Associations of coagulation parameters and thrombin generation potential with the incidence of type 2 diabetes: mediating role of glycoprotein acetylation.

Hypercoagulability is characterized by abnormal elevations of coagulation factor levels and increased thrombin generation potential. Prior studies demonstrated links between impaired glucose metabolism, endothelial dysfunction, and hypercoagulability. However, the associations between hypercoagulability and incident type 2 diabetes as well as its underlying mechanism remain unclear. We aimed to assess the associations between coagulation parameters including coagulation factor (F) VIII, FIX, FXI, fibrinogen, thrombin generation potential (lag time, endogenous thrombin potential [ETP], peak, time-to-peak, velocity) and incident type 2 diabetes, and to study the underlying mechanism by examining the mediating role of glycoprotein acetylation (GlycA). In the Netherlands Epidemiology of Obesity study, we applied a Cox Proportional-Hazards Model in 5718 participants after adjustment for confounders. We further conducted a mediation analysis investigating the mediation effect of GlycA on the observed associations. During a median follow-up of 6.7 years, 281 incident type 2 diabetes diagnoses were reported. Compared with the lowest quartile, hazard ratio (95% confidence interval) of the highest quartile was 2.47 (1.48-4.14) for FIX, 1.37 (0.85-2.20) for FVIII, 1.11 (0.76-1.63) for FXI, 0.98 (0.65-1.48) for fibrinogen, 1.56 (1.07-2.28) for ETP, 1.84 (1.23-2.74) for peak, 1.59 (1.08-2.33) for velocity, 0.92 (0.62-1.38) for lag time, and 1.21 (0.86-1.70) for time-to-peak. GlycA mediated only a small proportion of all observed associations. In conclusion, elevated levels of coagulation factor and thrombin generation potential are associated with incident type 2 diabetes, suggesting the involvement of hypercoagulability in the pathogenesis of type 2 diabetes.

Dietary intake of fat and fibre according to reference values relates to higher gut microbiota richness in overweight pregnant women.

The diet-microbiota-metabolism relationships during pregnancy are mostly unknown. We explored the effect of the habitual diet and adherence to the dietary reference values on gut microbiota composition and diversity. Further, the association of gut microbiota with serum lipidomics and low-grade inflammation was evaluated. Overweight and obese women (BMI 30·7 (sd 4·4) kg/m2, n 100) were studied at early pregnancy (≤17 weeks). Intakes of nutrients were calculated from 3-d food diaries. Faecal microbiota composition was analysed using 16S rRNA gene sequencing. Fasting serum lipidomic profiles were determined by NMR. High-sensitivity C-reactive protein, glycoprotein acetylation (GlycA) and lipopolysaccharide activity were used as markers for low-grade inflammation. The recommended dietary intake of fibre and fat was related to higher gut microbiota richness and lower abundance of Bacteroidaceae. Correlations were observed between gut microbiota richness and GlycA and between a few microbiota genera and serum lipoprotein particles. As a conclusion, adherence to the dietary reference intake of fat and fibre was associated with beneficial gut microbiota composition, which again contributed to lipidomic profile. Higher gut microbiota richness and nutrient intakes were linked to a lower level of low-grade inflammation marker GlycA. This finding offers novel insights and opportunities for dietary modification during pregnancy with potential of improving the health of the mother and the child.

Permafrost viremia and immune tweening.

The immune system, an exquisitely regulated physiological system, utilizes a wide spectrum of soluble factors and multiple cell populations and subpopulations at diverse states of maturation to monitor and protect the organism against foreign organisms. Immune surveillance is ensured by distinguishing self-antigens from self-associated with non-self (e.g., viral) peptides presented by major histocompatibility complexes (MHC). Pathology is often identified as unregulated inflammatory responses (e.g., cytokine storm), or recognizing self as a non-self entity (i.e., auto-immunity). Artificial intelligence (AI), and in particular specific machine learning (ML) paradigms (e.g., Deep Learning [DL]) proffer powerful algorithms to better understand and more accurately predict immune responses, immune regulation and homeostasis, and immune reactivity to challenges (i.e., immune allostasis) by their intrinsic ability to interpret immune parameters, pathways and events by analyzing large amounts of complex data and drawing predictive inferences (i.e., immune tweening). We propose here that DL models play an increasingly significant role in better defining and characterizing immunological surveillance to ancient and novel virus species released by thawing permafrost.

Meal-induced inflammation: postprandial insights from the Personalised REsponses to DIetary Composition Trial (PREDICT) study in 1000 participants.

BACKGROUND: Meal-induced metabolic changes trigger an acute inflammatory response, contributing to chronic inflammation and associated diseases. OBJECTIVES: We aimed to characterize variability in postprandial inflammatory responses using traditional (IL-6) and novel [glycoprotein acetylation (GlycA)] biomarkers of inflammation and dissect their biological determinants with a focus on postprandial glycemia and lipemia. METHODS: Postprandial (0-6 h) glucose, triglyceride (TG), IL-6, and GlycA responses were measured at multiple intervals after sequential mixed-nutrient meals (0 h and 4 h) in 1002 healthy adults aged 18-65 y from the PREDICT (Personalised REsponses to DIetary Composition Trial) 1 study, a single-arm dietary intervention study. Measures of habitual diet, blood biochemistry, gut microbiome composition, and visceral fat mass (VFM) were also collected. RESULTS: The postprandial changes in GlycA and IL-6 concentrations were highly variable between individuals. Participants eliciting an increase in GlycA and IL-6 (60% and 94% of the total participants, respectively) had mean 6-h increases of 11% and 190%, respectively. Peak postprandial TG and glucose concentrations were significantly associated with 6-h GlycA (r = 0.83 and r = 0.24, respectively; both P < 0.001) but not with 6-h IL-6 (both P > 0.26). A random forest model revealed the maximum TG concentration was the strongest postprandial TG predictor of postprandial GlycA and structural equation modeling revealed that VFM and fasting TG were most strongly associated with fasting and postprandial GlycA. Network Mendelian randomization demonstrated a causal link between VFM and fasting GlycA, mediated (28%) by fasting TG. Individuals eliciting enhanced GlycA responses had higher predicted cardiovascular disease risk (using the atherosclerotic disease risk score) than the rest of the cohort. CONCLUSIONS: The variable postprandial increases in GlycA and their associations with TG metabolism highlight the importance of modulating TG in concert with obesity to reduce GlycA and associated low-grade inflammation-related diseases.This trial was registered at clinicaltrials.gov as NCT03479866.

Serum GlycA Level is Elevated in Active Systemic Lupus Erythematosus and Correlates to Disease Activity and Lupus Nephritis Severity.

OBJECTIVE: Reliable non-invasive biomarkers are needed to assess disease activity and prognosis in patients with systemic lupus erythematosus (SLE). Glycoprotein acetylation (GlycA), a novel biomarker for chronic inflammation, has been reported to be increased in several inflammatory diseases. We investigated the relevance of serum GlycA in SLE patients exhibiting various levels of activity and severity, especially with regards to renal involvement. METHODS: Serum GlycA was measured by nuclear magnetic resonance spectroscopy in samples from well characterized SLE patients and from both healthy controls and patients with other kidney diseases (KD). Disease activity was evaluated using the Systemic Lupus Erythematosus Activity Index 2000 (SLEDAI-2K). Renal severity was assessed by kidney biopsy. RESULTS: Serum GlycA was elevated in active (n = 105) compared to quiescent SLE patients (n = 39, p < 10-6), healthy controls (n = 20, p = 0.009) and KD controls (n = 21, p = 0.04), despite a more severely altered renal function in the latter. GlycA level was correlated to disease activity (SLEDAI-2K, ρ = 0.37, p < 10-4), Creactive protein, neutrophil count, triglyceride levels, proteinuria and inversely to serum albumin. In patients with biopsy-proven lupus nephritis (LN), GlycA levels were higher in proliferative (n = 26) than non-proliferative LN (n = 10) in univariate analysis (p = 0.04), and was shown to predict proliferative LN independently of renal parameters, immunological activity, neutrophil count and daily corticosteroid dosage by multivariate analysis (p < 5 × 10-3 for all models). In LN patients with repeated longitudinal GlycA measurement (n = 11), GlycA varied over time and seemed to peak at the time of the flare. CONCLUSIONS: GlycA, as a summary measure for different inflammatory processes, could be a valuable biomarker of disease activity in patients with SLE, and a non-invasive biomarker of pathological severity in the context of LN.

GlycA, a Nuclear Magnetic Resonance Spectroscopy Measure for Protein Glycosylation, is a Viable Biomarker for Disease Activity in IBD.

BACKGROUND AND AIMS: Glycoprotein acetylation [GlycA] is a novel nuclear magnetic resonance [NMR] biomarker, measured in serum or plasma, that summarizes the signals originating from glycan groups of certain acute-phase glycoproteins. This biomarker has been shown to be robustly associated with cardiovascular and short-term all-cause mortality, and with disease severity in several inflammatory conditions. We investigated GlycA levels in a cohort of healthy individuals [HCs], patients with Crohn's disease [CD] and patients with ulcerative colitis [UC] prior to and after therapeutic control of inflammation. METHODS: Serum samples of 10 HCs, 37 CD patients and 21 UC patients before and after biologic therapy were subjected to high-throughput NMR analysis by Nightingale Health Ltd. Paired C-reactive protein [CRP] and fecal calprotectin [fCal] measurements were used to characterize baseline differences, treatment effects and post-treatment association with endoscopic response [50% SES-CD decrease at Week 24] and mucosal healing [SES-CD ≤ 2 for CD, Mayo endoscopic score ≤ 1 for UC]. RESULTS: GlycA levels were significantly higher in patients with active inflammamtory bowel disease [IBD] compared with those in healthy controls, and accurately reflected the mucosal recovery to a 'healthy' state in both CD and UC patients achieving mucosal healing. In CD patients who experienced an endoscopic response without achieving full mucosal healing, GlycA levels also decreased but did not normalize to HC levels. Overall, GlycA correlated well with CRP and fCal, and accurately tracked disease activity in CRP-negative patients [<5 mg/dL]. CONCLUSION: GlycA holds promise as a viable serological biomarker for disease activity in IBD, even in patients without elevated CRP, and should therefore be tested in large prospective cohorts.