SKELETAL MUSCLE & ADIPOSE TISSUES: Over the past few years, I have become exceptionally keen on working physiology and pathology at the species level on mammalian systems. We were fortunate to get human adipose and muscle tissue samples from normal and diabetic patients and their phenotypic characterization by our School of Medicine colleagues. With exhaustive transcriptional studies on these tissues, we have been able to map functional pathway alterations in patients resistant and sensitive to an important class of drugs, thiozolidenediones, used in the treatment of Type II diabetes. We have identified molecular and functional characteristics of insulin resistant subjects and distinctions between TZD treatment responder and nonresponder subjects. Insulin resistant subjects exhibited alterations in skeletal muscle (e.g., glycolytic flux and intramuscular adipocytes) and adipose tissue (e.g., mitochondrial metabolism and inflammation) that improved relative to TZD-induced insulin sensitization. Pre-TZD treatment expression of MLXIP in muscle and HLA-DRB1 in adipose tissue from insulin resistant subjects was linearly predictive of post-TZD insulin sensitization. We have uniquely characterized coordinated cellular and tissue functional pathways that are characteristic of insulin resistance, TZD-induced insulin sensitization, and potential TZD responsiveness. This work was published in the Proceedings of the National Academy of Sciences and we followed up with a model animal study. This approach to Systems Medicine is very promising and we have already begun to study mammalian development and other complex diseases.