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

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  • Luis F. Ferreira-Divino
  • Tommi Suvitaival
  • Viktor Rotbain Curovic
  • Nete Tofte
  • Kajetan Trošt
  • Ismo M. Mattila
  • Theilade, Karen Simone
  • Signe A. Winther
  • Tine W. Hansen
  • Marie Frimodt-Møller
  • Cristina Legido-Quigley
  • Rossing, Peter

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.

TidsskriftCardiovascular Diabetology
Antal sider10
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
P.R. reports having given lectures for AstraZeneca, Novo Nordisk, Eli Lilly, Bayer, Sanofi, and Boehringer Ingelheim; has served as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Astellas Gilead, and Novo Nordisk (all fees given to Steno Diabetes Center Copenhagen). S.T. has served as a consultant on advisory boards for Novo Nordisk. M.F.M reports having received research grants from Novo Nordisk and speaking fees from Boehringer Ingelheim, Novartis, Baxter and Sanofi. Since completion of data collection N.T. and S.A.W. are full-time employees of Novo Nordisk A/S.

Funding Information:
This work was supported by the Novo Nordisk Foundation (grant number NNF14OC0013659) PROTON Personalising treatment of diabetic kidney disease; internal funding was provided by Steno Diabetes Center Copenhagen, Gentofte, Denmark .

Publisher Copyright:
© 2022, The Author(s).

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