The Einstein-Mt Sinai Diabetes Center Stable Isotope & Metabolomics Core (SIMC) uses stable isotope flux and metabolite profiling to help formulate and test hypotheses about the metabolic consequences of various changes in gene expression and protein function, in order to guide further integrative systems biology analyses of the underlying mechanisms in diabetes, insulin resistance, obesity, and diabetic complications. The SIMC Facility is a nonprofit organization established at the Einstein Diabetes Center. It is designed to provide services on the recharge basis. The overall strategy of the SIMC is to provide unique but complementary approaches that synergize with the Animal Physiology, Human Islet & Adenovirus, Translational Research, and newly established Immuno-Technology Cores of the ES-DRC, as well as through our partnerships with the Einstein and Mount Sinai CTSAs. SIMC’s evaluation framework complements the analyses performed in the Animal Physiology Core, such as measurements of whole body carbohydrate/fatty acid oxidation.
Metabolomics is the global profiling of small metabolites such as amino acids, glycolytic, TCA and pentose cycle metabolites, and in combination with lipidomics (fatty acids, acyl carntines, phospholipids, di- and tri-glycerides) presents a powerful approach to functional biology for biomedical, clinical questions. For this purpose, using our new Sciex 6500+ QTRAP (Shared Instrument Grant Award) we have defined Mass spectrometric assays for a “Chem 2000”, that can be screened in 2 parts: a widely targeted small metabolite profile that can detect approximately 600 metabolites, and a widely targeted lipidomic profile that can detect ~1300 lipid species in 26 lipid classes. Other modules, including untargeted GC/MS analyses, can be added to this for further comprehensive screening.
Stable isotopes can be used to assess intra- and inter-organ flux, which in combination with the latest Seahorse XFe96 and XFe24 Flux Analyzers, can define specific pathways and formulate and test hypotheses underlying mechanisms in diabetes, obesity, and related metabolic diseases. Flux assessments, when combined with metabolomics, can yield a comprehensive picture of metabolic regulation, and how it is impacted by disease. Special needs can be accommodated by consultation, for design of flux experiments for aiding the understanding of energy expenditure, tissue-specific insulin sensitivity, glucose, protein and fatty acid metabolism.
To efficiently provide this resource, we have created a variety of specific SIMC Modules that are used to evaluate the basis of normal and pathophysiologic metabolism, and developed a working outline (Figure 1) that incorporates stable isotope assessment of specific metabolic rates, and layers other ‘omics, such as metabolomics and lipidomics assessments, in a hypothesis driven framework.
Fig 1. Framework for integrating fluxomic, metabolomic and lipidomic profiling for rodent studies. Our approach is to use stable isotope rates, and EU clamp, assessments as primary tools for metabolic phenotyping, and to layer additional ‘omic’ information, such as metabolomics and lipidomics, in a hypothesis-driven manner, and vice versa. (I) Discovery framework resulting from observing changes in fuel utilization by indirect calorimetry. (II) Discovery framework resulting from observing changes in body composition. (III) Discovery framework resulting from observing changes in glucose disposal utilizing the euglycemic-hyperinsulinemic (EU) clamp.
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