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Objective In this 7-day pilot study we randomized healthy, normal-weight men and women to either a dietary intervention with methionine and cysteine restriction enriched in PUFA (Met/Cys low  + PUFA, n = 7) or with high contents of methionine, cysteine and SFA (Met/Cys high  + SFA, n = 7). The objective was to describe the short-term responses in oral glucose tolerance, amino acid profile, total fatty acid profile, pyruvate and lactate following a Met/Cys low  + PUFA diet vs. Met/Cys high  + SFA. Results The diet groups consisted of five women and two men, aged 20–38 years. After the 7-d intervention median pre- and post-oral glucose tolerance test (OGTT) glucose concentrations were 5 mmol/L and 4 mmol/L respectively in the Met/Cys low  + PUFA group. In the Met/Cys high  + SFA group, median pre- and post-OGTT glucose concentrations were 4.8 mmol/L and 4.65 mmol/L after the 7-d intervention. The responses in the amino acid profiles were similar in both groups during the intervention with the exception of serine. Fatty acids decreased from baseline to day 7 in both groups. Plasma lactate and pyruvate were similar for both groups with an increase to day 3 before approaching baseline values at day 7. Trial registration ClinicalTrials.gov: NCT02647970, registration date: January 6 th 2016.

Objective The sulfur amino acid (SAA) cysteine is positively related, whereas polyunsaturated fatty acids (PUFAs) are inversely related to activity of the lipogenic enzyme stearoyl-CoA desaturase (SCD). High SCD activity promotes obesity in animals, and plasma activity indices positively associates with fat mass in humans. SCD may thus be a target for dietary intervention with SAA restriction and PUFA enrichment with unknown potential benefits for body composition. We randomized ten healthy individuals to a meal restricted in SAAs and enriched with PUFAs (Cys/Met low  + PUFA) (n = 5) or a meal enriched in SAA and saturated fatty acids (Cys/Met high  + SFA) (n = 5). We measured plasma SCD activity indices (SCD16 and SCD18) and SAAs response hourly from baseline and up to 4 h postprandial. Results SCD16 was unchanged whereas SCD18 tended to increase in the Cys/Met low  + PUFA compared to the Cys/Met high  + SFA group (p time*group interaction  = 0.08). Plasma concentrations of total cysteine fractions including free and reduced cysteine decreased in the Cys/Met low  + PUFA compared to the Cys/Met high  + SFA group (both p time*group interaction  < 0.001). In conclusion, a meal low in SAA but high in PUFAs reduced plasma cysteine fractions but not SCD activity indices. This pilot study can be useful for the design and diet composition of future dietary interventions that targets SCD and SAA. Trial registration ClinicalTrials.gov: NCT02647970, registration date: 6 January 2016

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.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19), has caused a global pandemic, and safe, effective vaccines are urgently needed 1 . Strong, Th1-skewed T cell responses can drive protective humoral and cell-mediated immune responses 2 and might reduce the potential for disease enhancement 3 . Cytotoxic T cells clear virus-infected host cells and contribute to control of infection 4 . Studies of patients infected with SARS-CoV-2 have suggested a protective role for both humoral and cell-mediated immune responses in recovery from COVID-19 (refs. 5 , 6 ). ChAdOx1 nCoV-19 (AZD1222) is a candidate SARS-CoV-2 vaccine comprising a replication-deficient simian adenovirus expressing full-length SARS-CoV-2 spike protein. We recently reported preliminary safety and immunogenicity data from a phase 1/2 trial of the ChAdOx1 nCoV-19 vaccine (NCT04400838) 7 given as either a one- or two-dose regimen. The vaccine was tolerated, with induction of neutralizing antibodies and antigen-specific T cells against the SARS-CoV-2 spike protein. Here we describe, in detail, exploratory analyses of the immune responses in adults, aged 18–55 years, up to 8 weeks after vaccination with a single dose of ChAdOx1 nCoV-19 in this trial, demonstrating an induction of a Th1-biased response characterized by interferon-γ and tumor necrosis factor-α cytokine secretion by CD4 + T cells and antibody production predominantly of IgG1 and IgG3 subclasses. CD8 + T cells, of monofunctional, polyfunctional and cytotoxic phenotypes, were also induced. Taken together, these results suggest a favorable immune profile induced by ChAdOx1 nCoV-19 vaccine, supporting the progression of this vaccine candidate to ongoing phase 2/3 trials to assess vaccine efficacy. A single dose of the ChAdOx1 nCoV-19 vaccine elicits antibodies and cytokine-producing T cells that might help control or prevent SARS-CoV-2 infection.

The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2. We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18–55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 1010 viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT50]; a microneutralisation assay [MNA50, MNA80, and MNA90]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606. Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05). There were no serious adverse events related to ChAdOx1 nCoV-19. In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 (median 856 spot-forming cells per million peripheral blood mononuclear cells, IQR 493–1802; n=43). Anti-spike IgG responses rose by day 28 (median 157 ELISA units [EU], 96–317; n=127), and were boosted following a second dose (639 EU, 360–792; n=10). Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in MNA80 and in 35 (100%) participants when measured in PRNT50. After a booster dose, all participants had neutralising activity (nine of nine in MNA80 at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R2=0·67 by Marburg VN; p<0·001). ChAdOx1 nCoV-19 showed an acceptable safety profile, and homologous boosting increased antibody responses. These results, together with the induction of both humoral and cellular immune responses, support large-scale evaluation of this candidate vaccine in an ongoing phase 3 programme. UK Research and Innovation, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and the German Center for Infection Research (DZIF), Partner site Gießen-Marburg-Langen.

Older adults (aged ≥70 years) are at increased risk of severe disease and death if they develop COVID-19 and are therefore a priority for immunisation should an efficacious vaccine be developed. Immunogenicity of vaccines is often worse in older adults as a result of immunosenescence. We have reported the immunogenicity of a novel chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19 (AZD1222), in young adults, and now describe the safety and immunogenicity of this vaccine in a wider range of participants, including adults aged 70 years and older. In this report of the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18–55 years, 56–69 years, and 70 years and older immunogenicity subgroups. Participants were eligible if they did not have severe or uncontrolled medical comorbidities or a high frailty score (if aged ≥65 years). First, participants were recruited to a low-dose cohort, and within each age group, participants were randomly assigned to receive either intramuscular ChAdOx1 nCoV-19 (2·2 × 1010 virus particles) or a control vaccine, MenACWY, using block randomisation and stratified by age and dose group and study site, using the following ratios: in the 18–55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56–69 years group, 3:1:3:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY; and in the 70 years and older, 5:1:5:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY. Prime-booster regimens were given 28 days apart. Participants were then recruited to the standard-dose cohort (3·5–6·5 × 1010 virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18–55 years group was assigned in a 5:1 ratio to two doses of ChAdOx1 nCoV-19 or two doses of MenACWY. Participants and investigators, but not staff administering the vaccine, were masked to vaccine allocation. The specific objectives of this report were to assess the safety and humoral and cellular immunogenicity of a single-dose and two-dose schedule in adults older than 55 years. Humoral responses at baseline and after each vaccination until 1 year after the booster were assessed using an in-house standardised ELISA, a multiplex immunoassay, and a live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microneutralisation assay (MNA80). Cellular responses were assessed using an ex-vivo IFN-γ enzyme-linked immunospot assay. The coprimary outcomes of the trial were efficacy, as measured by the number of cases of symptomatic, virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were by group allocation in participants who received the vaccine. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. This study is ongoing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137. Between May 30 and Aug 8, 2020, 560 participants were enrolled: 160 aged 18–55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56–69 years (120 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY), and 240 aged 70 years and older (200 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY). Seven participants did not receive the boost dose of their assigned two-dose regimen, one participant received the incorrect vaccine, and three were excluded from immunogenicity analyses due to incorrectly labelled samples. 280 (50%) of 552 analysable participants were female. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged ≥56 years) than younger adults. In those receiving two standard doses of ChAdOx1 nCoV-19, after the prime vaccination local reactions were reported in 43 (88%) of 49 participants in the 18–55 years group, 22 (73%) of 30 in the 56–69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18–55 years group, 23 (77%) in the 56–69 years group, and 32 (65%) in the 70 years and older group. As of Oct 26, 2020, 13 serious adverse events occurred during the study period, none of which were considered to be related to either study vaccine. In participants who received two doses of vaccine, median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar across the three age cohorts (standard-dose groups: 18–55 years, 20 713 arbitrary units [AU]/mL [IQR 13 898–33 550], n=39; 56–69 years, 16 170 AU/mL [10 233–40 353], n=26; and ≥70 years 17 561 AU/mL [9705–37 796], n=47; p=0·68). Neutralising antibody titres after a boost dose were similar across all age groups (median MNA80 at day 42 in the standard-dose groups: 18–55 years, 193 [IQR 113–238], n=39; 56–69 years, 144 [119–347], n=20; and ≥70 years, 161 [73–323], n=47; p=0·40). By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralising antibody responses. T-cell responses peaked at day 14 after a single standard dose of ChAdOx1 nCoV-19 (18–55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841–2428], n=24; 56–69 years: 797 SFCs [383–1817], n=29; and ≥70 years: 977 SFCs [458–1914], n=48). ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Further assessment of the efficacy of this vaccine is warranted in all age groups and individuals with comorbidities. UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.

The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4–12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. We present data from three single-blind randomised controlled trials—one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)—and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4–74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3–85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59–0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3–91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0–69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18–55 years (GMR 2·32 [2·01–2·68]). The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D’Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

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.

More than 190 vaccines are currently in development to prevent infection by the novel severe acute respiratory syndrome coronavirus 2. Animal studies suggest that while neutralizing antibodies against the viral spike protein may correlate with protection, additional antibody functions may also be important in preventing infection. Previously, we reported early immunogenicity and safety outcomes of a viral vector coronavirus vaccine, ChAdOx1 nCoV-19 (AZD1222), in a single-blinded phase 1/2 randomized controlled trial of healthy adults aged 18–55 years ( NCT04324606 ). Now we describe safety and exploratory humoral and cellular immunogenicity of the vaccine, from subgroups of volunteers in that trial, who were subsequently allocated to receive a homologous full-dose (SD/SD D56; n  = 20) or half-dose (SD/LD D56; n  = 32) ChAdOx1 booster vaccine 56 d following prime vaccination. Previously reported immunogenicity data from the open-label 28-d interval prime-boost group (SD/SD D28; n  = 10) are also presented to facilitate comparison. Additionally, we describe volunteers boosted with the comparator vaccine (MenACWY; n  = 10). In this interim report, we demonstrate that a booster dose of ChAdOx1 nCoV-19 is safe and better tolerated than priming doses. Using a systems serology approach we also demonstrate that anti-spike neutralizing antibody titers, as well as Fc-mediated functional antibody responses, including antibody-dependent neutrophil/monocyte phagocytosis, complement activation and natural killer cell activation, are substantially enhanced by a booster dose of vaccine. A booster dose of vaccine induced stronger antibody responses than a dose-sparing half-dose boost, although the magnitude of T cell responses did not increase with either boost dose. These data support the two-dose vaccine regime that is now being evaluated in phase 3 clinical trials. Two doses of the coronavirus disease 2019 vaccine ChAdOx1 nCoV-19 boost antibody responses and functions in phase 1/2 trial participants.

AimPlasma 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.MethodsSerum 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.ResultsAmong 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.ConclusionSpecific 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.