Molecular and signaling mechanisms of atherosclerosis in insulin resistance

Although the prevalence of cardiovascular complications is increased in insulin-resistant individuals, the underlying causes of this link have been elusive. Recent work suggests that several intracellular signal transduction pathways are inappropriately activated by hyperinsulinemia, hyperglycemia, increased free fatty acids, dyslipidemia, various inflammatory cytokines, and adipokines-factors that are increased in insulin resistance. Once activated, substantial cross talk occurs between these pathways, especially through reactive oxygen species-mediated mechanisms that induce a self-reinforcing cascade of vascular inflammation and cell dysfunction, greatly increasing the risk and severity of atherosclerosis in the insulin-resistant individual. We review several key cell-signaling pathways, describe how they are activated in the insulin-resistant state and the damage they induce, and discusses possible therapeutic approaches to limit vascular damage.