Ranganath Muniyappa,
Monica Montagnani,
Kwang Kon Koh and
Michael J. Quon
Diabetes Unit (R.M., M.J.Q.), National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland 20892; Department of Pharmacology and Human Physiology (M.M.), Section of Pharmacology, University of Bari Medical School, 70124 Bari, Italy; and Division of Cardiology (K.K.K.), Gil Heart Center, Gachon Medical School, Incheon 405760, Korea
Correspondence: Address all correspondence and requests for reprints to: Michael J. Quon, M.D., Ph.D., Chief, Diabetes Unit, National Center for Complementary and Alternative Medicine, National Institutes of Health, 10 Center Drive, Building 10, Room 6C-205, Bethesda, Maryland 20892-1632. E-mail: quonm{at}nih.gov
Insulin has important vascular actions to stimulate productionof nitric oxide from endothelium. This leads to capillary recruitment,vasodilation, increased blood flow, and subsequent augmentationof glucose disposal in classical insulin target tissues (e.g.,skeletal muscle). Phosphatidylinositol 3-kinase-dependent insulin-signalingpathways regulating endothelial production of nitric oxide sharestriking parallels with metabolic insulin-signaling pathways.Distinct MAPK-dependent insulin-signaling pathways (largelyunrelated to metabolic actions of insulin) regulate secretionof the vasoconstrictor endothelin-1 from endothelium. Theseand other cardiovascular actions of insulin contribute to couplingmetabolic and hemodynamic homeostasis under healthy conditions.Cardiovascular diseases are the leading cause of morbidity andmortality in insulin-resistant individuals. Insulin resistanceis typically defined as decreased sensitivity and/or responsivenessto metabolic actions of insulin. This cardinal feature of diabetes,obesity, and dyslipidemia is also a prominent component of hypertension,coronary heart disease, and atherosclerosis that are all characterizedby endothelial dysfunction. Conversely, endothelial dysfunctionis often present in metabolic diseases. Insulin resistance ischaracterized by pathway-specific impairment in phosphatidylinositol3-kinase-dependent signaling that in vascular endothelium contributesto a reciprocal relationship between insulin resistance andendothelial dysfunction. The clinical relevance of this couplingis highlighted by the findings that specific therapeutic interventionstargeting insulin resistance often also ameliorate endothelialdysfunction (and vice versa). In this review, we discuss molecularmechanisms underlying cardiovascular actions of insulin, thereciprocal relationships between insulin resistance and endothelialdysfunction, and implications for developing beneficial therapeuticstrategies that simultaneously target metabolic and cardiovasculardiseases.
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293(4):
H2009 - H2023.
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