The global obesity epidemic has emerged as one of the most important health care problems worldwide. Insulin resistance represents a prevalent pathophysiological abnormality that underlies mechanisms of cardiometabolic disease associated with obesity. Increasing basic, animal, and clinical data support a mechanistic link between insulin resistance and vascular dysfunction, and suggest that improving insulin sensitivity may represent a therapeutic target for combating atherosclerosis and cardiovascular disease. As clinical studies suggest that insulin resistance may play a key role in the cardiovascular benefit achieved with weight loss intervention, we will discuss our clinical perspective and provide evidence that obese individuals with hyperinsulinemia may derive the greatest improvement in vascular function with weight reduction. Lastly, we will address several important unanswered questions in the field that are likely to drive future clinical investigation.
