Insulin resistance is a key pathophysiologic feature of the "metabolic syndrome" and is strongly associated with co-existing cardiovascular risk factors and accelerated atherosclerosis. Strategies to improve insulin resistance by pharmacological means have represented the traditional approach for clinical medicine. However, because of the widespread use of dietary supplements by the general public, nutritional supplementation with the use of botanicals that effectively increase insulin sensitivity represent a very attractive and novel approach for future studies designed to intervene in the development of metabolic syndrome. Unfortunately, considerable controversy exists regarding the effect of botanical supplements on the metabolic syndrome as there is a paucity of data in humans in regard to the effect of botanicals to improve measures of insulin action in vivo or on cellular aspects of insulin action. However, we provide several lines of evidence in both in vitro and in vivo models to suggest that botanicals may modulate intracellular pathways of glucose metabolism. Specifically, we provide evidence that an alcoholic extract of Russian Tarragon (Artemisia dracunculus L) referred to as PMI-5011, may increase insulin action in vivo and have identified several novel intracellular pathways that may explain the effect. Thus, this project's overall objective is to examine the role of a specific botanical, PMI-5011, on insulin action in vivo and to elucidate potential cellular mechanism(s) of action. To accomplish our goal, we will conduct both in vitro and in vivo experiments with PMI-5011 and its bioactive components that are designed to assess insulin sensitivity and pathways of glucose metabolism with whole-body, cellular, and molecular approaches. We hypothesize that in both animal models and in subjects with the metabolic syndrome, dietary supplementation with PMI-5011 will improve whole-body insulin-mediated glucose uptake (i.e. insulin sensitivity) by increasing non-oxidative glucose disposal (Aim 1). This increase in whole body glucose disposal will be due to enhanced cellular signaling through the insulin receptor and modulation of skeletal muscle lipid metabolism (Aim 2). In Aim 3 we will conduct early phase human studies to evaluate safety, toxicity, dose response and proposed mechanisms in the human condition.