Current Hypertension Reports

, Volume 11, Issue 1, pp 48–55 | Cite as

Vascular insulin resistance: A potential link between cardiovascular and metabolic diseases

  • Ivonne Hernandez Schulman
  • Ming-Sheng ZhouEmail author


The physiologic actions of insulin in the vasculature serve to couple regulation of metabolic and hemodynamic homeostasis. Insulin activation of the phosphatidylinositol-3-kinase (PI3K) pathway promotes glucose uptake in insulin-responsive tissues and nitric oxide (NO) production in the endothelium. NO induces vasodilation and inhibits platelet aggregation and vascular smooth muscle cell growth. In contrast, insulin activation of the mitogen-activated protein kinase (MAPK) leads to vasoconstriction and pathologic vascular cellular growth. In states of insulin resistance, insulin activation of PI3K is selectively impaired, whereas the MAPK pathway is spared and activated normally. In the endothelium, selective impairment of insulin-mediated NO production may contribute to the development of hypertension, endothelial dysfunction, atherogenesis, and insulin resistance. This article reviews experimental and clinical data elucidating the physiologic and pathophysiologic role of insulin in the vasculature and the mechanisms contributing to the development of vascular and metabolic diseases.


Nitric Oxide Insulin Resistance PI3K Pathway Arterioscler Thromb Vasc Biol Vascular Smooth Muscle Cell Proliferation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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References and Recommended Reading

  1. 1.
    Muniyappa R, Montagnani M, Koh KK, Quon MJ: Cardiovascular actions of insulin. Endocr Rev 2007, 28:463–491.PubMedCrossRefGoogle Scholar
  2. 2.
    Kim JA, Montagnani M, Koh KK, Quon MJ: Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation 2006, 113:1888–1904.PubMedCrossRefGoogle Scholar
  3. 3.
    Jiang ZY, Lin YW, Clemont A, et al.: Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest 1999, 104:447–457.PubMedCrossRefGoogle Scholar
  4. 4.
    Wang CC, Gurevich I, Draznin B: Insulin affects vascular smooth muscle cell phenotype and migration via distinct signaling pathways. Diabetes 2003, 52:2562–2569.PubMedCrossRefGoogle Scholar
  5. 5.
    Hartell NA, Archer HE, Bailey CJ: Insulin-stimulated endothelial nitric oxide release is calcium independent and mediated via protein kinase B. Biochem Pharmacol 2005, 69:781–790.PubMedCrossRefGoogle Scholar
  6. 6.
    Baron AD, Brechtel-Hook G, Johnson A, et al.: Effect of perfusion rate on the time course of insulin-mediated skeletal muscle glucose uptake. Am J Physiol 1996, 271: E1067–E1072.PubMedGoogle Scholar
  7. 7.
    Scherrer U, Sartori C: Insulin as a vascular and sympathoexcitatory hormone: implications for blood pressure regulation, insulin sensitivity, and cardiovascular morbidity. Circulation 1997, 96:4104–4113.PubMedGoogle Scholar
  8. 8.
    Eringa EC, Stehouwer CD, van Nieuw Amerongen GP, et al.: Vasoconstrictor effects of insulin in skeletal muscle arterioles are mediated by ERK1/2 activation in endothelium. Am J Physiol Heart Circ Physiol 2004, 287: H2043–H2048.PubMedCrossRefGoogle Scholar
  9. 9.
    Berne C, Fagius J, Pollare T, Hjemdahl P: The sympathetic response to euglycaemic hyperinsulinaemia. Evidence from microelectrode nerve recordings in healthy subjects. Diabetologia 1992, 35:873–879.PubMedCrossRefGoogle Scholar
  10. 10.
    Cardillo C, Nambi SS, Kilcoyne CM, et al.: Insulin stimulates both endothelin and nitric oxide activity in the human forearm. Circulation 1999, 100:820–825.PubMedGoogle Scholar
  11. 11.
    Li J, Zhang H, Wu F, et al.: Insulin inhibits tumor necrosis factor-alpha induction in myocardial ischemia/reperfusion: role of Akt and endothelial nitric oxide synthase phosphorylation. Crit Care Med 2008, 36:1551–1558.PubMedCrossRefGoogle Scholar
  12. 12.
    Schulman IH, Zhou MS, Raij L: Interaction between nitric oxide and angiotensin II in the endothelium: role in atherosclerosis and hypertension. J Hypertens Suppl 2006, 24:S45–S50.PubMedCrossRefGoogle Scholar
  13. 13.
    Dandona P, Chaudhuri A, Ghanim H, Mohanty P: Proinflammatory effects of glucose and anti-inflammatory effect of insulin: relevance to cardiovascular disease. Am J Cardiol 2007, 99:15B–26B.PubMedCrossRefGoogle Scholar
  14. 14.
    Dandona P, Aljada A, O’Donnell A, et al.: Insulin is an anti-inflammatory and anti-atherosclerotic hormone. Metab Syndr Relat Disord 2004, 2:137–142.PubMedCrossRefGoogle Scholar
  15. 15.
    Aljada A, Ghanim H, Saadeh R, Dandona P: Insulin inhibits NFkappaB and MCP-1 expression in human aortic endothelial cells. J Clin Endocrinol Metab 2001, 86:450–453.PubMedCrossRefGoogle Scholar
  16. 16.
    Shamir R, Shehadeh N, Rosenblat M, et al.: Oral insulin supplementation attenuates atherosclerosis progression in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2003, 23:104–110.PubMedCrossRefGoogle Scholar
  17. 17.
    Dandona P, Chaudhuri A, Ghanim H, Mohanty P: Anti-inflammatory effects of insulin and pro-inflammatory effects of glucose: relevance to the management of acute myocardial infarction and other acute coronary syndromes. Rev Cardiovasc Med 2006, 7(Suppl 2):S25–S34.PubMedGoogle Scholar
  18. 18.
    Bucciarelli-Ducci C, Bianchi M, De Luca L, et al.: Effects of glucose-insulin-potassium infusion on myocardial perfusion and left ventricular remodeling in patients treated with primary angioplasty for ST-elevation acute myocardial infarction. Am J Cardiol 2006, 98:1349–1353.PubMedCrossRefGoogle Scholar
  19. 19.
    Xi XP, Graf K, Goetze S, et al.: Inhibition of MAP kinase blocks insulin-mediated DNA synthesis and transcriptional activation of c-fos by Elk-1 in vascular smooth muscle cells. FEBS Lett 1997, 417:283–286.PubMedCrossRefGoogle Scholar
  20. 20.
    Nigro J, Osman N, Dart AM, Little PJ: Insulin resistance and atherosclerosis. Endocr Rev 2006, 27:242–259.PubMedCrossRefGoogle Scholar
  21. 21.
    Boyle PJ: Diabetes mellitus and macrovascular disease: mechanisms and mediators. Am J Med 2007, 120:S12–S17.PubMedCrossRefGoogle Scholar
  22. 22.
    Zhou MS, Hernandez Schulman I, Pagano PJ, et al.: Reduced NAD(P)H oxidase in low renin hypertension: link among angiotensin II, atherogenesis, and blood pressure. Hypertension 2006, 47:81–86.PubMedCrossRefGoogle Scholar
  23. 23.
    Kamide K, Rakugi H, Nagai M, et al.: Insulin-mediated regulation of the endothelial renin-angiotensin system and vascular cell growth. J Hypertens 2004, 22:121–127.PubMedCrossRefGoogle Scholar
  24. 24.
    Tuck ML, Bounoua F, Eslami P, et al.: Insulin stimulates endogenous angiotensin II production via a mitogen-activated protein kinase pathway in vascular smooth muscle cells. J Hypertens 2004, 22:1779–1785.PubMedCrossRefGoogle Scholar
  25. 25.
    Andreozzi F, Laratta E, Sciacqua A, et al.: Angiotensin II impairs the insulin signaling pathway promoting production of nitric oxide by inducing phosphorylation of insulin receptor substrate-1 on Ser(312) and Ser(616) in human umbilical vein endothelial cells. Circ Res 2004, 94:1211–1218.PubMedCrossRefGoogle Scholar
  26. 26.
    Taniyama Y, Hitomi H, Shah A, et al.: Mechanisms of reactive oxygen species-dependent downregulation of insulin receptor substrate-1 by angiotensin II. Arterioscler Thromb Vasc Biol 2005, 25:1142–1147.PubMedCrossRefGoogle Scholar
  27. 27.
    Huang PL, Huang ZH, Mashimo H, et al.: Hypertension in mice lacking the gene for endothelial nitric-oxide synthase. Nature 1995, 377:239–242.PubMedCrossRefGoogle Scholar
  28. 28.
    Ohashi Y, Kawashima S, Hirata K, et al.: Hypotension and reduced nitric oxide-elicited vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase. J Clin Invest 1998, 102:2061–2071.PubMedCrossRefGoogle Scholar
  29. 29.
    Cosentino F, Barker JE, Brand MP, et al.: Reactive oxygen species mediate endothelium-dependent relaxations in tetrahydrobiopterin-deficient mice. Arterioscler Thromb Vasc Biol 2001, 21:496–502.PubMedGoogle Scholar
  30. 30.
    Park JL, Loberg RD, Duquaine D, et al.: GLUT4 facilitative glucose transporter specifically and differentially contributes to agonist-induced vascular reactivity in mouse aorta. Arterioscler Thromb Vasc Biol 2005, 25:1596–1602.PubMedCrossRefGoogle Scholar
  31. 31.
    Jiang ZY, Lin YW, Clemont A, et al.: Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest 1999, 104:447–457.PubMedCrossRefGoogle Scholar
  32. 32.
    Eringa EC, Stehouwer CD, Walburg K, et al.: Physiological concentrations of insulin induce endothelin-dependent vasoconstriction of skeletal muscle resistance arteries in the presence of tumor necrosis factor-alpha dependence on c-Jun N-terminal kinase. Arterioscler Thromb Vasc Biol 2006, 26:274–280.PubMedCrossRefGoogle Scholar
  33. 33.
    Schulman IH, Zhou MS, Jaimes EA, Raij L: Dissociation between metabolic and vascular insulin resistance in aging. Am J Physiol Heart Circ Physiol 2007, 293: H853–H859.PubMedCrossRefGoogle Scholar
  34. 34.
    Montagnani M, Golovchenko I, Kim I, et al.: Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells. J Biol Chem 2002, 277:1794–1799.PubMedCrossRefGoogle Scholar
  35. 35.
    Cusi K, Maezono K, Osman A, et al.: Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest 2000, 105:311–320.PubMedCrossRefGoogle Scholar
  36. 36.
    Williams SB, Cusco JA, Roddy MA, et al.: Impaired nitric oxide-mediated vasodilation in patients with non-insulindependent diabetes mellitus. J Am Coll Cardiol 1996, 27:567–574.PubMedCrossRefGoogle Scholar
  37. 37.
    Vincent MA, Barrett EJ, Lindner JR, et al.: Inhibiting NOS blocks microvascular recruitment and blunts muscle glucose uptake in response to insulin. Am J Physiol Endocrinol Metab 2003, 285:E123–E129.PubMedGoogle Scholar
  38. 38.
    Shankar SS, Considine RV, Gorski JC, Steinberg HO: Insulin sensitivity is preserved despite disrupted endothelial function. Am J Physiol Endocrinol Metab 2006, 291:E691–E696.PubMedCrossRefGoogle Scholar
  39. 39.
    Clark MG, Wallis MG, Barrett EJ, et al.: Blood flow and muscle metabolism: a focus on insulin action. Am J Physiol Endocrinol Metab 2003, 284:E241–E258.PubMedGoogle Scholar
  40. 40.
    Serne EH, de Jongh RT, Eringa EC, et al.: Microvascular dysfunction: a potential pathophysiological role in the metabolic syndrome. Hypertension 2007, 50:204–211.PubMedCrossRefGoogle Scholar
  41. 41.
    Verma S, Yao L, Stewart DJ, et al.: Endothelin antagonism uncovers insulin-mediated vasorelaxation in vitro and in vivo. Hypertension 2001, 37:328–333.PubMedGoogle Scholar
  42. 42.
    Schroeder CA Jr, Chen YL, Messina EJ: Inhibition of NO synthesis or endothelium removal reveals a vasoconstrictor effect of insulin on isolated arterioles. Am J Physiol 1999, 276:H815–H820.PubMedGoogle Scholar
  43. 43.
    Eringa EC, Stehouwer CD, Merlijn T, et al.: Physiological concentrations of insulin induce endothelin-mediated vasoconstriction during inhibition of NOS or PI3-kinase in skeletal muscle arterioles. Cardiovasc Res 2002, 56:464–471.PubMedCrossRefGoogle Scholar
  44. 44.
    Prasad A, Quyyumi AA: Renin-angiotensin system and angiotensin receptor blockers in the metabolic syndrome. Circulation 2004, 110:1507–1512.PubMedCrossRefGoogle Scholar
  45. 45.
    Henriksen EJ, Jacob S, Kinnick TR, et al.: Selective angiotensin II receptor antagonism reduces insulin resistance in obese Zucker rats. Hypertension 2001, 38:884–890.PubMedCrossRefGoogle Scholar
  46. 46.
    Shiuchi T, Iwai M, Li HS, et al.: Angiotensin II type-1 receptor blocker valsartan enhances insulin sensitivity in skeletal muscles of diabetic mice. Hypertension 2004, 43:1003–1010.PubMedCrossRefGoogle Scholar
  47. 47.
    Bigazzi R, Bianchi S, Baldari G, Campese VM: Clustering of cardiovascular risk factors in salt-sensitive patients with essential hypertension: role of insulin. Am J Hypertens 1996, 9:24–32.PubMedCrossRefGoogle Scholar
  48. 48.
    Cubeddu LX, Hoffmann IS, Aponte LM, et al.: Role of salt sensitivity, blood pressure, and hyperinsulinemia in determining high upper normal levels of urinary albumin excretion in a healthy adult population. Am J Hypertens 2003, 16:343–349.PubMedCrossRefGoogle Scholar
  49. 49.
    Weinberger MH, Fineberg NS, Fineberg SE, Weinberger M: Salt sensitivity, pulse pressure, and death in normal and hypertensive humans. Hypertension 2001, 37:429–432.PubMedGoogle Scholar
  50. 50.
    Suzuki M, Kimura Y, Tsushima M, Harano Y: Association of insulin resistance with salt sensitivity and nocturnal fall of blood pressure. Hypertension 2000, 35:864–868.PubMedGoogle Scholar
  51. 51.
    Sharma AM, Ruland K, Spies KP, Distler A: Salt Sensitivity in Young Normotensive Subjects Is Associated with a Hyperinsulinemic Response to Oral Glucose. J Hypertens 1991, 9:329–335.PubMedCrossRefGoogle Scholar
  52. 52.
    Reaven GM, Twersky J, Chang H: Abnormalities of carbohydrate and lipid-metabolism in Dahl rats. Hypertension 1991, 18:630–635.PubMedGoogle Scholar
  53. 53.
    Zhou MS, Adam AG, Jaimes EA, Raij L: In salt-sensitive hypertension, increased superoxide production is linked to functional upregulation of angiotensin II. Hypertension 2003, 42:945–951.PubMedCrossRefGoogle Scholar
  54. 54.
    Kobori H, Nishiyama A, Abe Y, Navar LG: Enhancement of intrarenal angiotensinogen in Dahl salt-sensitive rats on high salt diet. Hypertension 2003, 41:592–597.PubMedCrossRefGoogle Scholar
  55. 55.
    Zhou MS, Schulman IH, Raij L: Nitric oxide, angiotensin II, and hypertension. Semin Nephrol 2004, 24:366–378.PubMedCrossRefGoogle Scholar
  56. 56.
    Shinozaki K, Ayajiki K, Nishio Y, et al.: Evidence for a causal role of the renin-angiotensin system in vascular dysfunction associated with insulin resistance. Hypertension 2004, 43:255–262.PubMedCrossRefGoogle Scholar
  57. 57.
    Zhou M-S, Jaimes EA, Schulman IH, Raij L: In salt-sensitive hypertension impairment of the vascular and metabolic actions of insulin is linked to an increase in oxidative stress mediated by angiotensin II [abstract]. Hypertension 2007, 50:e138.Google Scholar
  58. 58.
    Lakka HM, Laaksonen DE, Lakka TA, et al.: The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002, 288:2709–2716.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group LLC 2009

Authors and Affiliations

  1. 1.Vascular Biology InstituteUniversity of Miami Miller School of Medicine, Veterans Affairs Medical Center, Nephrology-Hypertension SectionMiamiUSA

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