Abstract
Background‘You are what you eat’ is an accurate summary for humans and animals when it comes to carbon isotope abundance. In biological material, natural13C/12C ratio is subject to minute variations due to diet composition (mainly from ingestion of C3 and C4 metabolism plants) and to the discrimination between ‘light’ and ‘heavy’ isotopes during biochemical reactions (isotope effects and isotopic fractionation).Methodology/Principal FindingsCarbon isotopic abundance was measured in ZDF (fa/+) and ZDF (fa/fa), (lean and obese-diabetic rats respectively) fed the same diet. By analysing plasma metabolites (glucose and non-esterified fatty acids), breath and liver tissue by high-precision isotope ratio mass spectrometry, we demonstrate for the first time statistically distinguishable metabolic carbon isotope abundance between ZDF (fa/+) and ZDF (fa/fa) rats based on plasma glucose, palmitic, oleic, linoleic, arachidonic acids and bulk analysis of liver tissue (P<0.005) resulting into clear isotopic fingerprints using principal component analysis. We studied the variation of isotopic abundance between both groups for each metabolite and through the metabolic pathways using the precursor/product approach. We confirmed that lipids were depleted in 13C compared to glucose in both genotypes. We found that isotopic abundance of linoleic acid (C18: 2n-6), even though both groups had the same feed, differed significantly between both groups. The likely reason for these changes between ZDF (fa/+) and ZDF (fa/fa) are metabolic dysregulation associated with various routing and fluxes of metabolites.Conclusion/SignificanceThis work provides evidence that measurement of natural abundance isotope ratio of both bulk tissue and individual metabolites can provide meaningful information about metabolic changes either associated to phenotype or to genetic effects; irrespective of concentration. In the future measuring the natural abundance δ13C of key metabolites could be used as endpoints for studying in vivo metabolism, especially with regards to metabolic dysregulation, and development and progression of metabolic diseases.
Highlights
In medicine and biology, metabolite concentration or metabolic profiling is often used to diagnose disease state and provide insights into metabolic processes [1]
Zucker Diabetic Fatty (ZDF) develop diabetes due to being homozygous for a spontaneous mutation that leads to a non-functional leptin receptor as well as a second mutation that impairs β-cell function [22]
Food intake is more than 1.5 times higher for ZDF rats compared to ZDF rats [25], this is not known to influence the isotopic abundance of plasma metabolites or body tissues under these conditions
Summary
Metabolite concentration or metabolic profiling is often used to diagnose disease state and provide insights into metabolic processes [1]. In the diagnosis of diabetes mellitus type 2 (T2DM), fasting plasma or blood glucose concentrations have long been the first indicator of the development of the disease. Other biomarkers such as acylcarnitines and amino acids have been suggested for the diagnosis of T2DM [2]. One different approach to disease diagnosis is to measure fluxes through relevant pathways using stable isotopes. Phenotype (defined by the interaction of the gene, nutrients and environment) and its perturbation (e.g. fasting, postprandial and disease conditions) can be more accurately described through the flux measurements of pathways than measuring concentrations alone [3,4,5]
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