Setting: A disordered lipid metabolism is implicated in the development of skeletal muscle insulin resistance. Lipid droplet proteins of the PAT (Perilipin, ADRP - Adipocyte differentiation-related protein - and TIP47) family have been shown to regulate lipid accumulation and intracellular metabolism in other tissues. Objective: This study aimed to explore the role of the PAT proteins OXPAT and ADRP in skeletal muscle lipid metabolism and their putative role in modulating insulin sensitivity. Design: Muscle OXPAT and ADRP protein content was examined during the development of insulin resistance in Zucker diabetic fatty (ZDF) rats, and in type 2 diabetes patients and BMI-matched control subjects. Furthermore, we examined the effect of 8 weeks of insulin sensitizing by rosiglitazone on muscle OXPAT and ADRP content. Results: OXPAT and ADRP protein expression is muscle fiber-type specific in humans and rats, with highest protein content in fibers containing most intramyocellular lipids (IMCL). Muscle OXPAT and ADRP protein content was 2-3 fold higher in ZDF rats during the progression of type 2 diabetes than in lean normoglycemic control rats, which was paralleled by high IMCL levels. Muscle OXPAT and ADRP content, as well as IMCL level, were not different between type 2 diabetes patients and control subjects. ADRP content was negatively associated with insulin-stimulated glucose uptake (r -0.50, P 0.017). Interestingly, rosiglitazone treatment decreased muscle OXPAT (-29%) and ADRP (-28%) content in diabetes patients, without affecting IMCL. Conclusions: These results indicate involvement of OXPAT and ADRP in muscular lipid accumulation and type 2 diabetes.