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Plasma fatty acid metabolic profiling coupled with clinical research reveals the risk factors for atherosclerosis development in type 2 diabetes mellitus.

ABSTRACT: Many publications have reported that the incidence of atherosclerotic cardiovascular diseases is higher in patients with type 2 diabetes mellitus (T2DM) than in the non-diabetic population; however, until now, the reason has been unclear. In this study, 25 males (25/64, 39.06%) and 19 females (19/54, 35.19%) had complications with atherosclerosis after two years. To reveal the risk factors for developing atherosclerosis in patients with T2DM, plasma fatty acid metabolic profiling based on gas chromatography-mass spectrometry was combined with the analysis of clinical biochemical indices. The results of partial least squares-discriminant and canonical correlation analyses suggested that C20:0, C22:6n-3, glycosylated hemoglobin, waist circumference, and waist-to-hip ratio are likely to be closely related to T2DM complicated with atherosclerosis. Metabolomic information is a beneficial supplement to existing clinical indices and is useful in predicting the development of a patient's disease and optimizing the treatment.

SUBMITTER: Zhou Q

PROVIDER: S-EPMC9074937 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Plasma fatty acid metabolic profiling coupled with clinical research reveals the risk factors for atherosclerosis development in type 2 diabetes mellitus.

Zhou Qianyu Q Ren Dabing D Xiao Yang Y Yi Lunzhao L Zhou Zhiguang Z

RSC advances 20191106 62

Many publications have reported that the incidence of atherosclerotic cardiovascular diseases is higher in patients with type 2 diabetes mellitus (T2DM) than in the non-diabetic population; however, until now, the reason has been unclear. In this study, 25 males (25/64, 39.06%) and 19 females (19/54, 35.19%) had complications with atherosclerosis after two years. To reveal the risk factors for developing atherosclerosis in patients with T2DM, plasma fatty acid metabolic profiling based on gas ch ...[more]

PMID: 35540605

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Project description:Background and purposeAtherosclerosis results from a maladaptive inflammatory response initiated by the intramural retention of LDL in susceptible areas of the arterial vasculature. The ω-3 polyunsaturated fatty acids (ω-3) have protective effects in atherosclerosis; however, their molecular mechanism is still largely unknown. The present study used a metabolomic approach to reveal the atheroprotective metabolites of ω-3 and investigate the underlying mechanisms.Experimental approachWe evaluated the development of atherosclerosis in LDL receptor-deficient mice (LDLR-/- ) fed a Western-type diet (WTD) plus ω-3 and also LDLR-/- and fat-1 transgenic (LDLR-/- -fat-1tg ) mice fed a WTD. The profiles of ω-3 in the plasma were screened by LC-MS/MS using unbiased systematic metabolomics analysis. We also studied the effect of metabolites of eicosapentaenoic acid (EPA) on endothelial activation in vitro.Key resultsThe ω-3 diet and fat-1 transgene decreased monocyte infiltration, inhibited the expression of pro-inflammatory genes and significantly attenuated atherosclerotic plaque formation and enhanced plaque stability in LDLR-/- mice. The content of 18-hydroxy-eicosapentaenoic acid (18-HEPE) and 17,18-epoxy-eicosatetraenoic acid (17,18-EEQ), from the cytochrome P450 pathway of EPA, was significantly higher in plasma from both ω-3-treated LDLR-/- and LDLR-/- -fat-1tg mice as compared with WTD-fed LDLR-/- mice. In vitro in endothelial cells, 18-HEPE or 17,18-EEQ decreased inflammatory gene expression induced by TNFα via NF-κB signalling and thereby inhibited monocyte adhesion to endothelial cells.Conclusions and implicationsEPA protected against the development of atherosclerosis in atheroprone mice via the metabolites 18-HEPE and/or 17,18-EEQ, which reduced endothelial activation. These compounds may have therapeutic implications in atherosclerosis.Linked articlesThis article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

Project description:BackgroundLimited studies have explored the difference of fatty acid profile between women with and without gestational diabetes mellitus (GDM), and the results were inconsistent. Individual fatty acids tend to be interrelated because of the shared food sources and metabolic pathways. Thus, whether fatty acid patters during pregnancy were related to GDM odds needs further exploration.ObjectiveTo identify plasma fatty acid patters during pregnancy and their associations with odds of GDM.MethodsA hospital-based case-control study including 217 GDM cases and 217 matched controls was carried out in urban Wuhan, China from August 2012 to April 2015. All the participants were enrolled at the time of GDM screening and provided fasting blood samples with informed consent. We measured plasma concentrations of fatty acids by gas chromatography-mass spectrometry, and derived potential fatty acid patterns (FAPs) through principal components analysis. Conditional logistic regression and restricted cubic spline model were used to evaluate the associations between individual fatty acids or FAPs and odds of GDM.ResultsTwenty individual fatty acids with relative concentrations ≥0.05% were included in the analyses. Compared with control group, GDM group had significantly higher concentrations of total fatty acids, 24:1n-9, and relatively lower levels of 14:0, 15:0, 17:0, 18:0, 24:0, 16:1n-7, 20:1n-9,18:3n-6, 20:2n-6, 18:3n-3, 20:3n-3, 22:5n-3. Two novel patterns of fatty acids were identified to be associated with lower odds of GDM: (1) relatively higher odd-chain fatty acids, 14:0, 18:0, 18:3n-3, 20:2n-6, 20:3n-6 and lower 24:1n-9 and 18:2n-6 [adjusted odds ratio (OR) (95% confidence interval) (CI) for quartiles 4 vs. 1: 0.42 (0.23-0.76), P-trend = 0.002], (2) relatively higher n-3 polyunsaturated fatty acids, 24:0, 18:3n-6 and lower 16:0 and 20:4n-6 [adjusted OR (95% CI) for quartiles 4 vs. 1: 0.48 (0.26-0.90), P-trend = 0.018].ConclusionOur findings suggested that two novel FAPs were inversely associated with GDM odds. The combination of circulating fatty acids could be a more significant marker of GDM development than individual fatty acids or their subgroups.

Project description:Gestational diabetes mellitus (GDM) is characterized by insulin resistance accompanied by low/absent beta-cell compensatory adaptation to the increased insulin demand. Although the molecular mechanisms and factors acting on beta-cell compensatory response during pregnancy have been partially elucidated and reported, those inducing an impaired beta-cell compensation and function, thus evolving in GDM, have yet to be fully addressed. MicroRNAs (miRNAs) are a class of small endogenous non-coding RNAs, which negatively modulate gene expression through their sequence-specific binding to 3'UTR of mRNA target. They have been described as potent modulators of cell survival and proliferation and, furthermore, as orchestrating molecules of beta-cell compensatory response and function in diabetes. Moreover, it has been reported that miRNAs can be actively secreted by cells and found in many biological fluids (e.g., serum/plasma), thus representing both optimal candidate disease biomarkers and mediators of tissues crosstalk(s). Here, we analyzed the expression profiles of circulating miRNAs in plasma samples obtained from n = 21 GDM patients and from n = 10 non-diabetic control pregnant women (24-33 weeks of gestation) using TaqMan array microfluidics cards followed by RT-real-time PCR single assay validation. The results highlighted the upregulation of miR-330-3p in plasma of GDM vs non-diabetics. Furthermore, the analysis of miR-330-3p expression levels revealed a bimodally distributed GDM patients group characterized by high or low circulating miR-330 expression and identified as GDM-miR-330high and GDM-miR-330low. Interestingly, GDM-miR-330high subgroup retained lower levels of insulinemia, inversely correlated to miR-330-3p expression levels, and a significant higher rate of primary cesarean sections. Finally, miR-330-3p target genes analysis revealed major modulators of beta-cell proliferation and of insulin secretion, such as the experimentally validated genes E2F1 and CDC42 as well as AGT2R2, a gene involved in the differentiation of mature beta-cells. In conclusion, we demonstrated that plasma miR-330-3p could be of help in identifying GDM patients with potential worse gestational diabetes outcome; in GDM, miR-330-3p may directly be transferred from plasma to beta-cells thus modulating key target genes involved in proliferation, differentiation, and insulin secretion.

Project description:BackgroundThis study aims to identify early metabolomic biomarkers of gestational diabetes mellitus (GDM) and evaluate their association with hepatic steatosis.MethodsWe compared maternal serum metabolomic profiles between women who developed GDM (n = 118) and matched controls (n = 118) during the first (10-14 gestational weeks) and second (24-28 gestational weeks) trimesters using ultra-performance liquid chromatography coupled with mass spectrometry. Mediation analysis was performed to evaluate the mediating role of metabolic dysfunction-associated steatotic liver disease (MASLD) in the relationship between metabolites and subsequent development of GDM. A refined prediction model was developed to predict GDM using established clinical factors and selected metabolites.ResultsSignificant alterations in circulating metabolites, including amino acids, bile acids, and phospholipids, were observed in the GDM group compared to controls during early pregnancy. Mediation analysis revealed that several metabolites, including glycocholic acid (proportion mediated (PM) = 31.9%), butanoyl carnitine (PM = 25.7%), and uric acid (PM = 22.4%), had significant indirect effects on GDM incidence mediated by hepatic steatosis. The refined prediction model composed of clinical factors and selected metabolites in the first trimester demonstrated higher performance in predicting GDM development than the established prediction model composed solely of clinical factors (AUC, 0.85 vs. 0.63, p < 0.001).ConclusionsWomen who developed GDM exhibited altered metabolomic profiles from early pregnancy, which showed a significant correlation with GDM, with MASLD as a mediator. Selected metabolomic biomarkers may serve as predictive markers and potential targets for early risk assessment and intervention in GDM.Research insightsWHAT IS CURRENTLY KNOWN ABOUT THIS TOPIC?: Gestational diabetes mellitus (GDM) is a common pregnancy complication with significant health risks. Early identification of women at high risk for GDM is crucial for timely intervention and improved outcomes. WHAT IS THE KEY RESEARCH QUESTION?: What alterations in circulating metabolites during early pregnancy are associated with subsequent GDM development? Does metabolic dysfunction-associated steatotic liver disease (MASLD) mediate the association between specific metabolites and GDM risk? WHAT IS NEW?: Significant alterations in bile acids, amino acids, phosphatidylethanolamines, and phosphatidylinositols were observed in early pregnancy sera of women who later developed GDM. MASLD significantly mediated the effects of several metabolites on GDM risk, with mediation proportions ranging from 9.7 to 31.9%. A refined prediction model composed of clinical factors and metabolites significantly improved the performance in predicting GDM development. HOW MIGHT THIS STUDY INFLUENCE CLINICAL PRACTICE?: These results provide new insights into early metabolic alterations associated with GDM development and highlight the potential mediating role of MASLD. This comprehensive metabolomic approach may contribute to the development of improved risk prediction models and targeted interventions for GDM prevention.

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Plasma fatty acid metabolic profiling coupled with clinical research reveals the risk factors for atherosclerosis development in type 2 diabetes mellitus.

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Plasma fatty acid metabolic profiling coupled with clinical research reveals the risk factors for atherosclerosis development in type 2 diabetes mellitus.

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