The increasing prevalence of diabetes, in particular type 2 diabetes mellitus (T2DM), warrants improved understanding of the molecular mechanisms and adaptations of not only primary targets of damage, but also those associated with the progression of the disease. The clinical etiology of T2DM suggests that insulin resistance of peripheral tissues arising from an energetic imbalance and increased adiposity pre-dates pancreatic hyperinsulinemia, in an attempt to lower blood glucose levels in response to this resistance. These events proceed pancreatic exhaustion and eventual insufficiency and the characteristic elevated blood glucose levels associated with T2DM. Given the complexities associated with disease progression and the potential for whole body effects involving diverse target organs, we took a systems-wide approach to investigate proteome adaptations in response to T2DM. We used a rodent T2DM model that combines the effects of increased calorie-loading via a high-fat diet (HFD) and pancreatic insufficiency by injection with streptozotocin (STZ; HFD STZ) and compared this with associated feed control (CHOW) control groups (CHOW control, CHOW STZ, and HFD control). Using this model, we observed elevated BGL in both STZ groups (STZ control and HFD STZ) indicative of pancreatic insufficiency. Dyslipidemia was noted, with elevated serum triglycerides present in HFD treated groups (HFD control and HFD STZ). We harvested 7 different organs including adipose tissue, brain, heart, kidney, liver, pancreas and skeletal muscle from across the 4 biological groups and subjected each to a quantitative label-based proteomics workflow using offline HILIC fractionation coupled to RPLC-MS/MS on a Q-Exactive HF instrument. We mapped over 10,500 proteins across these organs and performed hierarchical clustering to observe which organs showed increased sensitivity to the individual effects of HFD, STZ and finally the combined HFD STZ. This approach showed that T2DM has both systems-wide and organ-specific effects that have not previously been considered in the pathogenesis of this disease.