Selected Publication:

SHR Neuro Cancer Cardio Lipid Metab Microb

Regan, JA; Mentz, RJ; Nguyen, M; Green, JB; Truby, LK; Ilkayeva, O; Newgard, CB; Buse, JB; Sourij, H; Sjöström, CD; Sattar, N; McGarrah, RW; Zheng, Y; McGuire, DK; Standl, E; Armstrong, P; Peterson, ED; Hernandez, AF; Holman, RR; Shah, SH.
Mitochondrial metabolites predict adverse cardiovascular events in individuals with diabetes.
JCI Insight. 2023; 8(17): e168563 Doi: 10.1172/jci.insight.168563 [OPEN ACCESS]
Web of Science PubMed FullText FullText_MUG

 

Co-authors Med Uni Graz

Sourij Harald

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Abstract:

Metabolic mechanisms underlying the heterogeneity of major adverse cardiovascular (CV) event (MACE) risk in individuals with type 2 diabetes mellitus (T2D) remain unclear. We hypothesized that circulating metabolites reflecting mitochondrial dysfunction predict incident MACE in T2D. Targeted mass-spectrometry profiling of 60 metabolites was performed on baseline plasma samples from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS; discovery cohort) and Exenatide Study of Cardiovascular Event Lowering (EXSCEL; validation cohort) biomarker substudy cohorts. A principal components analysis metabolite factor comprising medium-chain acylcarnitines (MCACs) was associated with MACE in TECOS and validated in EXSCEL, with higher levels associated with higher MACE risk. Meta-analysis showed that long-chain acylcarnitines (LCACs) and dicarboxylacylcarnitines were also associated with MACE. Metabolites remained associated with MACE in multivariate models and favorably changed with exenatide therapy. A third cohort (Cardiac Catheterization Genetics [CATHGEN]) with T2D was assessed to determine whether these metabolites improved discriminative capability of multivariate models for MACE. Nine metabolites (MCACs and LCACs and 1 dicarboxylacylcarnitine) were associated with time to MACE in the CATHGEN cohort. Addition of these metabolites to clinical models minimally improved the discriminative capability for MACE but did significantly down reclassify risk. Thus, metabolites reporting on dysregulated mitochondrial fatty acid oxidation are present in higher levels in individuals with T2D who experience subsequent MACE. These biomarkers may improve CV risk prediction models, be therapy responsive, and highlight emerging risk mechanisms.

Find related publications in this database (using NLM MeSH Indexing)

Humans - administration & dosage

Diabetes Mellitus, Type 2 - complications, drug therapy

Exenatide - therapeutic use

Cardiovascular System - metabolism

Mitochondria - metabolism

Biomarkers - administration & dosage

Cardiovascular Diseases - metabolism

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