This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Muniyappa, R. Articles by Quon, M. J. Search for Related Content PubMed PubMed Citation Articles by Muniyappa, R. Articles by Quon, M. J.

Cardiovascular Actions of Insulin

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 production of nitric oxide from endothelium. This leads to capillary recruitment, vasodilation, increased blood flow, and subsequent augmentation of glucose disposal in classical insulin target tissues (e.g., skeletal muscle). Phosphatidylinositol 3-kinase-dependent insulin-signaling pathways regulating endothelial production of nitric oxide share striking parallels with metabolic insulin-signaling pathways. Distinct MAPK-dependent insulin-signaling pathways (largely unrelated to metabolic actions of insulin) regulate secretion of the vasoconstrictor endothelin-1 from endothelium. These and other cardiovascular actions of insulin contribute to coupling metabolic and hemodynamic homeostasis under healthy conditions. Cardiovascular diseases are the leading cause of morbidity and mortality in insulin-resistant individuals. Insulin resistance is typically defined as decreased sensitivity and/or responsiveness to 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 characterized by endothelial dysfunction. Conversely, endothelial dysfunction is often present in metabolic diseases. Insulin resistance is characterized by pathway-specific impairment in phosphatidylinositol 3-kinase-dependent signaling that in vascular endothelium contributes to a reciprocal relationship between insulin resistance and endothelial dysfunction. The clinical relevance of this coupling is highlighted by the findings that specific therapeutic interventions targeting insulin resistance often also ameliorate endothelial dysfunction (and vice versa). In this review, we discuss molecular mechanisms underlying cardiovascular actions of insulin, the reciprocal relationships between insulin resistance and endothelial dysfunction, and implications for developing beneficial therapeutic strategies that simultaneously target metabolic and cardiovascular diseases.

This article has been cited by other articles:

				B. Laczy, B. G. Hill, K. Wang, A. J. Paterson, C. R. White, D. Xing, Y.-F. Chen, V. Darley-Usmar, S. Oparil, and J. C. Chatham Protein O-GlcNAcylation: a new signaling paradigm for the cardiovascular system Am J Physiol Heart Circ Physiol, January 1, 2009; 296(1): H13 - H28. [Abstract] [Full Text] [PDF]

				R. Muniyappa, G. Hall, T. L Kolodziej, R. J Karne, S. K Crandon, and M. J Quon Cocoa consumption for 2 wk enhances insulin-mediated vasodilatation without improving blood pressure or insulin resistance in essential hypertension Am. J. Clinical Nutrition, December 1, 2008; 88(6): 1685 - 1696. [Abstract] [Full Text] [PDF]

				N. Stefan, K. Kantartzis, and H.-U. Haring Causes and Metabolic Consequences of Fatty Liver Endocr. Rev., December 1, 2008; 29(7): 939 - 960. [Abstract] [Full Text] [PDF]

				A. A. Lteif, A. D. Fulford, R. V. Considine, I. Gelfand, A. D. Baron, and K. J. Mather Hyperinsulinemia fails to augment ET-1 action in the skeletal muscle vascular bed in vivo in humans Am J Physiol Endocrinol Metab, December 1, 2008; 295(6): E1510 - E1517. [Abstract] [Full Text] [PDF]

				H. Chen, A. S. Lin, Y. Li, C. E. N. Reiter, M. R. Ver, and M. J. Quon Dehydroepiandrosterone Stimulates Phosphorylation of FoxO1 in Vascular Endothelial Cells via Phosphatidylinositol 3-Kinase- and Protein Kinase A-dependent Signaling Pathways to Regulate ET-1 Synthesis and Secretion J. Biol. Chem., October 24, 2008; 283(43): 29228 - 29238. [Abstract] [Full Text] [PDF]

				M. G. Clark Impaired microvascular perfusion: a consequence of vascular dysfunction and a potential cause of insulin resistance in muscle Am J Physiol Endocrinol Metab, October 1, 2008; 295(4): E732 - E750. [Abstract] [Full Text] [PDF]

				D. Romualdi, B. Costantini, L. Selvaggi, M. Giuliani, F. Cristello, F. Macri, A. Bompiani, A. Lanzone, and M. Guido Metformin improves endothelial function in normoinsulinemic PCOS patients: a new prospective Hum. Reprod., September 1, 2008; 23(9): 2127 - 2133. [Abstract] [Full Text] [PDF]

				A. Kawakami, M. Osaka, M. Tani, H. Azuma, F. M. Sacks, K. Shimokado, and M. Yoshida Apolipoprotein CIII Links Hyperlipidemia With Vascular Endothelial Cell Dysfunction Circulation, August 12, 2008; 118(7): 731 - 742. [Abstract] [Full Text] [PDF]

				L. Bertrand, S. Horman, C. Beauloye, and J.-L. Vanoverschelde Insulin signalling in the heart Cardiovasc Res, July 15, 2008; 79(2): 238 - 248. [Abstract] [Full Text] [PDF]

				I. Fleming Double Tribble: Two TRIB3 Variants, Insulin, Akt, and eNOS Arterioscler. Thromb. Vasc. Biol., July 1, 2008; 28(7): 1216 - 1218. [Full Text] [PDF]

				G. Murdolo, M. Sjostrand, L. Strindberg, S. Gudbjornsdottir, L. Lind, P. Lonnroth, and P.-A. Jansson Effects of Intrabrachial Metacholine Infusion on Muscle Capillary Recruitment and Forearm Glucose Uptake during Physiological Hyperinsulinemia in Obese, Insulin-Resistant Individuals J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2764 - 2773. [Abstract] [Full Text] [PDF]

				K. K. Koh, S. M. Park, and M. J. Quon Leptin and Cardiovascular Disease: Response to Therapeutic Interventions Circulation, June 24, 2008; 117(25): 3238 - 3249. [Full Text] [PDF]

				E. D. Abel, S. E. Litwin, and G. Sweeney Cardiac Remodeling in Obesity Physiol Rev, April 1, 2008; 88(2): 389 - 419. [Abstract] [Full Text] [PDF]

				K. K. Koh, M. J. Quon, S. H. Han, Y. Lee, J. Y. Ahn, S. J. Kim, Y. Koh, and E. K. Shin Simvastatin Improves Flow-Mediated Dilation but Reduces Adiponectin Levels and Insulin Sensitivity in Hypercholesterolemic Patients Diabetes Care, April 1, 2008; 31(4): 776 - 782. [Abstract] [Full Text] [PDF]

				A. O. Chavez, J. C. Lopez-Alvarenga, M. E. Tejero, C. Triplitt, R. A. Bastarrachea, A. Sriwijitkamol, P. Tantiwong, V. S. Voruganti, N. Musi, A. G. Comuzzie, et al. Physiological and Molecular Determinants of Insulin Action in the Baboon Diabetes, April 1, 2008; 57(4): 899 - 908. [Abstract] [Full Text] [PDF]

				C. M. Brown, A. G. Dulloo, G. Yepuri, and J.-P. Montani Fructose ingestion acutely elevates blood pressure in healthy young humans Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2008; 294(3): R730 - R737. [Abstract] [Full Text] [PDF]

				J.-a Kim, Y. Wei, and J. R. Sowers Role of Mitochondrial Dysfunction in Insulin Resistance Circ. Res., February 29, 2008; 102(4): 401 - 414. [Abstract] [Full Text] [PDF]

				R. Muniyappa, S. Lee, H. Chen, and M. J. Quon Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage Am J Physiol Endocrinol Metab, January 1, 2008; 294(1): E15 - E26. [Abstract] [Full Text] [PDF]

				S. A. Cooper, A. Whaley-Connell, J. Habibi, Y. Wei, G. Lastra, C. Manrique, S. Stas, and J. R. Sowers Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2009 - H2023. [Abstract] [Full Text] [PDF]