University of Virginia Health System

One of the most important actions of insulin is the clearance of glucose from the blood into skeletal muscle and fat tissue. With increasing age and adiposity the body often becomes less sensitive to insulin. This state of insulin resistance is a gateway disorder which predisposes individuals to developing glucose intolerance, hyperinsulinemia, and more deleterious metabolic diseases such as Type 2 Diabetes and cardiovascular disease. Our group is interested in defining the earliest cellular and molecular defects that define the pathology of insulin resistance. Our overall expectation is that this will reveal novel insight into the development of the condition and will provide new avenues and hope for the treatment of metabolic disease.

We have developed a diverse range of insulin resistance models in our lab involving high fat feeding in rodents, and hyperlipidemia, inflammation, oxidative stress, steroids, and hyperinsulinemia in cultured muscle and fat cells. By using minimal insults required to achieve insulin resistance and cross-comparing these models we have revealed early and widespread roles for mitochondria-derived oxidative end products and lipid metabolites such as ceramide species. Our lab currently focuses on 3 major questions. First, how do mitochondria-derived reactive oxygen species (ROS) antagonize the insulin action pathway? Second, are ceramides and mitochondrial ROS independent risk factors for insulin resistance or are they connected in a linear or cyclic pathway? Third, is increasing lipid oxidation in skeletal muscle an effective strategy for preventing insulin resistance vis-à-vis reduced ceramide accumulation? We are currently recruiting graduate students to pursue each of these questions.