Serum Orotidine: A Novel Biomarker of Increased CVD Risk in Type 2 Diabetes Discovered Through Metabolomics Studies.

OBJECTIVE: To identify novel biomarkers of cardiovascular disease (CVD) risk in type 2 diabetes (T2D) via a hypothesis-free global metabolomics study, while taking into account renal function, an important confounder often overlooked in previous metabolomics studies of CVD. RESEARCH DESIGN AND METHODS: We conducted a global serum metabolomics analysis using the Metabolon platform in a discovery set from the Joslin Kidney Study having a nested case-control design comprising 409 individuals with T2D. Logistic regression was applied to evaluate the association between incident CVD events and each of the 671 metabolites detected by the Metabolon platform, before and after adjustment for renal function and other CVD risk factors. Significant metabolites were followed up with absolute quantification assays in a validation set from the Joslin Heart Study including 599 individuals with T2D with and without clinical evidence of significant coronary heart disease (CHD). RESULTS: In the discovery set, serum orotidine and 2-piperidinone were significantly associated with increased odds of incident CVD after adjustment for glomerular filtration rate (GFR) (odds ratio [OR] per SD increment 1.94 [95% CI 1.39-2.72], P = 0.0001, and 1.62 [1.26-2.08], P = 0.0001, respectively). Orotidine was also associated with increased odds of CHD in the validation set (OR 1.39 [1.11-1.75]), while 2-piperidinone did not replicate. Furthermore, orotidine, being inversely associated with GFR, mediated 60% of the effects of declining renal function on CVD risk. Addition of orotidine to established clinical predictors improved (P < 0.05) C statistics and discrimination indices for CVD risk (ΔAUC 0.053, rIDI 0.48, NRI 0.42) compared with the clinical predictors alone. CONCLUSIONS: Through a robust metabolomics approach, with independent validation, we have discovered serum orotidine as a novel biomarker of increased odds of CVD in T2D, independent of renal function. Additionally, orotidine may be a biological mediator of the increased CVD risk associated with poor kidney function and may help improve CVD risk prediction in T2D.

Metabolomics study of COVID-19 patients in four different clinical stages.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the coronavirus strain causing the respiratory pandemic COVID-19 (coronavirus disease 2019). To understand the pathobiology of SARS-CoV-2 in humans it is necessary to unravel the metabolic changes that are produced in the individuals once the infection has taken place. The goal of this work is to provide new information about the altered biomolecule profile and with that the altered biological pathways of patients in different clinical situations due to SARS-CoV-2 infection. This is done via metabolomics using HPLC-QTOF-MS analysis of plasma samples at COVID-diagnose from a total of 145 adult patients, divided into different clinical stages based on their subsequent clinical outcome (25 negative controls (non-COVID); 28 positive patients with asymptomatic disease not requiring hospitalization; 27 positive patients with mild disease defined by a total time in hospital lower than 10 days; 36 positive patients with severe disease defined by a total time in hospital over 20 days and/or admission at the ICU; and 29 positive patients with fatal outcome or deceased). Moreover, follow up samples between 2 and 3 months after hospital discharge were also obtained from the hospitalized patients with mild prognosis. The final goal of this work is to provide biomarkers that can help to better understand how the COVID-19 illness evolves and to predict how a patient could progress based on the metabolites profile of plasma obtained at an early stage of the infection. In the present work, several metabolites were found as potential biomarkers to distinguish between the end-stage and the early-stage (or non-COVID) disease groups. These metabolites are mainly involved in the metabolism of carnitines, ketone bodies, fatty acids, lysophosphatidylcholines/phosphatidylcholines, tryptophan, bile acids and purines, but also omeprazole. In addition, the levels of several of these metabolites decreased to "normal" values at hospital discharge, suggesting some of them as early prognosis biomarkers in COVID-19 at diagnose.

Lipidomics as Tools for Finding Biomarkers of Intestinal Pathology: From Irritable Bowel Syndrome to Colorectal Cancer.

Lipidomics is an emerging and promising omic that analyzes different lipid molecules in a biological sample. It is considered as a branch of metabolomics, which is defined as the comprehensive analysis of metabolites in a biological specimen. Nonetheless, in recent years lipidomics is being considered a distinct discipline in the biomedicine field. Lipids play important roles in many biological pathways and could work as biomarkers of disease or as therapeutic targets for treatment diseases. The major lipidomics strategies are shotgun lipidomics and liquid chromatography coupled with mass spectrometry. Gastrointestinal diseases such as irritable bowel syndrome or inflammatory bowel disease are chronic diseases that need non-invasive biomarkers for prognosis and diagnosis. Even more, patients with inflammatory bowel disease are at a significantly increased risk of colorectal cancer, principally resulting from the pro-neoplastic effects of chronic intestinal inflammation. Current screening methods utilized globally include sigmoidoscopy, or standard colonoscopy but it is important to develop non-invasive and accurate screening tools to facilitate early detection and precise staging of colorectal cancer. Disease progression and response to treatment may benefit also from the application of these potential new tools. This review is focused on studies that use lipidomics approaches to discover potential biomarkers for monitoring the mentioned intestinal diseases and, particularly, tumour progression.

Serum resistin and glomerular filtration rate in patients with type 2 diabetes.

BACKGROUND: High serum levels of the pro-inflammatory adipokine resistin have been associated with decreased renal function in the general population. The goal of this study was to investigate whether such association is also present among diabetic subjects, who are at increased risk of renal function loss. METHODS: The cross-sectional association between serum resistin levels and estimated glomerular filtration rate (eGFR) was investigated in 1,560 type 2 diabetic (T2D) patients of European ancestry comprised in two different cohorts: 762 patients from San Giovanni Rotondo (SGR; Italy) and 798 patients from Boston (US). RESULTS: Serum resistin was inversely associated with eGFR in SGR [ß (SE) for one SD of resistin increment = -1.01 (0.70) ml/min/1.73 m(2), p = 0.019] and in Boston [ß (SE) = -5.31 (0.74) ml/min/1.73 m(2), p < 0.001] samples, as well as in the two studies combined [ß (SE) = -3.42 (0.52) ml/min/1.73 m(2), p < 0.001]. The association was unaffected by adjustment for smoking habits, BMI, waist circumference, diabetes duration, HbA1c, insulin treatment, hypertension and lipid-lowering therapy: ß (SE) for one SD of resistin increment = -1.07 (0.70), p = 0.02; -5.50 (0.88), p < 0.001; and -2.81 (0.55) ml/min/1.73 m(2), p < .001, in SGR, Boston and the two studies combined, respectively. The association was significantly stronger in men than in women (p for resistin-by-gender interaction = 0.003). For each resistin SD increment, the odds of having eGFR < 0 ml/min/1.7 3m(2) increased by 22% (OR = 1.22; 95% CI 1.02-1.44; p = 0.025) in SGR sample, 69% (OR = 1.69; 95% CI 1.38-2.07; p < 0.001) in Boston sample, and 47% (OR = 1.47; 95% CI 1.29-1.68; p < 0.001) in the two studies considered together. Similar associations were observed in the adjusted model: OR 95% CI for each SD resistin increment being 1.23 (1.03-1.46), p = 0.021; 1.52 (1.20-1.92), p < 0.001; 1.33 (1.16-1.53), p < 0.001, in SGR, Boston and the two studies combined, respectively. CONCLUSIONS: This is the first report of an association between high serum resistin and low eGFR in patients with T2D of European ancestry.