Acute effects of oral mesna administration on the full amino acid profile and 3-methylhistidine: secondary results from the CYLOB dose-finding study.

Plasma total cysteine (tCys) is strongly associated with fat mass in humans. Mesna lowers plasma tCys in a dose-dependent manner, but it is not known whether it interferes with metabolism of other amino acids or protein. In this Phase-1 study, we show that a single dose of mesna administered at 400, 800, 1200 or 1600 mg to 6-7 individuals per dose only slightly affects amino acid profiles, with increases in plasma valine across dose levels. There were no effects of mesna on 3-methylhistidine, a marker of protein breakdown.

Elevated homocysteine is associated with increased rates of epigenetic aging in a population with mild cognitive impairment.

Elevated plasma total homocysteine (tHcy) is associated with the development of Alzheimer's disease and other forms of dementia. In this study, we report the relationship between tHcy and epigenetic age in older adults with mild cognitive impairment from the VITACOG study. Epigenetic age and rate of aging (ROA) were assessed using various epigenetic clocks, including those developed by Horvath and Hannum, DNAmPhenoAge, and with a focus on Index, a new principal component-based epigenetic clock that, like DNAmPhenoAge, is trained to predict an individual's "PhenoAge." We identified significant associations between tHcy levels and ROA, suggesting that hyperhomocysteinemic individuals were aging at a faster rate. Moreover, Index revealed a normalization of accelerated epigenetic aging in these individuals following treatment with tHcy-lowering B-vitamins. Our results indicate that elevated tHcy is a risk factor for accelerated epigenetic aging, and this can be ameliorated with B-vitamins. These findings have broad relevance for the sizable proportion of the worldwide population with elevated tHcy.

Dietary sulfur amino acid restriction in humans with overweight and obesity: Evidence of an altered plasma and urine sulfurome, and a novel metabolic signature that correlates with loss of fat mass and adipose tissue gene expression.

BACKGROUND: In animals, dietary sulfur amino acid restriction (SAAR) improves metabolic health, possibly mediated by altering sulfur amino acid metabolism and enhanced anti-obesogenic processes in adipose tissue. AIM: To assess the effects of SAAR over time on the plasma and urine SAA-related metabolites (sulfurome) in humans with overweight and obesity, and explore whether such changes were associated with body weight, body fat and adipose tissue gene expression. METHODS: Fifty-nine subjects were randomly allocated to SAAR (∼2 g SAA, n = 31) or a control diet (∼5.6 g SAA, n = 28) consisting of plant-based whole-foods and supplemented with capsules to titrate contents of SAA. Sulfurome metabolites in plasma and urine at baseline, 4 and 8 weeks were measured using HPLC and LC-MS/MS. mRNA-sequencing of subcutaneous white adipose tissue (scWAT) was performed to assess changes in gene expression. Data were analyzed with mixed model regression. Principal component analyses (PCA) were performed on the sulfurome data to identify potential signatures characterizing the response to SAAR. RESULTS: SAAR led to marked decrease of the main urinary excretion product sulfate (p < 0.001) and plasma and/or 24-h urine concentrations of cystathionine, sulfite, thiosulfate, H2S, hypotaurine and taurine. PCA revealed a distinct metabolic signature related to decreased transsulfuration and H2S catabolism that predicted greater weight loss and android fat mass loss in SAAR vs. controls (all pinteraction < 0.05). This signature correlated positively with scWAT expression of genes in the tricarboxylic acid cycle, electron transport and ß-oxidation (FDR = 0.02). CONCLUSION: SAAR leads to distinct alterations of the plasma and urine sulfurome in humans, and predicted increased loss of weight and android fat mass, and adipose tissue lipolytic gene expression in scWAT. Our data suggest that SAA are linked to obesogenic processes and that SAAR may be useful for obesity and related disorders. TRIAL IDENTIFIER: https://clinicaltrials.gov/study/NCT04701346.

Dietary sulfur amino acid restriction in humans with overweight and obesity: a translational randomized controlled trial.

BACKGROUND: Dietary sulfur amino acid restriction (SAAR) improves metabolic health in animals. In this study, we investigated the effect of dietary SAAR on body weight, body composition, resting metabolic rate, gene expression profiles in white adipose tissue (WAT), and an extensive blood biomarker profile in humans with overweight or obesity. METHODS: N = 59 participants with overweight or obesity (73% women) were randomized stratified by sex to an 8-week plant-based dietary intervention low (~ 2 g/day, SAAR) or high (~ 5.6 g/day, control group) in sulfur amino acids. The diets were provided in full to the participants, and both investigators and participants were blinded to the intervention. Outcome analyses were performed using linear mixed model regression adjusted for baseline values of the outcome and sex. RESULTS: SAAR led to a ~ 20% greater weight loss compared to controls (ß 95% CI - 1.14 (- 2.04, - 0.25) kg, p = 0.013). Despite greater weight loss, resting metabolic rate remained similar between groups. Furthermore, SAAR decreased serum leptin, and increased ketone bodies compared to controls. In WAT, 20 genes were upregulated whereas 24 genes were downregulated (FDR < 5%) in the SAAR group compared to controls. Generally applicable gene set enrichment analyses revealed that processes associated with ribosomes were upregulated, whereas processes related to structural components were downregulated. CONCLUSION: Our study shows that SAAR leads to greater weight loss, decreased leptin and increased ketone bodies compared to controls. Further research on SAAR is needed to investigate the therapeutic potential for metabolic conditions in humans. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04701346, registered Jan 8th 2021, https://www. CLINICALTRIALS: gov/study/NCT04701346.

Determination of underivatized amino acids in human plasma using ion pair liquid chromatography/tandem mass spectrometry.

Accurate quantification of amino acids (AA) is essential for several applications, including clinical research, food analysis, and pharmaceutical studies. In this study, we developed an analytical method based on liquid chromatography with electrospray ionization coupled to tandem mass spectrometry detection (LC-ESI-MS/MS). This method was devised to accurately quantify a spectrum of amino acids, notably taurine, creatinine, glutathione (GSH), and sulfur-containing amino acids (SAAs) such as methionine, cysteine, and homocysteine, using only 10 µL of human plasma. A stable isotope derivative of each AA is used as an internal standard (IS) for accurate quantification. For retention and separation on a C18 column, heptafluorobutyric acid (HFBA) was employed as an ion pair agent. Multiple reaction monitoring (MRM) in positive mode with the precursor-to-product ion transitions at m/z is used for quantification. The method showed excellent linearity for all AA with a high correlation coefficient (r > 0.9927). The linear fit indicates that the detector response is linear over the tested range of standard concentrations. The accuracy and precision of the method were within the acceptable range of 92-110% and < 15%, respectively. The limit of detection (LOD) and limit of quantification (LOQ) were in the range of 0.001-1.80 µM and 0.004-6.0 µM, respectively. No significant ion suppression or carry over was observed. In conclusion, the assay was validated and found to have adequate accuracy, precision, linearity, sensitivity and selectivity. The assay has been successfully applied to the analysis of human plasma.

Divergent Survival Outcomes Associated with Elevated Branched-Chain Amino Acid Levels among Older Adults with or without Hypertension and Diabetes: A Validated, Prospective, Longitudinal Follow-Up Study.

Branched-chain amino acids are critical metabolic intermediates that can indicate increased risk of cardiometabolic disease when levels are elevated or, alternatively, suggest sufficient mitochondrial energy metabolism and reserve in old age. The interpretation of BCAA levels can be context-dependent, and it remains unclear whether abnormal levels can inform prognosis. This prospective longitudinal study aimed to determine the interrelationship between mortality hazard and fasting serum BCAA levels among older men and women aged ≥65 years with or without hypertension and diabetes mellitus. At baseline (0Y), fasting serum BCAA concentration in 2997 community-living older men and women were measured. Approximately 14 years later (14Y), 860 study participants returned for repeat measurements. Deaths were analysed and classified into cardiovascular and non-cardiovascular causes using International Classification of Diseases codes. Survival analysis and multivariable Cox regression were performed. During a median follow-up of 17Y, 971 (78.6%) non-cardiovascular and 263 (21.4%) cardiovascular deaths occurred among 1235 (41.2%) deceased (median age, 85.8 years [IQR 81.7-89.7]). From 0Y to 14Y, BCAA levels declined in both sexes, whereas serum creatinine concentration increased (both p < 0.0001). In older adults without hypertension or diabetes mellitus, the relationship between mortality hazard and BCAA level was linear and above-median BCAA levels were associated with improved survival, whereas in the presence of cardiometabolic disease the relationship was U-shaped. Overall, adjusted Cox regression determined that each 10% increment in BCAA concentration was associated with a 7% (p = 0.0002) and 16% (p = 0.0057) reduction in mortality hazard estimated at 0Y and 14Y, respectively. Our findings suggested that abnormally high or low (dyshomeostatic) BCAA levels among older adults with hypertension and/or diabetes mellitus were associated with increased mortality, whereas in those with neither disease, increased BCAA levels was associated with improved survival, particularly in the oldest-old.

Cysteine-lowering treatment with mesna against obesity: Proof of concept and results from a human phase I, dose-finding study.

AIM: To investigate whether mesna-sodium-2-mercaptoethane sulfonate) can reduce diet-induced fat gain in mice, and to assess the safety of single ascending mesna doses in humans to find the dose associated with lowering of plasma tCys by at least 30%. METHODS: C3H/HeH mice were shifted to a high-fat diet ± mesna in drinking water; body composition was measured at weeks 0, 2 and 4. In an open, phase I, single ascending dose study, oral mesna (400, 800, 1200, 1600 mg) was administered to 17 men with overweight or obesity. Mesna and tCys concentrations were measured repeatedly for a duration of 48 hours postdosing in plasma, as well as in 24-hour urine. RESULTS: Compared with controls, mesna-treated mice had lower tCys and lower estimated mean fat mass gain from baseline (week 2: 4.54 ± 0.40 vs. 6.52 ± 0.36 g; week 4: 6.95 ± 0.35 vs. 8.19 ± 0.34 g; Poverall = .002), but similar lean mass gain. In men with overweight, mesna doses of 400-1600 mg showed dose linearity and were well tolerated. Mesna doses of 800 mg or higher decreased plasma tCys by 30% or more at nadir (4h post-dosing). With increasing mesna dose, tCys AUC0-12h decreased (Ptrend < .001), and urine tCys excretion increased (Ptrend = .004). CONCLUSIONS: Mesna reduces diet-induced fat gain in mice. In men with overweight, single oral doses of mesna (800-1600 mg) were well tolerated and lowered plasma tCys efficiently. The effect of sustained tCys-lowering by repeated mesna administration on weight loss in humans deserves investigation.

Association of Long-term Exposure to Air Pollution and Dementia Risk: The Role of Homocysteine, Methionine, and Cardiovascular Burden.

BACKGROUND AND OBJECTIVES: Growing evidence links air pollution with dementia risk, but the biological mechanisms are largely unknown. We investigated the role played by homocysteine (tHcy) and methionine in this association and explored whether this could be explained by cardiovascular diseases (CVDs). METHODS: Data were extracted from the ongoing Swedish National study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal population-based study. At baseline, 2,512 dementia-free participants were examined up to 2013 (mean follow-up: 5.18 ± 2.96 years). Two air pollutants (particulate matter ≤2.5 µm [PM2.5] and nitrogen oxides [NOx]) were assessed yearly from 1990 until 2013 using dispersion models at residential addresses. The hazard ratio of dementia over air pollution levels was estimated using Cox models adjusted for age, sex, education, smoking, socioeconomic status, physical activity, retirement age, creatinine, year of assessment, and the use of supplements. The total effect of air pollutants on dementia was decomposed into 4 pathways involving tHcy/methionine: (1) direct effect; (2) indirect effect (mediation); (3) effect due to interaction; and (4) effect due to both mediation and interaction. To test whether the association was independent from CVDs (ischemic heart disease, atrial fibrillation, heart failure, and stroke), we repeated the analyses excluding those individuals who developed CVDs. RESULTS: The mean age of the study participants was 73.4 years (SD: 10.4), and 62.1% were female individuals. During an average period of 5 years (mean: 5.18; SD: 2.96 years), 376 cases with incident dementia were identified. There was a 70% increased hazard of dementia per unit increase of PM2.5 during the 5 years before baseline (hazard ratio [HR]: 1.71; 95% CI 1.33-2.09). Overall, 50% (51.6%; 95% CI 9.0-94.1) of the total effect of PM2.5 on dementia was due to mediation of tHcy (6.6%; 95% CI 1.6-11.6) and/or interaction (47.8%; 95% CI 4.9-91.7) with tHcy and 48.4% (p = 0.03) to the direct effect of PM2.5 on dementia. High levels of methionine reduced the dementia hazard linked to PM2.5 by 31% (HR: 0.69; 95% CI 0.56-0.85) with 24.8% attributable to the interaction with methionine and 25.9% (p = 0.001) to the direct effect of PM2.5. No mediation effect was found through methionine. Attenuated results were obtained for NOx. Findings for tHcy were attenuated after excluding those who developed CVDs, while remained similar for methionine. DISCUSSION: High levels of homocysteine enhanced the dementia risk attributed to air pollution, while high methionine concentrations reduced this risk. The impact of homocysteine on cardiovascular conditions partly explains this association. Alternative pathways other than cardiovascular mechanisms may be at play between methionine and dementia.

The Associations of Habitual Intake of Sulfur Amino Acids, Proteins and Diet Quality with Plasma Sulfur Amino Acid Concentrations: The Maastricht Study.

BACKGROUND: Plasma sulfur amino acids (SAAs), i.e., methionine, total cysteine (tCys), total homocysteine (tHcy), cystathionine, total glutathione (tGSH), and taurine, are potential risk factors for obesity and cardiometabolic disorders. However, except for plasma tHcy, little is known about how dietary intake modifies plasma SAA concentrations. OBJECTIVE: To investigate whether the intake of SAAs and proteins or diet quality is associated with plasma SAAs. METHODS: Data from a cross-sectional subset of The Maastricht Study (n = 1145, 50.5% men, 61 interquartile range: [55, 66] y, 22.5% with prediabetes and 34.3% with type 2 diabetes) were investigated. Dietary intake was assessed using a validated food frequency questionnaire. The intake of SAAs (total, methionine, and cysteine) and proteins (total, animal, and plant) was estimated from the Dutch and Danish food composition tables. Diet quality was assessed using the Dutch Healthy Diet Index, the Mediterranean Diet Score, and the Dietary Approaches to Stop Hypertension score. Fasting plasma SAAs were measured by liquid chromatography (LC) tandem mass spectrometry (MS) (LC/MS-MS). Associations were investigated with multiple linear regressions with tertiles of dietary intake measures (main exposures) and z-standardized plasma SAAs (outcomes). RESULTS: Intake of total SAAs and total proteins was positively associated with plasma tCys and cystathionine. Associations were stronger in women and in those with normal body weight. Higher intake of cysteine and plant proteins was associated with lower plasma tHcy and higher cystathionine. Higher methionine intake was associated with lower plasma tGSH, whereas cysteine intake was positively associated with tGSH. Higher intake of methionine and animal proteins was associated with higher plasma taurine. Better diet quality was consistently related to lower plasma tHcy concentrations, but it was not associated with the other SAAs. CONCLUSION: Targeted dietary modifications might be effective in modifying plasma concentrations of tCys, tHcy, and cystathionine, which have been associated with obesity and cardiometabolic disorders.

The association of fasting plasma thiol fractions with body fat compartments, biomarker profile, and adipose tissue gene expression.

People with high plasma total cysteine (tCys) have higher fat mass and higher concentrations of the atherogenic apolipoprotein B (apoB). The disulfide form, cystine, enhanced human adipogenesis and correlated with total fat mass in a Middle-Eastern cohort. In 35 European adults with overweight (88.6% women) and with dual-X-ray absorptiometry measurements of regional fat, we investigated how cystine compared to other free disulfides in their association with total regional adiposity, plasma lipid and glucose biomarkers, and adipose tissue lipid enzyme mRNA (n = 19). Most total plasma homocysteine (tHcy) (78%) was protein-bound; 63% of total glutathione (tGSH) was reduced. tCys was 49% protein-bound, 30% mixed-disulfide, 15% cystine, and 6% reduced. Controlling for age and lean mass, cystine and total free cysteine were the fractions most strongly associated with android and total fat: 1% higher cystine predicted 1.97% higher android fat mass (95% CI 0.64, 3.31) and 1.25% (0.65, 2.98) higher total fat mass (both p = 0.005). A positive association between tCys and apoB (ß: 0.64%; 95% CI 0.17, 1.12%, p = 0.009) was apparently driven by free cysteine and cystine; cystine was also inversely associated with the HDL-associated apolipoprotein A1 (ß: -0.57%; 95% CI -0.96, -0.17%, p = 0.007). No independent positive associations with adiposity were noted for tGSH or tHcy fractions. Plasma cystine correlated with CPT1a mRNA (Spearman's r = 0.68, p = 0.001). In conclusion, plasma cystine-but not homocysteine or glutathione disulfides-is associated with android adiposity and an atherogenic plasma apolipoprotein profile. The role of cystine in human adiposity and cardiometabolic risk deserves investigation. ClinicalTrials.gov identifiers: NCT02647970 and NCT03629392.

The importance of vitamin B12 for individuals choosing plant-based diets.

Vitamin B12 is an essential nutrient that is not made by plants; consequently, unfortified plant-based foods are not a reliable supply. Recent estimates suggest high rates of vitamin B12 deficiency among the vegetarian and vegan populations, particularly in pregnant women or women of child-bearing age who, for ethical and health reasons, are shifting towards higher consumption of plant-based foods in ever-increasing numbers. Vitamin B12 plays crucial metabolic roles across the life-course and in particular during pregnancy and in early development (first 1000 days of life). Evidence now implicates vitamin B12 deficiency with increased risk to a range of neuro, vascular, immune, and inflammatory disorders. However, the current UK recommended nutrient intake for vitamin B12 does not adequately consider the vitamin B12 deficit for those choosing a plant-based diet, including vegetarianism and in particular veganism, representing a hidden hunger. We provide a cautionary note on the importance of preventing vitamin B12 deficits for those individuals choosing a plant-based diet and the health professionals advising them.

Associations between plasma sulfur amino acids and specific fat depots in two independent cohorts: CODAM and The Maastricht Study.

PURPOSE: Sulfur amino acids (SAAs) have been associated with obesity and obesity-related metabolic diseases. We investigated whether plasma SAAs (methionine, total cysteine (tCys), total homocysteine, cystathionine and total glutathione) are related to specific fat depots. METHODS: We examined cross-sectional subsets from the CODAM cohort (n = 470, 61.3% men, median [IQR]: 67 [61, 71] years) and The Maastricht Study (DMS; n = 371, 53.4% men, 63 [55, 68] years), enriched with (pre)diabetic individuals. SAAs were measured in fasting EDTA plasma with LC-MS/MS. Outcomes comprised BMI, skinfolds, waist circumference (WC), dual-energy X-ray absorptiometry (DXA, DMS), body composition, abdominal subcutaneous and visceral adipose tissues (CODAM: ultrasound, DMS: MRI) and liver fat (estimated, in CODAM, or MRI-derived, in DMS, liver fat percentage and fatty liver disease). Associations were examined with linear or logistic regressions adjusted for relevant confounders with z-standardized primary exposures and outcomes. RESULTS: Methionine was associated with all measures of liver fat, e.g., fatty liver disease [CODAM: OR = 1.49 (95% CI 1.19, 1.88); DMS: OR = 1.51 (1.09, 2.14)], but not with other fat depots. tCys was associated with overall obesity, e.g., BMI [CODAM: ß = 0.19 (0.09, 0.28); DMS: ß = 0.24 (0.14, 0.34)]; peripheral adiposity, e.g., biceps and triceps skinfolds [CODAM: ß = 0.15 (0.08, 0.23); DMS: ß = 0.20 (0.12, 0.29)]; and central adiposity, e.g., WC [CODAM: ß = 0.16 (0.08, 0.25); DMS: ß = 0.17 (0.08, 0.27)]. Associations of tCys with VAT and liver fat were inconsistent. Other SAAs were not associated with body fat. CONCLUSION: Plasma concentrations of methionine and tCys showed distinct associations with different fat depots, with similar strengths in the two cohorts.

Cysteine restriction-specific effects of sulfur amino acid restriction on lipid metabolism.

Decreasing the dietary intake of methionine exerts robust anti-adiposity effects in rodents but modest effects in humans. Since cysteine can be synthesized from methionine, animal diets are formulated by decreasing methionine and eliminating cysteine. Such diets exert both methionine restriction (MR) and cysteine restriction (CR), that is, sulfur amino acid restriction (SAAR). Contrarily, SAAR diets formulated for human consumption included cysteine, and thus might have exerted only MR. Epidemiological studies positively correlate body adiposity with plasma cysteine but not methionine, suggesting that CR, but not MR, is responsible for the anti-adiposity effects of SAAR. Whether this is true, and, if so, the underlying mechanisms are unknown. Using methionine- and cysteine-titrated diets, we demonstrate that the anti-adiposity effects of SAAR are due to CR. Data indicate that CR increases serinogenesis (serine biosynthesis from non-glucose substrates) by diverting substrates from glyceroneogenesis, which is essential for fatty acid reesterification and triglyceride synthesis. Molecular data suggest that CR depletes hepatic glutathione and induces Nrf2 and its downstream targets Phgdh (the serine biosynthetic enzyme) and Pepck-M. In mice, the magnitude of SAAR-induced changes in molecular markers depended on dietary fat concentration (60% fat >10% fat), sex (males > females), and age-at-onset (young > adult). Our findings are translationally relevant as we found negative and positive correlations of plasma serine and cysteine, respectively, with triglycerides and metabolic syndrome criteria in a cross-sectional epidemiological study. Controlled feeding of low-SAA, high-polyunsaturated fatty acid diets increased plasma serine in humans. Serinogenesis might be a target for treating hypertriglyceridemia.

The Association of Circulating Amino Acids and Dietary Inflammatory Potential with Muscle Health in Chinese Community-Dwelling Older People.

Amino acids (AAs) and dietary inflammatory potential play essential roles in muscle health. We examined the associations of dietary inflammatory index (DII) of habitual diet with serum AA profile, and ascertained if the associations between DII and muscle outcomes were mediated by serum AAs, in 2994 older Chinese community-dwelling men and women (mean age 72 years) in Hong Kong. Higher serum branched chain AAs (BCAAs), aromatic AAs and total glutathione (tGSH) were generally associated with better muscle status at baseline. A more pro-inflammatory diet, correlating with higher serum total homocysteine and cystathionine, was directly (90.2%) and indirectly (9.8%) through lower tGSH associated with 4-year decline in hand grip strength in men. Higher tGSH was associated with favorable 4-year changes in hand grip strength, gait speed and time needed for 5-time chair stands in men and 4-year change in muscle mass in women. Higher leucine and isoleucine were associated with decreased risk of sarcopenia in men; the associations were abolished after adjustment for BMI. In older men, perturbations in serum sulfur AAs metabolism may be biomarkers of DII related adverse muscle status, while the lower risk of sarcopenia with higher BCAAs may partly be due to preserved BMI.

The association of serum sulfur amino acids and related metabolites with incident diabetes: a prospective cohort study.

AIM: Plasma total cysteine (tCys) is associated with fat mass and insulin resistance, whereas taurine is inversely related to diabetes risk. We investigated the association of serum sulfur amino acids (SAAs) and related amino acids (AAs) with incident diabetes. METHODS: Serum AAs were measured at baseline in 2997 subjects aged ≥ 65 years. Diabetes was recorded at baseline and after 4 years. Logistic regression evaluated the association of SAAs [methionine, total homocysteine (tHcy), cystathionine, tCys, and taurine] and related metabolites [serine, total glutathione (tGSH), glutamine, and glutamic acid] with diabetes risk. RESULTS: Among 2564 subjects without diabetes at baseline, 4.6% developed diabetes. Each SD increment in serum tCys was associated with a 68% higher risk (95% CI 1.27, 2.23) of diabetes [OR for upper vs. lower quartile 2.87 (1.39, 5.91)], after full adjustments (age, sex, other AAs, adiposity, eGFR, physical activity, blood pressure, diet and medication); equivalent ORs for cystathionine were 1.33 (1.08, 1.64) and 1.68 (0.85, 3.29). Subjects who were simultaneously in the upper tertiles of both cystathionine and tCys had a fivefold risk [OR = 5.04 (1.55, 16.32)] of diabetes compared with those in the lowest tertiles. Higher serine was independently associated with a lower risk of developing diabetes [fully adjusted OR per SD = 0.68 (0.54, 0.86)]. Glutamic acid and glutamine showed positive and negative associations, respectively, with incident diabetes in age- and sex-adjusted analysis, but only the glutamic acid association was independent of other confounders [fully adjusted OR per SD = 1.95 (1.19, 3.21); for upper quartile = 7.94 (3.04, 20.75)]. tGSH was inversely related to diabetes after adjusting for age and sex, but not other confounders. No consistent associations were observed for methionine, tHcy or taurine. CONCLUSION: Specific SAAs and related metabolites show strong and independent associations with incident diabetes. This suggests that perturbations in the SAA metabolic pathway may be an early marker for diabetes risk.

The dihydrofolate reductase 19-bp deletion modifies the beneficial effect of B-vitamin therapy in mild cognitive impairment: pooled study of two randomized placebo-controlled trials.

BACKGROUND: Higher serum homocysteine is associated with cognitive decline in older people. But homocysteine-lowering trials including folic acid (FA) show inconsistent results on cognitive decline. The reduction of FA to dihydrofolate by dihydrofolate reductase (DHFR) is slow in humans. OBJECTIVE: We examined the effects of the DHFR 19-bp deletion/insertion (del/ins) polymorphism on FA-containing treatment on cognitive decline and brain atrophy in older people with mild cognitive impairment (MCI). METHODS: This study used pooled data from two randomized B-vitamin trials on 545 MCI subjects who received either FA-containing B vitamins or placebo for 24 months. Subjects were typed for the DHFR genotype. Primary outcome was the Clinical Dementia Rating scale-global score (CDR-global). Secondary outcomes were CDR-sum of boxes score (CDR-SOB), memory and executive Z-scores and whole brain atrophy rate by serial MRI. RESULTS: The proportions of subjects with del/del, del/ins and ins/ins genotype were 29.5, 44.3 and 26.1%, respectively. DHFR genotypes modified the effects of B vitamins on CDR-global, CDR-SOB and executive function Z-score (Pinteraction = 0.017, 0.014 and 0.052, respectively), with significant benefits being observed only in those with ins/ins genotype (Beta = -1.367, -0.614 and 0.315, P = 0.004, 0.014 and 0.012, respectively). The interaction was not significant for memory Z-score and whole brain atrophy rate. Notably, the supplements only slowed brain atrophy in members of the 'ins/ins' group who were not using aspirin. CONCLUSIONS: Our data indicate that the beneficial effects of B vitamins including FA on cognitive function are only apparent in those with ins/ins genotype, i.e. relatively better preserved DHFR activity.