Insulin resistance is a hallmark of type 2 diabetes, which is a highly heterogeneous disease with diverse pathology. Understanding the molecular signatures of insulin resistance and its association with individual phenotypic traits is crucial for advancing precision medicine in type 2 diabetes. Underlying the development of type 2 diabetes are changes to the protein composition of tissues, termed the proteome. Proteostasis is the process that maintains a healthy proteome, cell, and ultimately the organism. Proteostasis involves a complex coordination of protein synthesis and breakdown, to ensure that damaged proteins are removed from the cell and replaced with new, functional proteins. Using proteomics, we have identified that perturbed ubiquitin-mediated proteolysis (protein breakdown) is a major driver of insulin resistance and type 2 diabetes.