The Metabolic and Proteomic Signature of Insulin Resistance in Muscle
Access to this document is restricted. Some items have been embargoed at the request of the author, but will be made publicly available after the "No Access Until" date.
During the embargo period, you may request access to the item by clicking the link to the restricted file(s) and completing the request form. If we have contact information for a Cornell author, we will contact the author and request permission to provide access. If we do not have contact information for a Cornell author, or the author denies or does not respond to our inquiry, we will not be able to provide access. For more information, review our policies for restricted content.
Insulin resistance is associated with a wide range of diseases, such as type 2 diabetes (T2D), cardiovascular disease, obesity, and metabolic syndrome. Worldwide, the prevalence of many diseases, with insulin resistance as a symptom, is expected to increase over the coming years. Despite the high incidence of diseases associated with insulin resistance worldwide, researchers have yet to describe the complete pathogenesis of insulin resistance.Stable isotope tracing and metabolomics are high-throughput techniques that can be used to characterize the metabolic characteristics of a cell. Stable isotope tracing is used to characterize a cell's substrate utilization and metabolic fluxes. Metabolomics can be used to gather information about the current metabolic state of a healthy or diseased cell. Chapter 2 assesses the applicability of stable isotope tracing to study insulin signaling. There is no established method to study insulin resistance or signaling in vitro. The varying methodologies used to induce insulin resistance in vitro lead to inconsistent results between studies. Moreover, it is important to establish a method that does not induce abnormal metabolic patterns in cells, or incorrect interpretations will occur. In the case of stable isotope tracing, dialyzed fetal bovine serum (dFBS) provides nutrients to the cell and allows researchers to substitute isotopically labeled substrates for unlabeled substrates. Chapter 3 formally evaluates the use of dFBS and stable isotope tracing to identify potential risks associated with using dFBS to study insulin signaling. Insulin relies on multiple protein effectors and post-translational modifications to induce a metabolic response. Therefore, analyzing the proteome and phosphoproteome can provide insight into what impacts the insulin response in muscle. In Chapter 4, the phosphoproteome of induced pluripotent stem cells converted into myoblasts derived from the muscle and blood of participants with T2D and insulin resistance, respectively, was analyzed to assess how insulin stimulation, sex, and insulin sensitivity alter the proteome and phosphoproteome.