Obesity and diabetes are caused by defects in metabolically sensitive tissues. Attention has been paid to insulin resistance as the key relevant pathosis, with a detailed focus on signal transduction pathways in metabolic tissues. Evidence exists to support an important role for each tissue in metabolic homeostasis and a potential causative role in both diabetes and obesity. The redox metabolome, that coordinates tissue responses and reflects shared control and regulation, is our focus. Consideration is given to the possibility that pathosis results from contributions of all relevant tissues, by virtue of a circulating communication system. Validation of this model would support simultaneous regulation of all collaborating metabolic organs through changes in the circulation, regardless of whether change was initiated exogenously or by a single organ.