Abstract
Human disease is heterogeneous, with similar disease phenotypes resulting from distinct combinations of genetic and environmental factors. Small-molecule profiling can address disease heterogeneity by evaluating the underlying biologic state of individuals through non-invasive interrogation of plasma metabolite levels. We analyzed metabolite profiles from an oral glucose tolerance test (OGTT) in 50 individuals, 25 with normal (NGT) and 25 with impaired glucose tolerance (IGT). Our focus was to elucidate underlying biologic processes. Although we initially found little overlap between changed metabolites and preconceived definitions of metabolic pathways, the use of unbiased network approaches identified significant concerted changes. Specifically, we derived a metabolic network with edges drawn between reactant and product nodes in individual reactions and between all substrates of individual enzymes and transporters. We searched for “active modules”—regions of the metabolic network enriched for changes in metabolite levels. Active modules identified relationships among changed metabolites and highlighted the importance of specific solute carriers in metabolite profiles. Furthermore, hierarchical clustering and principal component analysis demonstrated that changed metabolites in OGTT naturally grouped according to the activities of the System A and L amino acid transporters, the osmolyte carrier SLC6A12, and the mitochondrial aspartate-glutamate transporter SLC25A13. Comparison between NGT and IGT groups supported blunted glucose- and/or insulin-stimulated activities in the IGT group. Using unbiased pathway models, we offer evidence supporting the important role of solute carriers in the physiologic response to glucose challenge and conclude that carrier activities are reflected in individual metabolite profiles of perturbation experiments. Given the involvement of transporters in human disease, metabolite profiling may contribute to improved disease classification via the interrogation of specific transporter activities.
Highlights
Disease heterogeneity has challenged the practice of medicine
The field of metabolomics involves the analysis of a broad array of metabolite levels from clinical fluid samples such as blood or urine and can be used to evaluate disease states
We have focused on the oral glucose tolerance test, used to diagnose diabetes, and have found that multiple transporters play an important role in the normal response to ingesting sugar
Summary
Disease heterogeneity has challenged the practice of medicine. Individuals with the same apparent disease at our current diagnostic resolution often show remarkable variation in prognosis and treatment responsiveness, presumably because a superficially similar disease state can arise from diverse combinations of genetic and environmental factors [1]. Efforts to resolve the heterogeneity have focused on collecting increasing amounts of quantitative patient information, including genotypic [2] and mRNA [3] and protein expression data [4] with the hope of establishing better clinical classifiers based on aberrant activities of specific, targetable biological pathways. For complex human diseases that span multiple organ systems, metabolomics—the analysis of a broad array of metabolite levels from biologic fluid samples such as blood or urine—represents a minimally-invasive way to obtain quantitative biologic information from patients to uncover disease pathophysiology and aid diagnostic and prognostic classification [7]. The integration of network information from protein-protein interaction data or predefined biologic pathways has greatly assisted elucidation of underlying processes and led to the development of increasingly robust and accurate gene-based classifiers for disease [8,9]. We hypothesize that the characterization of human disease by metabolomic profiling should benefit from interpreting metabolite changes in the context of known metabolic reactions
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