Insulin action and insulin resistance in vascular endothelium Ranganath Muniyappa and Michael J. Quon Purpose of review Vasodilator actions of insulin are mediated by phosphatidylinositol 3-kinase dependent insulin signaling pathways in endothelium, which stimulate production of nitric oxide. Insulin-stimulated nitric oxide mediates capillary recruitment, vasodilation, increased blood flow, and subsequent augmentation of glucose disposal in skeletal muscle. Distinct mitogen-activated protein kinase dependent insulin signaling pathways regulate secretion of the vasoconstrictor endothelin-1 from endothelium. These vascular actions of insulin contribute to the coupling of metabolic and hemodynamic homeostasis that occurs under healthy conditions. Insulin resistance is characterized by pathway-specific impairment in phosphatidylinositol 3-kinase dependent signaling in both metabolic and vascular insulin target tissues. Here we discuss consequences of pathway- specific insulin resistance in endothelium and therapeutic interventions targeting this selective impairment. Recent findings Shared causal factors such as glucotoxicity, lipotoxicity, and inflammation selectively impair phosphatidylinositol 3-kinase dependent insulin signaling pathways, creating reciprocal relationships between insulin resistance and endothelial dysfunction. Diet, exercise, cardiovascular drugs, and insulin sensitizers simultaneously modulate phosphatidylinositol 3-kinase and mitogen-activated protein kinase dependent pathways, improving metabolic and vascular actions of insulin. Summary Pathway-specific impairment in insulin action contributes to reciprocal relationships between endothelial dysfunction and insulin resistance, fostering clustering of metabolic and cardiovascular diseases in insulin-resistant states. Therapeutic interventions that target this selective impairment often simultaneously improve both metabolic and vascular function. Keywords endothelial dysfunction, insulin resistance, metabolic syndrome, nitric oxide Curr Opin Clin Nutr Metab Care 10:523–530. ß 2007 Lippincott Williams & Wilkins. Diabetes Unit, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland, USA Correspondence to Michael J. Quon, MD, PhD, Chief, Diabetes Unit, NCCAM, NIH, 10 Center Drive, Building 10, Room 6C-205, Bethesda, MD 20892-1632, USA Tel: +1 301 496 6269; fax: +1 301 402 1679; e-mail: quonm@nih.gov Current Opinion in Clinical Nutrition and Metabolic Care 2007, 10:523– 530 Abbreviations EGCG epigallocatechin gallate FFA free fatty acid IRS insulin receptor substrate MAPK mitogen-activated protein kinase NOS nitric oxide synthase PAI plasminogen activator inhibitor PDK 3-phosphoinositide-dependent protein kinase PI3K phosphatidylinositol 3-kinase ROS reactive oxygen species SHR spontaneously hypertensive rat TNF tumor necrosis factor VCAM vascular cell adhesion molecule ß 2007 Lippincott Williams & Wilkins 1363-1950 Introduction The vascular actions of insulin to stimulate production of nitric oxide from the endothelium lead to vasodilation and increased blood flow, which enhances glucose uptake in skeletal muscle [1,2  ]. Endothelial dysfunc- tion, characterized by reduced nitric oxide dependent vascular activity, is a consistent feature of insulin-resistant states including diabetes, obesity, and the metabolic syndrome [2  ]. This may increase susceptibility of patients to accelerated atherosclerosis, coronary heart disease, and hypertension. Insulin binding to the insulin receptor activates two major branches of a signal transduction cascade; metabolic signaling pathways tend to be mediated by phosphatidylinositol 3-kinase (PI3K), whereas mitogenic signaling pathways tend to be mediated by mitogen-activated protein kinase (MAPK) [3] (Fig. 1). Insulin-signaling pathways regulating endo- thelial production of nitric oxide exhibit striking paral- lels with metabolic insulin signaling pathways in skeletal muscle and adipose tissue. In insulin-resistant states, glucotoxicity, lipotoxicity, and inflammation indepen- dently contribute to the development of both insulin resistance and endothelial dysfunction by inhibiting the PI3K pathway and over-stimulating the MAPK pathway [2  ]. In this review, we explore interactions between these pathways and consider therapeutic approaches that simultaneously target insulin resistance and endothelial dysfunction. Signaling pathways mediating insulin-stimulated production of nitric oxide One of the key vascular actions of insulin is to stimulate production of the potent vasodilator nitric oxide from endothelium. Recent studies have elucidated a complete biochemical insulin signaling pathway in endothelium that regulates production of nitric oxide 523