was strongest at PLP concentrations < ∼20 nmol/L, a recognized threshold for vitamin B-6 deficiency. Finally, PLP and HKr demonstrated highly sex-specific and corroborating associations with age.

Conclusions: The results demonstrate that by combining 5 metabolites in the Kyn pathway into a simple index, HKr, a sensitive and specific indicator of intracellular vitamin B-6 status is obtained. The data also underscore the merit of evaluating alterations in Kyn metabolism when investigating vitamin B-6 and health.
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http://dx.doi.org/10.1093/ajcn/nqz228DOI Listing
January 2020

TMAO, creatine and 1-methylhistidine in serum and urine are potential biomarkers of cod and salmon intake: a randomised clinical trial in adults with overweight or obesity.

Eur J Nutr 2020 Aug 10;59(5):2249-2259. Epub 2019 Aug 10.

Dietary Protein Research Group, Department of Clinical Medicine, University of Bergen, Haukeland University Hospital, 5021, Bergen, Norway.

Purpose: To identify biomarkers to assess participants' compliance in an intervention study with high intake of cod or salmon, compared to a fish-free diet.

Methods: In this randomised clinical trial, 62 healthy overweight/obese participants consumed 750 g/week of either cod (N = 21) or salmon (N = 22) across 5 weekly dinners, or were instructed to continue their normal eating habits but avoid fish intake (Control group, N = 19) for 8 weeks.

Results: After cod intake, serum concentrations of trimethylamine N-oxide (TMAO, p = 0.0043), creatine (p = 0.024) and 1-methylhistidine (1-MeHis, p = 0.014), and urine concentrations (relative to creatinine) of TMAO (p = 2.8 × 10), creatine (p = 8.3 × 10) and 1-MeHis (p = 0.016) were increased when compared to Control group. After salmon intake, serum concentrations of 1-MeHis (p = 2.0 × 10) and creatine (p = 6.1 × 10), and urine concentrations (relative to creatinine) of 1-MeHis (p = 4.2 × 10) and creatine (p = 4.0 × 10) were increased when compared to Control group. Serum and urine concentrations of TMAO were more increased following cod intake compared to salmon intake (p = 0.028 and 2.9 × 10, respectively), and serum and urine 1-MeHis concentrations were more increased after salmon intake compared to cod intake (p = 8.7 × 10 and 1.2 × 10, respectively). Cod and salmon intake did not affect serum and urine concentrations of 3-methylhistidine, and only marginally affected concentrations of free amino acids and amino acid metabolites.

Conclusion: TMAO measured in serum or urine is a potential biomarker of cod intake, and 1-MeHis measured in serum or urine is a potential biomarker of salmon intake.
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http://dx.doi.org/10.1007/s00394-019-02076-4DOI Listing
August 2020

Urine and plasma concentrations of amino acids and plasma vitamin status differ, and are differently affected by salmon intake, in obese Zucker fa/fa rats with impaired kidney function and in Long-Evans rats with healthy kidneys.

Br J Nutr 2019 08 9;122(3):262-273. Epub 2019 Aug 9.

Dietary Protein Research Group, Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway.

Kidney function affects amino acid metabolism and vitamin status. The aims of the present study were to investigate urine and plasma concentrations of amino acids as well as plasma vitamin status in rats with impaired renal function (Zucker fa/fa rats) and in rats with normal kidney function (Long-Evans rats), and to explore the effects of salmon intake on these parameters and potential biomarkers of salmon intake in both rat strains. Male rats were fed diets with casein as sole protein source (control diet) or 25 % protein from baked salmon and 75 % casein for 4 weeks. Urine concentrations of markers of renal function and most amino acids and plasma concentrations of most vitamins were higher, and plasma concentrations of several amino acids including arginine, total glutathione and most tryptophan metabolites were lower in Zucker fa/fa rats compared with Long-Evans rats fed the control diet. Concentrations of kidney function markers were lower after salmon intake only in Zucker fa/fa rats. A trend towards lower urine concentrations of amino acids was seen in both rat strains fed the salmon diet, but this was more pronounced in Long-Evans rats and did not reflect the dietary amino acid content. Urine 1-methylhistidine, 3-methylhistidine, trimethylamineoxide and creatine concentrations, and plasma 1-methylhistidine and creatine concentrations were higher after salmon intake in both rat strains. To conclude, concentrations of amino acids in urine and plasma as well as vitamin status were different in Zucker fa/fa and Long-Evans rats, and the effects of salmon intake differed by rat strain for some of these parameters.
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http://dx.doi.org/10.1017/S0007114519001284DOI Listing
August 2019

Using metabolic profiling and gene expression analyses to explore molecular effects of replacing saturated fat with polyunsaturated fat-a randomized controlled dietary intervention study.

Am J Clin Nutr 2019 05;109(5):1239-1250

Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway.

Background: Replacing dietary saturated fatty acids (SFAs) with polyunsaturated fatty acids (PUFA) reduces the plasma low-density lipoprotein (LDL) cholesterol and subsequently the risk of cardiovascular disease. However, beyond changes in LDL cholesterol, we lack a complete understanding of the physiologic alterations that occur when improving dietary fat quality.

Objectives: The aim of this study was to gain knowledge of metabolic alterations paralleling improvements in the fat quality of the diet.

Methods: We recently conducted an 8-wk, double-blind, randomized controlled trial replacing SFAs with PUFAs in healthy subjects with moderate hypercholesterolemia (n = 99). In the present substudy, we performed comprehensive metabolic profiling with multiple platforms (both nuclear magnetic resonance- and mass spectrometry-based technology) (n = 99), and analyzed peripheral blood mononuclear cell gene expression (n = 95) by quantitative real-time polymerase chain reaction.

Results: A large number of lipoprotein subclasses, myristoylcarnitine and palmitoylcarnitine, and kynurenine were reduced when SFAs were replaced with PUFAs. In contrast, bile acids, proprotein convertase subtilisin/kexin type 9, acetate, and acetoacetate were increased by the intervention. Some amino acids were also altered by the intervention. The mRNA levels of LXRA and LDLR were increased, in addition to several liver X receptor α target genes and genes involved in inflammation, whereas the mRNA levels of UCP2 and PPARD were decreased in peripheral blood mononuclear cells after replacing SFAs with PUFAs. Partial least squares-discriminant analysis showed that the 30 most important variables that contributed to class separation spanned all classes of biomarkers, and was in accordance with the univariate analysis.

Conclusions: Applying metabolomics in randomized controlled dietary intervention trials has the potential to extend our knowledge of the biological and molecular effects of dietary fat quality. This study was registered at clinicaltrials.gov as NCT01679496.
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http://dx.doi.org/10.1093/ajcn/nqy356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499508PMC
May 2019

Plasma Amino Acids and Incident Type 2 Diabetes in Patients With Coronary Artery Disease.

Diabetes Care 2019 07 29;42(7):1225-1233. Epub 2019 Apr 29.

Department of Clinical Science, University of Bergen, Bergen, Norway.

Objective: Altered plasma amino acid levels have been implicated as markers of risk for incident type 2 diabetes; however, amino acids are also related to established diabetes risk factors. Therefore, potential for confounding and the impact from competing risks require evaluation.

Research Design And Methods: We prospectively followed 2,519 individuals with coronary artery disease but without diabetes. Mixed Gaussian modeling identified potential for confounding. Confounding, defined as a change in effect estimate (≥10%), was investigated by comparing amino acid-incident diabetes risk in a Cox model containing age and sex with that in models adjusted for potential confounders (BMI, estimated glomerular filtration rate, HDL cholesterol, triacylglycerol, C-reactive protein), which were further adjusted for plasma glucose, competing risks, and multiple comparisons (false discovery rate = 0.05, Benjamini-Hochberg method). Finally, component-wise likelihood-based boosting analysis including amino acids and confounders was performed and adjusted for competing risks in order to identify an optimal submodel for predicting incident diabetes.

Results: The mean age of the source population was 61.9 years; 72% were men. During a median follow-up of 10.3 years, 267 incident cases of diabetes were identified. In age- and sex-adjusted models, several amino acids, including the branched-chain amino acids, significantly predicted incident diabetes. Adjustment for confounders, however, attenuated associations. Further adjustment for glucose and multiple comparisons rendered only arginine significant (hazard ratio/1 SD 1.21 [95% CI 1.07-1.37]). The optimal submodel included arginine and asparagine.

Conclusions: Adjustment for relevant clinical factors attenuated the amino acid-incident diabetes risk. Although these findings do not preclude the potential pathogenic role of other amino acids, they suggest that plasma arginine is independently associated with incident diabetes. Both arginine and asparagine were identified in an optimal model for predicting new-onset type 2 diabetes.
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http://dx.doi.org/10.2337/dc18-2217DOI Listing
July 2019

Effects of low doses of fish and milk proteins on glucose regulation and markers of insulin sensitivity in overweight adults: a randomised, double blind study.

Eur J Nutr 2020 Apr 10;59(3):1013-1029. Epub 2019 Apr 10.

Dietary Protein Research Group, Department of Clinical Medicine, University of Bergen, 5020, Bergen, Norway.

Purpose: To examine whether supplementation with low doses of fish or milk proteins would affect glucose regulation and circulating lipid concentrations in overweight healthy adults.

Methods: Ninety-three overweight adults were assigned to receive 2.5 g protein/day from herring (HER), salmon (SAL), cod (COD) or milk (CAS, a casein-whey mixture as positive control) as tablets for 8 weeks.

Results: Seventy-seven participants were included in the analyses. HER and SAL did not affect glucose and insulin concentrations. COD significantly reduced within-group changes in 90 and 120 min postprandial glucose concentrations but changes were not different from HER and SAL groups. CAS supplementation significantly reduced the area under the curve for glucose concentrations (- 7%), especially when compared to SAL group, and reduced postprandial insulin c-peptide concentration (- 23%). Reductions in acetoacetate (- 24%) and β-hydroxybutyrate (- 29%) serum concentrations in HER group were more prominent compared to SAL and COD groups, with no differences between fish protein groups for α-hydroxybutyrate. Serum concentrations of α-hydroxybutyrate (- 23%), acetoacetate (- 39%) and β-hydroxybutyrate (- 40%) were significantly reduced within CAS group, and the decreases were significantly more pronounced when compared to SAL group. Serum lipid concentrations were not altered in any of the intervention groups.

Conclusion: Findings indicate that 2.5 g/day of proteins from fish or milk may be sufficient to improve glucose regulation in overweight adults. The effects were most pronounced after supplementation with proteins from cod, herring and milk, whereas salmon protein did not affect any of the measurements related to glucose regulation.

Clinical Trail Registration: This trial was registered at clinicaltrials.gov as NCT01641055.
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http://dx.doi.org/10.1007/s00394-019-01963-0DOI Listing
April 2020

Hyperglycemia and Metformin Use Are Associated With B Vitamin Deficiency and Cognitive Dysfunction in Older Adults.

J Clin Endocrinol Metab 2019 10;104(10):4837-4847

Nutrition Innovation Centre for Food and Health, Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, United Kingdom.

Context: Emerging evidence suggests that deficiencies of folate-related B vitamins can arise with metformin treatment and are independently linked with cognitive dysfunction, a comorbidity of diabetes.

Objective: To determine the impact of hyperglycemia and metformin use on relevant B vitamin biomarkers and cognitive outcomes in older adults.

Setting And Participants: Community-dwelling older adults (74.1 ± 8.3 years, n = 4160) without dementia, recruited to the Trinity, Ulster and Department of Agriculture cohort study in 2008 to 2012, were classified as normoglycemic (n = 1856) or hyperglycemic, based on HbA1c ≥5.7% (39 mmol/mol), either with (n = 318) or without (n = 1986) metformin treatment.

Main Outcome Measures: Biomarkers of folate, vitamin B12, vitamin B6, and riboflavin were measured. Cognitive assessments included the Repeatable Battery for Assessment of Neuropsychological Status (RBANS) and the Frontal Assessment Battery (FAB).

Results: Metformin use was associated with higher risk of deficiency of vitamin B12 (combined B12 index ≤-1; OR 1.45; 95% CI, 1.03 to 2.02) and vitamin B6 (plasma pyridoxal 5-phosphate <30.0 nmol/L; OR 1.48; 95% CI, 1.02 to 2.15). Fortified foods when eaten regularly had a positive impact on all relevant B vitamin biomarkers, even with hyperglycemia. After adjustment for relevant covariates, metformin use was associated with an increased risk of cognitive dysfunction as assessed with the RBANS (OR 1.36; 95% CI, 1.03 to 1.80) and FAB (OR 1.34; 95% CI, 1.03 to 1.74).

Conclusions: Use of metformin by older adults is associated with poorer cognitive performance; B vitamin deficiency may be implicated. Fortified foods can optimize B vitamin status and may be beneficial for maintaining better cognitive health in older people with or at risk for diabetes.
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http://dx.doi.org/10.1210/jc.2018-01791DOI Listing
October 2019

Methionine restriction prevents onset of type 2 diabetes in NZO mice.

FASEB J 2019 06 6;33(6):7092-7102. Epub 2019 Mar 6.

Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.

Dietary methionine restriction (MR) is well known to reduce body weight by increasing energy expenditure (EE) and insulin sensitivity. An elevated concentration of circulating fibroblast growth factor 21 (FGF21) has been implicated as a potential underlying mechanism. The aims of our study were to test whether dietary MR in the context of a high-fat regimen protects against type 2 diabetes in mice and to investigate whether vegan and vegetarian diets, which have naturally low methionine levels, modulate circulating FGF21 in humans. New Zealand obese (NZO) mice, a model for polygenic obesity and type 2 diabetes, were placed on isocaloric high-fat diets (protein, 16 kcal%; carbohydrate, 52 kcal%; fat, 32 kcal%) that provided methionine at control (Con; 0.86% methionine) or low levels (0.17%) for 9 wk. Markers of glucose homeostasis and insulin sensitivity were analyzed. Among humans, low methionine intake and circulating FGF21 levels were investigated by comparing a vegan and a vegetarian diet to an omnivore diet and evaluating the effect of a short-term vegetarian diet on FGF21 induction. In comparison with the Con group, MR led to elevated plasma FGF21 levels and prevented the onset of hyperglycemia in NZO mice. MR-fed mice exhibited increased insulin sensitivity, higher plasma adiponectin levels, increased EE, and up-regulated expression of thermogenic genes in subcutaneous white adipose tissue. Food intake and fat mass did not change. Plasma FGF21 levels were markedly higher in vegan humans compared with omnivores, and circulating FGF21 levels increased significantly in omnivores after 4 d on a vegetarian diet. These data suggest that MR induces FGF21 and protects NZO mice from high-fat diet-induced glucose intolerance and type 2 diabetes. The normoglycemic phenotype in vegans and vegetarians may be caused by induced FGF21. MR akin to vegan and vegetarian diets in humans may offer metabolic benefits increased circulating levels of FGF21 and merits further investigation.-Castaño-Martinez, T., Schumacher, F., Schumacher, S., Kochlik, B., Weber, D., Grune, T., Biemann, R., McCann, A., Abraham, K., Weikert, C., Kleuser, B., Schürmann, A., Laeger, T. Methionine restriction prevents onset of type 2 diabetes in NZO mice.
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http://dx.doi.org/10.1096/fj.201900150RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529347PMC
June 2019

The kynurenine pathway and cognitive performance in community-dwelling older adults. The Hordaland Health Study.

Brain Behav Immun 2019 01 25;75:155-162. Epub 2018 Oct 25.

Department of Internal Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway; Institute of Clinical Science, University of Bergen, Norway.

Introduction: Tryptophan, its downstream metabolites in the kynurenine pathway and neopterin have been associated with inflammation and dementia. We aimed to study the associations between plasma levels of these metabolites and cognitive function in community-dwelling, older adults.

Methods: This cross-sectional study included 2174 participants aged 70-72 years of the community-based Hordaland Health Study. Tryptophan, kynurenine, neopterin and eight downstream kynurenines were measured in plasma. Kendrick Object Learning Test (KOLT), Digit Symbol Test (DST) and the Controlled Oral Word Association Test (COWAT) were all outcomes in standardized Zellner's regression. The Wald test of a composite linear hypothesis of an association with each metabolite was adjusted by the Bonferroni method. Age, body mass index, C-reactive protein, depressive symptoms, diabetes, education, glomerular filtration rate, hypertension, previous myocardial infarction, prior stroke, pyridoxal 5'phosphate, sex and smoking were considered as potential confounders.

Results: Higher levels of the kynurenine-to-tryptophan ratio (KTR) and neopterin were significantly associated with poorer, overall cognitive performance (p < 0.002). Specifically, KTR was negatively associated with KOLT (β -0.08, p = 0.001) and COWAT (β -0.08, p = 0.001), but not with DST (β -0.03, p = 0.160). This pattern was also seen for neopterin (KOLT: β -0.07; p = 0.001; COWAT: β -0.06, p = 0.010; DST: β -0.01, p = 0.800). The associations were not confounded by the examined variables. No significant associations were found between the eight downstream kynurenines and cognition.

Conclusion: Higher KTR and neopterin levels, biomarkers of cellular immune activation, were associated with reduced cognitive performance, implying an association between the innate immune system, memory, and language.
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http://dx.doi.org/10.1016/j.bbi.2018.10.003DOI Listing
January 2019
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