Insulin resistance is a hallmark of type 2 diabetes, a highly heterogeneous condition with diverse pathological characteristics. Understanding the molecular adaptation to insulin resistance and its association with individual phenotypic traits is crucial for advancing precision medicine in diabetes. By utilizing cutting-edge proteomics technology, we mapped the proteome and phosphoproteome of basal and insulin-stimulated skeletal muscle from >120 individuals with varying degrees of insulin sensitivity, both with and without type 2 diabetes. Leveraging deep in vivo phenotyping data, we reveal that the basal proteome and phosphoproteome are strong predictors of insulin sensitivity. The insulin-stimulated phosphoproteome identified preserved and dysregulated signaling even in individuals with the most severe insulin resistance. Our study elucidates substantial differences in the male and female (phospho)proteome; however, the molecular signature associated with insulin resistance remains largely similar between sexes. These findings emphasize the importance of recognizing disease heterogeneity and advocate for the precision medicine approach for effective care in type 2 diabetes.