Comprehensive metabolic analysis for understanding of obesity and diabetes mechanisms

We seek to apply comprehensive metabolic analysis tools (sometimes called “metabolomics”) for understanding of mechanisms underlying chronic human diseases such as diabetes, obesity, and cardiovascular disease. Current approaches include analysis of metabolic flux by 13 C NMR‐based mass isotopomer analysis (in collaboration with Drs. Shawn Burgess and A. Dean Sherry and associates, Dallas, TX) and metabolic profiling of important groups of metabolic intermediates by both “targeted” and “unbiased” mass spectrometry (in collaboration with Drs. James Bain, Robert Stevens, Olga Ilkayeva, Brett Wenner, Michael Muehlbauer, Mark Butler, and David Millington at Duke). These tools have been used to investigate the metabolic mechanisms underlying islet β‐cell dysfunction and development of peripheral insulin resistance in animals and humans. Studies in islet β‐cells have demonstrated a critical role of a pyruvate/isocitrate cycling pathway in generation of signals for insulin secretion, and impairment of this cycle associated with loss of β‐cell function. We have also recently identified perturbations of branched chain amino acid (BCAA) catabolism in obese, insulin resistant humans compared to normally insulin sensitive lean controls and have translated these findings to rodent models to demonstrate a contribution of BCAA to development of insulin resistance that is independent of body weight. Finally, in collaboration with Dr. Alan Attie at the University of Wisconsin, we have integrated transcriptomic and metabolomic analysis to identify new pathways that control hepatic gluconeogenesis and PEPCK expression. These examples will serve to illustrate the potential of comprehensive metabolic profiling methods for providing insights into diabetes and obesity mechanisms.