Global Metabolomic and Isobaric
Tagging Capillary
Liquid Chromatography–Tandem Mass Spectrometry Approaches for
Uncovering Pathway Dysfunction in Diabetic Mouse Aorta
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Abstract
Despite
the prevalence of diabetes and the global health risks
it poses, the biochemical pathogenesis of diabetic complications remains
poorly understood with few effective therapies. This study employs
capillary liquid chromatography (capLC) and tandem mass spectrometry
(MS/MS) in conjunction with both global metabolomics and isobaric
tags specific to amines and carbonyls to probe aortic metabolic content
in diabetic mice with hyperglycemia, hyperlipidemia, hypertension,
and stenotic vascular damage. Using these combined techniques, metabolites
well-characterized in diabetes as well as novel pathways were investigated.
A total of 53 986 features were detected, 719 compounds were
identified as having significant fold changes (thresholds ≥2
or ≤0.5), and 48 metabolic pathways were found to be altered
with at least 2 metabolite hits in diabetic samples. Pathways related
to carbonyl stress, carbohydrate metabolism, and amino acid metabolism
showed the greatest number of metabolite changes. Three novel pathways
with previously limited or undescribed roles in diabetic complicationsvitamin
B6, propanoate, and butanoate metabolismwere also shown to
be altered in multiple points along the pathway. These discoveries
support the theory that diabetic vascular complications arise from
the interplay of a myriad of metabolic pathways in conjunction with
oxidative and carbonyl stress, which may provide not only new and
much needed biomarkers but also insights into novel therapeutic targets