Circulating metabolites and molecular lipid species are associated with future cardiovascular morbidity and mortality in type 1 diabetes

Abstract

Background Cardiovascular disease remains the leading cause of mortality in individuals with diabetes and improved understanding of its pathophysiology is needed. We investigated the association of a large panel of metabolites and molecular lipid species with future cardiovascular events in type 1 diabetes. Methods The study included 669 individuals with type 1 diabetes. Non-targeted serum metabolomics and lipidomics analyses were performed using mass spectrometry. Data on cardiovascular events (cardiovascular mortality, coronary artery disease, stroke, and peripheral arterial interventions) were obtained from Danish Health registries and analyzed by Cox hazards models. Metabolites and molecular lipid species were analyzed in univariate models adjusted for false discovery rate (FDR). Metabolites and molecular lipid species fulfilling a pFDR < 0.05 were subsequently analyzed in adjusted models including age, sex, hemoglobin A1c, mean arterial pressure, smoking, body mass index, low-density lipoprotein cholesterol, estimated glomerular filtration rate, urinary albumin excretion rate and previous cardiovascular disease. Analyses of molecular lipid species were further adjusted for triglycerides and statin use. Results Of the included participants, 55% were male and mean age was 55 ± 13 years. Higher 4-hydroxyphenylacetic acid (HR 1.35, CI [1.01–1.80], p = 0.04) and lower threonine (HR 0.81, CI [0.67–0.98] p = 0.03) were associated with development of cardiovascular events (n = 95). In lipidomics analysis, higher levels of three different species, diacyl-phosphatidylcholines (PC)(36:2) (HR 0.82, CI [0.70–0.98], p = 0.02), alkyl-acyl-phosphatidylcholines (PC-O)(34:2) (HR 0.76, CI [0.59–0.98], p = 0.03) and (PC-O)(34:3) (HR 0.75, CI [0.58–0.97], p = 0.03), correlated with lower risk of cardiovascular events, whereas higher sphingomyelin (SM)(34:1) (HR 1.32, CI [1.04–1.68], p = 0.02), was associated with an increased risk. Conclusions Circulating metabolites and molecular lipid species were associated with future cardiovascular events in type 1 diabetes. While the causal effect of these biomolecules on the cardiovascular system remains unknown, our findings support that omics-based technologies, although still in an early phase, may have the potential to unravel new pathways and biomarkers in the field of cardiovascular disease in type 1 diabetes.

Circulating metabolomic markers in association with overall burden of microvascular complications in type 1 diabetes

“…We have previously investigated the associations between circulating metabolites and lipid species and diabetic complications in T1D, both cross-sectionally and prospectively 4–9. Through these studies, we have identified hydroxybutyrate isomers, ribose derivatives, and branched-chain amino acids that were associated with presence and development or progression of DR,8 kidney disease,5 and cardiovascular disease 10. Similar results were also identified in relation to cardiac autonomic neuropathy 4 11.…”

Nuclear Magnetic Resonance-Based Lipidomics in the Assessment of Cardiometabolic Risk in Type 1 Diabetes: An Exploratory Analysis

“…Lipidomic analysis is a new technique that identifies a broad range of lipid species, which could uncover some variables potentially associated with chronic complications in this population [10]. Preliminary data from our group also showed that some dietary-related lipid parameters could identify individuals with T1D more prone to suffer from CVD [11,12].…”

“…In this sense, some previous studies from the Scandinavian population showed that this lipid variable was directly associated with worse kidney [37][38][39] and coronary heart disease outcomes [39]. Nevertheless, other studies using a more powerful lipidomic analysis (which could identify up to 106 different molecular lipid species) showed that several sphingomyelin subclasses were associated with worse kidney outcomes and cardiovascular mortality while other subclasses were associated with better outcomes [10,38]. Furthermore, no significant relationships were found between any of the sphingomyelin subclasses and stroke [10].…”

“…Nevertheless, other studies using a more powerful lipidomic analysis (which could identify up to 106 different molecular lipid species) showed that several sphingomyelin subclasses were associated with worse kidney outcomes and cardiovascular mortality while other subclasses were associated with better outcomes [10,38]. Furthermore, no significant relationships were found between any of the sphingomyelin subclasses and stroke [10]. Also, a prospection of the Multi-Ethnic Study of Atherosclerosis cohort [40], in the general population and primary prevention, found no association between sphingomyelin levels and incident CVD, and the association was even inverse in some models.…”

The right ventricular dysfunction and ventricular interdependence in patients with DM: assessment using cardiac MR feature tracking

“…Cardiovascular disease is a common complication in patients with diabetes [ 8 , 21 ]. A large number of scholars have conducted intensive research on diabetes-related cardiomyopathy.…”