doi: 10.1161/CIRCULATIONAHA.105.563213
(Circulation. 2006;113:1888-1904.)
© 2006 American Heart Association, Inc.
Basic Science for Clinicians |
Reciprocal Relationships Between Insulin Resistance and Endothelial Dysfunction
Molecular and Pathophysiological Mechanisms
From the Diabetes Unit, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Md (J.K., M.J.Q.); Department of Pharmacology and Human Physiology, Section of Pharmacology, University of Bari Medical School, Bari, Italy (M.M.); and the Division of Cardiology, Gil Heart Center, Gachon Medical School, Incheon, Korea (K.K.K.).
Correspondence to Michael J. Quon, MD, PhD, Chief, Diabetes Unit, NCCAM, NIH, 10 Center Dr, Building 10, Room 6C-205, Bethesda, MD 20892-1632. E-mail quonm{at}nih.gov
Endothelial dysfunction contributes to cardiovascular diseases, including hypertension, atherosclerosis, and coronary artery disease, which are also characterized by insulin resistance. Insulin resistance is a hallmark of metabolic disorders, including type 2 diabetes mellitus and obesity, which are also characterized by endothelial dysfunction. Metabolic actions of insulin to promote glucose disposal are augmented by vascular actions of insulin in endothelium to stimulate production of the vasodilator nitric oxide (NO). Indeed, NO-dependent increases in blood flow to skeletal muscle account for 25% to 40% of the increase in glucose uptake in response to insulin stimulation. Phosphatidylinositol 3-kinase–dependent insulin-signaling pathways in endothelium related to production of NO share striking similarities with metabolic pathways in skeletal muscle that promote glucose uptake. Other distinct nonmetabolic branches of insulin-signaling pathways regulate secretion of the vasoconstrictor endothelin-1 in endothelium. Metabolic insulin resistance is characterized by pathway-specific impairment in phosphatidylinositol 3-kinase–dependent signaling, which in endothelium may cause imbalance between production of NO and secretion of endothelin-1, leading to decreased blood flow, which worsens insulin resistance. Therapeutic interventions in animal models and human studies have demonstrated that improving endothelial function ameliorates insulin resistance, whereas improving insulin sensitivity ameliorates endothelial dysfunction. Taken together, cellular, physiological, clinical, and epidemiological studies strongly support a reciprocal relationship between endothelial dysfunction and insulin resistance that helps to link cardiovascular and metabolic diseases. In the present review, we discuss pathophysiological mechanisms, including inflammatory processes, that couple endothelial dysfunction with insulin resistance and emphasize important therapeutic implications.
Key Words: diabetes mellitus • endothelium • hypertension • insulin
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|
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|
|
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|
|
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