Several plasma metabolites were associated with incidence of T2DM and CAD; elevated glutamate and reduced asparagine levels were associated with both diseases. We thus discovered associations that might help shed additional light on why T2DM and CAD commonly co-occur.

ObjectivesWe recently identified a health conscious food pattern (HCFP) associated with reduced risk of cardiometabolic disease. However, the molecular events linking the healthy food pattern to reduced risk of cardiometabolic disease are unknown. Our aim was to identify plasma metabolites associated with the HCFP and test if such metabolites predict cardiometabolic disease and mortality.MethodsUsing liquid-chromatography mass-spectrometry, 112 plasma metabolites were measured in 3236 participants without cardiovascular disease (CVD) and diabetes mellitus from the population-based Malmö Diet and Cancer study. Metabolites associated with the HCFP were identified using multivariable adjusted linear regressions followed by Bonferroni correction. The healthy dietary biomarkers were subsequently related to risk of cardiometabolic disease and mortality during long-term follow-up with multivariable adjusted Cox proportional hazards models.ResultsDuring a median follow-up time of 21.4 years, 603 participants developed CVD, 362 developed diabetes mellitus and 843 participants died. Five healthy dietary biomarkers were associated with the HCFP at baseline (p<0.0004) and four predicted at least one of the studied end points (p<0.05). Ergothioneine was the metabolite most strongly connected to the HCFP and was associated with a lower risk of coronary disease (HR per 1 SD increment of ergothioneine, HR=0.85, p=0.01), cardiovascular mortality (HR=0.79, p=0.002) and overall mortality (HR=0.86, p=4e-5).ConclusionsWe identified that higher ergothioneine was an independent marker of lower risk of cardiometabolic disease and mortality, which potentially can be induced by a specific healthy dietary intake.

Context Metabolomics has the potential to generate biomarkers that can facilitate understanding relevant pathways in the pathophysiology of type 2 diabetes (T2DM). Methods Nontargeted metabolomics was performed, via liquid chromatography–mass spectrometry, in a discovery case-cohort study from the Malmö Preventive Project (MPP), which consisted of 698 metabolically healthy participants, of whom 202 developed T2DM within a follow-up time of 6.3 years. Metabolites that were significantly associated with T2DM were replicated in the population-based Malmö Diet and Cancer–Cardiovascular Cohort (MDC-CC) (N = 3423), of whom 402 participants developed T2DM within a follow-up time of 18.2 years. Results Using nontargeted metabolomics, we observed alterations in nine metabolite classes to be related to incident T2DM, including 11 identified metabolites. N2,N2-dimethylguanosine (DMGU) (OR = 1.94; P = 4.9e-10; 95% CI, 1.57 to 2.39) was the metabolite most strongly associated with an increased risk, and beta-carotene (OR = 0.60; P = 1.8e-4; 95% CI, 0.45 to 0.78) was the metabolite most strongly associated with a decreased risk. Identified T2DM-associated metabolites were replicated in MDC-CC. Four metabolites were significantly associated with incident T2DM in both the MPP and the replication cohort MDC-CC, after adjustments for traditional diabetes risk factors. These included associations between three metabolites, DMGU, 7-methylguanine (7MG), and 3-hydroxytrimethyllysine (HTML), and incident T2DM. Conclusions We used nontargeted metabolomics in two Swedish prospective cohorts comprising >4000 study participants and identified independent, replicable associations between three metabolites, DMGU, 7MG, and HTML, and future risk of T2DM. These findings warrant additional studies to investigate a potential functional connection between these metabolites and the onset of T2DM.

Objective: The gut microbiota is increasingly being implicated in cardiovascular health. Metabolites produced by bacteria have been suggested to be mediators in the bacterial action on cardiovascular health. We aimed to identify gut microbiota-related plasma metabolites and test whether these metabolites associate with future risk of coronary artery disease (CAD). Methods: Nontargeted metabolomics was performed using liquid chromatography-mass spectrometry in order to measure 1446 metabolite features in the Malmö Offspring Study (MOS) (N = 776). The gut microbiota was characterized using 16S rRNA sequencing. Gut bacteria-related metabolites were measured in two independent prospective cohorts, the Malmö Diet and Cancer – Cardiovascular Cohort (MDC-CC) (N = 3361) and the Malmö Preventive Project (MPP) (N = 880), in order to investigate the associations between gut bacteria-related metabolites and risk of CAD. Results: In MOS, 33 metabolite features were significantly (P < 4.8e-7) correlated with at least one operational taxonomic unit. Phenylacetylglutamine (PAG) was associated with an increased risk of future CAD, using inverse variance weighted meta-analysis of age and sex-adjusted logistic regression models in MDC-CC and MPP. PAG remained significantly associated with CAD (OR = 1.17, 95% CI = 1.06–1.29, P = 1.9e-3) after adjustments for cardiovascular risk factors. Conclusion: The levels of 33 plasma metabolites were correlated with the gut microbiota. Out of these, PAG was associated with an increased risk of future CAD independently of other cardiovascular risk factors. Our results highlight a link between the gut microbiota and CAD risk and should encourage further studies testing if modification of PAG levels inhibits development of CAD.

BackgroundIdentification of lifestyle modifiable metabolic pathways related to cardiometabolic disease risk is essential for improvement of primary prevention in susceptible individuals. It was recently shown that plasma dimethylguanidino valerate (DMGV) levels are associated with incident type 2 diabetes mellitus. Our aims were to investigate whether plasma DMGV is related to risk of future coronary artery disease and with cardiovascular mortality and to replicate the association with type 2 diabetes mellitus and pinpoint candidate lifestyle interventions susceptible to modulate DMGV levels.Methods and ResultsPlasma DMGV levels were measured using liquid chromatography‐mass spectrometry in a total of 5768 participants from the MDC (Malmö Diet and Cancer Study—Cardiovascular Cohort), MPP (Malmö Preventive Project), and MOS (Malmö Offspring Study). Dietary intake assessment was performed in the MOS. Baseline levels of DMGV associated with incident coronary artery disease in both the MDC (hazard ratio=1.29; CI=1.16–1.43; P<0.001) and MPP (odds ratio=1.25; CI=1.08–1.44; P=2.4e‐3). In the MDC, DMGV was associated with cardiovascular mortality and incident coronary artery disease, independently of traditional risk factors. Furthermore, the association between DMGV and incident type 2 diabetes mellitus was replicated in both the MDC (hazard ratio=1.83; CI=1.63–2.05; P<0.001) and MPP (odds ratio=1.65; CI=1.38–1.98; P<0.001). Intake of sugar‐sweetened beverages was associated with increased levels of DMGV, whereas intake of vegetables and level of physical activity was associated with lower DMGV.ConclusionsWe discovered novel independent associations between plasma DMGV and incident coronary artery disease and cardiovascular mortality, while replicating the previously reported association with incident type 2 diabetes mellitus. Additionally, strong associations with sugar‐sweetened beverages, vegetable intake, and physical activity suggest the potential to modify DMGV levels using lifestyle interventions.