Abstract Insulin resistance and the resultant glucose intolerance are central to the pathophysiology of acquired diabetes, common health issues among veterans. Insulin resistance is also a powerful independent risk factor and a common co-morbidity in cardiovascular diseases. The prevalence of insulin resistance in multiple tissues associated diabetes and other diseases suggest a potential common mechanism of impaired glucose transport. We believe that we have identified a critical missing link between impaired insulin regulation and diabetes. Our data suggest that poorly balanced input from the brain via the sympathetic branch of the autonomic nervous system may underlie disruption of both glucose metabolism and cardiovascular function. I will explore a novel mechanism by which insulin regulates glucose uptake in a beta2 adrenergic receptor (beta2AR)-dependent manner and elucidate the contribution of this mechanism to the development of insulin resistance, the fundamental cause of Type II diabetes. I hypothesize that activation of a newly characterized insulin receptor/ beta2AR complex by insulin traffics a specific subcellular pool of activated Akt via transactivation of a beta2AR/Gi/PI3K cascade, which is essential for translocation of GLUT4 to the cell surface for glucose uptake. Our evidence suggests that this novel IR/beta2AR complex may hold the key to understanding insulin resistance in diverse tissues associated with diabetes. My ultimate goal is to advance the understanding of the pathophysiology of insulin resistance by identifying previously unidentified mechanisms involved in insulin-induced mobilization of GLUT4. These studies have the potential to lead to entirely new therapeutic targets to increase insulin sensitivity, of which relatively few agents currently exist.