Microvascular dysfunction: An emerging pathway in the pathogenesis of obesity-related insulin resistance

  • Dennis M. J. Muris
  • Alfons J. H. M. Houben
  • Miranda T. Schram
  • Coen D. A. Stehouwer
Article

Abstract

The prevalence of type 2 diabetes mellitus (T2DM) and its major risk factor, obesity, has reached epidemic proportions in Western society. How obesity leads to insulin resistance and subsequent T2DM is incompletely understood. It has been established that insulin can redirect blood flow in skeletal muscle from non-nutritive to nutritive capillary networks, without increasing total blood flow. This results in a net increase of the overall number of perfused nutritive capillary networks and thereby increases insulin-mediated glucose uptake by skeletal muscle. This process, referred to as functional (nutritive) capillary recruitment, has been shown to be endothelium-dependent and to require activation of the phosphatidylinositol-kinase (PI3K) pathway in the endothelial cell. Several studies have demonstrated that these processes are impaired in states of microvascular dysfunction. In obesity, changes in several adipokines are likely candidates to influence insulin signaling pathways in endothelial cells, thereby causing microvascular dysfunction. Microvascular dysfunction, in turn, impairs the timely access of glucose and insulin to their target tissues, and may therefore be an additional cause of insulin resistance. Thus, microvascular dysfunction may be a key feature in the development of obesity-related insulin resistance. In the present review, we will discuss the evidence for this emerging role for the microcirculation as a possible link between obesity and insulin resistance.

Keywords

Microcirculation Type 2 diabetes mellitus Insulin resistance Endothelial dysfunction 

References

  1. 1.
    Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA. 2012;307(5):491–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Han TS, Feskens EJ, Lean ME, Seidell JC. Associations of body composition with type 2 diabetes mellitus. Diabet Med. 1998;15(2):129–35.PubMedCrossRefGoogle Scholar
  3. 3.
    Manson JE, Nathan DM, Krolewski AS, Stampfer MJ, Willett WC, Hennekens CH. A prospective study of exercise and incidence of diabetes among US male physicians. JAMA. 1992;268(1):63–7.PubMedCrossRefGoogle Scholar
  4. 4.
    International Diabetes Federation (IDF). Diabetes atlas, 4th edition. Brussels: IDF; 2009.Google Scholar
  5. 5.
    Tooke JE, Goh KL. Vascular function in Type 2 diabetes mellitus and pre-diabetes: the case for intrinsic endotheiopathy. Diabet Med. 1999;16(9):710–5.PubMedCrossRefGoogle Scholar
  6. 6.
    de Jongh RT, Serne EH, Ijzerman RG, de Vries G, Stehouwer CD. Impaired microvascular function in obesity: implications for obesity-associated microangiopathy, hypertension, and insulin resistance. Circulation. 2004;109(21):2529–35.PubMedCrossRefGoogle Scholar
  7. 7.
    Jonk AM, Houben AJ, Schaper NC, de Leeuw PW, Serne EH, Smulders YM, et al. Obesity is associated with impaired endothelial function in the postprandial state. Microvasc Res. 2011;82(3):423–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Jonk AM, Houben AJ, Schaper NC, de Leeuw PW, Serne EH, Smulders YM, et al. Meal-related increases in microvascular vasomotion are impaired in obese individuals: a potential mechanism in the pathogenesis of obesity-related insulin resistance. Diabetes Care. 2011;34 Suppl 2:S342–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Agapitov AV, Correia ML, Sinkey CA, Dopp JM, Haynes WG. Impaired skeletal muscle and skin microcirculatory function in human obesity. J Hypertens. 2002;20(7):1401–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Keske MA, Clerk LH, Price WJ, Jahn LA, Barrett EJ. Obesity blunts microvascular recruitment in human forearm muscle after a mixed meal. Diabetes Care. 2009;32(9):1672–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Jonk AM, Houben AJ, de Jongh RT, Serne EH, Schaper NC, Stehouwer CD. Microvascular dysfunction in obesity: a potential mechanism in the pathogenesis of obesity-associated insulin resistance and hypertension. Physiology (Bethesda). 2007;22:252–60.CrossRefGoogle Scholar
  12. 12.
    De Boer MP, Meijer RI, Wijnstok NJ, Jonk AM, Houben AJ, Stehouwer CD, et al. Microvascular dysfunction: a potential mechanism in the pathogenesis of obesity-associated insulin resistance and hypertension. Microcirculation. 2012;19(1):5–18.PubMedCrossRefGoogle Scholar
  13. 13.
    Houben AJ, Eringa EC, Jonk AM, Serne EH, Smulders YM, Stehouwer CD. Perivascular fat and the microcirculation: relevance to insulin resistance, diabetes, and cardiovascular disease. Curr Cardiovasc Risk Rep. 2012;6(1):80–90.PubMedCrossRefGoogle Scholar
  14. 14.
    Levy BI, Schiffrin EL, Mourad JJ, Agostini D, Vicaut E, Safar ME, et al. Impaired tissue perfusion: a pathology common to hypertension, obesity, and diabetes mellitus. Circulation. 2008;118(9):968–76.PubMedCrossRefGoogle Scholar
  15. 15.
    Levy BI, Ambrosio G, Pries AR, Struijker-Boudier HA. Microcirculation in hypertension: a new target for treatment? Circulation. 2001;104(6):735–40.PubMedCrossRefGoogle Scholar
  16. 16.
    Verdant C, De Backer D. How monitoring of the microcirculation may help us at the bedside. Curr Opin Crit Care. 2005;11(3):240–4.PubMedCrossRefGoogle Scholar
  17. 17.
    Knotzer H, Hasibeder WR. Microcirculatory function monitoring at the bedside–a view from the intensive care. Physiol Meas. 2007;28:R65–86.PubMedCrossRefGoogle Scholar
  18. 18.
    Jonk AM. Microvascular actions of insulin: studies on the interaction with angiotensin II and on the postprandial state. Amsterdam: GVO drukkers & vormgevers B.V., Ponsen & Looijen; 2011.Google Scholar
  19. 19.
    Minson CT, Berry LT, Joyner MJ. Nitric oxide and neurally mediated regulation of skin blood flow during local heating. J Appl Physiol. 2001;91(4):1619–26.PubMedGoogle Scholar
  20. 20.
    Serne EH, Gans RO, ter Maaten JC, Tangelder GJ, Donker AJ, Stehouwer CD. Impaired skin capillary recruitment in essential hypertension is caused by both functional and structural capillary rarefaction. Hypertension. 2001;38(2):238–42.PubMedCrossRefGoogle Scholar
  21. 21.
    Houben AJ, Stehouwer CD. Retinal microvascular abnormalities: can they predict future risk of hypertension? J Hypertens. 2009;27(12):2346–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Ikram MK, de Jong FJ, Vingerling JR, Witteman JC, Hofman A, Breteler MM, et al. Are retinal arteriolar or venular diameters associated with markers for cardiovascular disorders? The Rotterdam study. Invest Ophthalmol Vis Sci. 2004;45:2129–34.PubMedCrossRefGoogle Scholar
  23. 23.
    Klein R, Sharrett AR, Klein BE, Chambless LE, Cooper LS, Hubbard LD, et al. Are retinal arteriolar abnormalities related to atherosclerosis?: the atherosclerosis risk in communities study. Arterioscler Thromb Vasc Biol. 2000;20:1644–50.PubMedCrossRefGoogle Scholar
  24. 24.
    Wong TY, Islam FM, Klein R, Klein BE, Cotch MF, Castro C, et al. Retinal vascular caliber, cardiovascular risk factors, and inflammation: the multi-ethnic study of atherosclerosis (MESA). Invest Ophthalmol Vis Sci. 2006;47(6):2341–50.PubMedCrossRefGoogle Scholar
  25. 25.
    Wilkinson-Berka JL. Vasoactive factors and diabetic retinopathy: vascular endothelial growth factor, cycoloxygenase-2 and nitric oxide. Curr Pharm Des. 2004;10:3331–48.PubMedCrossRefGoogle Scholar
  26. 26.
    Delles C, Michelson G, Harazny J, Oehmer S, Hilgers KF, Schmieder RE. Impaired endothelial function of the retinal vasculature in hypertensive patients. Stroke. 2004;35(6):1289–93.PubMedCrossRefGoogle Scholar
  27. 27.
    Stehouwer CD. Is measurement of endothelial dysfunction clinically useful? Eur J Clin Invest. 1999;29(6):459–61.PubMedCrossRefGoogle Scholar
  28. 28.
    Kubes P, Kerfoot SM. Leukocyte recruitment in the microcirculation: the rolling paradigm revisited. News Physiol Sci. 2001;16:76–80.PubMedGoogle Scholar
  29. 29.
    Stehouwer CD. Endothelial dysfunction in diabetic nephropathy: state of the art and potential significance for non-diabetic renal disease. Nephrol Dial Transplant. 2004;19(4):778–81.PubMedCrossRefGoogle Scholar
  30. 30.
    Stehouwer CD, Lambert J, Donker AJ, van Hinsbergh VW. Endothelial dysfunction and pathogenesis of diabetic angiopathy. Cardiovasc Res. 1997;34(1):55–68.PubMedCrossRefGoogle Scholar
  31. 31.
    Kasprzak JD, Klosinska M, Drozdz J. Clinical aspects of assessment of endothelial function. Pharmacol Rep. 2006;58(Suppl):33–40.PubMedGoogle Scholar
  32. 32.
    Schram MT, Stehouwer CD. Endothelial dysfunction, cellular adhesion molecules and the metabolic syndrome. Horm Metab Res. 2005;37 Suppl 1:49–55.PubMedCrossRefGoogle Scholar
  33. 33.
    Szmitko PE, Wang CH, Weisel RD, de Almeida JR, Anderson TJ, Verma S. New markers of inflammation and endothelial cell activation: part I. Circulation. 2003;108(16):1917–23.PubMedCrossRefGoogle Scholar
  34. 34.
    Wolinsky H. A proposal linking clearance of circulating lipoproteins to tissue metabolic activity as a basis for understanding atherogenesis. Circ Res. 1980;47:301–11.PubMedCrossRefGoogle Scholar
  35. 35.
    Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A. Albuminuria reflects widespread vascular damage. The steno hypothesis. Diabetologia. 1989;32(4):219–26.PubMedCrossRefGoogle Scholar
  36. 36.
    Jensen T, Bjerre-Knudsen J, Feldt-Rasmussen B, Deckert T. Features of endothelial dysfunction in early diabetic nephropathy. Lancet. 1989;1(8636):461–3.PubMedCrossRefGoogle Scholar
  37. 37.
    Ochodnicky P, Henning RH, van Dokkum RP, de Zeeuw D. Microalbuminuria and endothelial dysfunction: emerging targets for primary prevention of end-organ damage. J Cardiovasc Pharmacol. 2006;47 Suppl 2:S151–62. discussion S172–156.PubMedCrossRefGoogle Scholar
  38. 38.
    Stehouwer CD, Smulders YM. Microalbuminuria and risk for cardiovascular disease: analysis of potential mechanisms. J Am Soc Nephrol. 2006;17:2106–11.PubMedCrossRefGoogle Scholar
  39. 39.
    Kim JA, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation. 2006;113(15):1888–904.PubMedCrossRefGoogle Scholar
  40. 40.
    Serne EH, de Jongh RT, Eringa EC, Ijzerman RG, Stehouwer CD. Microvascular dysfunction: a potential pathophysiological role in the metabolic syndrome. Hypertension. 2007;50(1):204–11.PubMedCrossRefGoogle Scholar
  41. 41.
    Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest. 2000;106(2):171–6.PubMedCrossRefGoogle Scholar
  42. 42.
    Shulman GI. Unraveling the cellular mechanism of insulin resistance in humans: new insights from magnetic resonance spectroscopy. Physiology (Bethesda). 2004;19:183–90.CrossRefGoogle Scholar
  43. 43.
    Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444(7121):860–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Savage DB, Petersen KF, Shulman GI. Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol Rev. 2007;87(2):507–20.PubMedCrossRefGoogle Scholar
  45. 45.
    Schalkwijk CG, Stehouwer CD. Vascular complications in diabetes mellitus: the role of endothelial dysfunction. Clin Sci (Lond). 2005;109(2):143–59.CrossRefGoogle Scholar
  46. 46.
    Karlsson HK, Zierath JR. Insulin signaling and glucose transport in insulin resistant human skeletal muscle. Cell Biochem Biophys. 2007;48(2–3):103–13.PubMedCrossRefGoogle Scholar
  47. 47.
    Taubes G. Insulin resistance. Prosperity’s plague. Science. 2009;325(5938):256–60.PubMedCrossRefGoogle Scholar
  48. 48.
    Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. J Clin Invest. 1990;85(6):1844–52.PubMedCrossRefGoogle Scholar
  49. 49.
    Baron AD, Steinberg H, Brechtel G, Johnson A. Skeletal muscle blood flow independently modulates insulin-mediated glucose uptake. Am J Physiol. 1994;266(2 Pt 1):E248–53.PubMedGoogle Scholar
  50. 50.
    de Haan CH, van Dielen FM, Houben AJ, de Leeuw PW, Huvers FC, De Mey JG, et al. Peripheral blood flow and noradrenaline responsiveness: the effect of physiological hyperinsulinemia. Cardiovasc Res. 1997;34(1):192–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Tack CJ, Lutterman JA, Vervoort G, Thien T, Smits P. Activation of the sodium-potassium pump contributes to insulin-induced vasodilation in humans. Hypertension. 1996;28(3):426–32.PubMedCrossRefGoogle Scholar
  52. 52.
    Clark MG, Wallis MG, Barrett EJ, Vincent MA, Richards SM, Clerk LH, et al. Blood flow and muscle metabolism: a focus on insulin action. Am J Physiol Endocrinol Metab. 2003;284:E241–58.PubMedGoogle Scholar
  53. 53.
    Yki-Jarvinen H, Utriainen T. Insulin-induced vasodilatation: physiology or pharmacology? Diabetologia. 1998;41(4):369–79.PubMedCrossRefGoogle Scholar
  54. 54.
    Zhang L, Vincent MA, Richards SM, Clerk LH, Rattigan S, Clark MG, et al. Insulin sensitivity of muscle capillary recruitment in vivo. Diabetes. 2004;53(2):447–53.PubMedCrossRefGoogle Scholar
  55. 55.
    Vincent MA, Clerk LH, Lindner JR, Klibanov AL, Clark MG, Rattigan S, et al. Microvascular recruitment is an early insulin effect that regulates skeletal muscle glucose uptake in vivo. Diabetes. 2004;53(6):1418–23.PubMedCrossRefGoogle Scholar
  56. 56.
    Kubota T, Kubota N, Kumagai H, Yamaguchi S, Kozono H, Takahashi T, et al. Impaired insulin signaling in endothelial cells reduces insulin-induced glucose uptake by skeletal muscle. Cell Metab. 2011;13(3):294–307.PubMedCrossRefGoogle Scholar
  57. 57.
    Wang H, Wang AX, Barrett EJ. Insulin-induced endothelial cell cortical actin filament remodeling: a requirement for trans-endothelial insulin transport. Mol Endocrinol. 2012;26(8):1327–38.PubMedCrossRefGoogle Scholar
  58. 58.
    Johansson GS, Chisalita SI, Arnqvist HJ. Human microvascular endothelial cells are sensitive to IGF-I but resistant to insulin at the receptor level. Mol Cell Endocrinol. 2008;296(1–2):58–63.PubMedCrossRefGoogle Scholar
  59. 59.
    Rattigan S, Clark MG, Barrett EJ. Hemodynamic actions of insulin in rat skeletal muscle: evidence for capillary recruitment. Diabetes. 1997;46:1381–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Clark AD, Barrett EJ, Rattigan S, Wallis MG, Clark MG. Insulin stimulates laser Doppler signal by rat muscle in vivo, consistent with nutritive flow recruitment. Clin Sci (Lond). 2001;100(3):283–90.CrossRefGoogle Scholar
  61. 61.
    Vincent MA, Dawson D, Clark AD, Lindner JR, Rattigan S, Clark MG, et al. Skeletal muscle microvascular recruitment by physiological hyperinsulinemia precedes increases in total blood flow. Diabetes. 2002;51(1):42–8.PubMedCrossRefGoogle Scholar
  62. 62.
    Clerk LH, Vincent MA, Jahn LA, Liu Z, Lindner JR, Barrett EJ. Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle. Diabetes. 2006;55(5):1436–42.PubMedCrossRefGoogle Scholar
  63. 63.
    Coggins M, Lindner J, Rattigan S, Jahn L, Fasy E, Kaul S, et al. Physiologic hyperinsulinemia enhances human skeletal muscle perfusion by capillary recruitment. Diabetes. 2001;50(12):2682–90.PubMedCrossRefGoogle Scholar
  64. 64.
    de Jongh RT, Clark AD, Ijzerman RG, Serne EH, de Vries G, Stehouwer CD. Physiological hyperinsulinaemia increases intramuscular microvascular reactive hyperaemia and vasomotion in healthy volunteers. Diabetologia. 2004;47(6):978–86.PubMedCrossRefGoogle Scholar
  65. 65.
    Serne EH, Gans RO, ter Maaten JC, ter Wee PM, Donker AJ, Stehouwer CD. Capillary recruitment is impaired in essential hypertension and relates to insulin’s metabolic and vascular actions. Cardiovasc Res. 2001;49(1):161–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Francischetti EA, Tibirica E, da Silva EG, Rodrigues E, Celoria BM, de Abreu VG. Skin capillary density and microvascular reactivity in obese subjects with and without metabolic syndrome. Microvasc Res. 2011;81(3):325–30.PubMedCrossRefGoogle Scholar
  67. 67.
    Serne EH, Stehouwer CD, ter Maaten JC, ter Wee PM, Rauwerda JA, Donker AJ, et al. Microvascular function relates to insulin sensitivity and blood pressure in normal subjects. Circulation. 1999;99(7):896–902.PubMedCrossRefGoogle Scholar
  68. 68.
    Grassi G, Seravalle G, Scopelliti F, Dell’Oro R, Fattori L, Quarti-Trevano F, et al. Structural and functional alterations of subcutaneous small resistance arteries in severe human obesity. Obesity (Silver Spring). 2010;18(1):92–8.CrossRefGoogle Scholar
  69. 69.
    Lampinen KH, Ronnback M, Groop PH, Kaaja RJ. A relationship between insulin sensitivity and vasodilation in women with a history of preeclamptic pregnancy. Hypertension. 2008;52(2):394–401.PubMedCrossRefGoogle Scholar
  70. 70.
    Clough GF, L’Esperance V, Turzyniecka M, Walter L, Chipperfield AJ, Gamble J, et al. Functional dilator capacity is independently associated with insulin sensitivity and age in central obesity and is not improved by high dose statin treatment. Microcirculation. 2011;18(1):74–84.PubMedCrossRefGoogle Scholar
  71. 71.
    Vincent MA, Clerk LH, Rattigan S, Clark MG, Barrett EJ. Active role for the vasculature in the delivery of insulin to skeletal muscle. Clin Exp Pharmacol Physiol. 2005;32(4):302–7.PubMedCrossRefGoogle Scholar
  72. 72.
    Serne EH, Ijzerman RG, Gans RO, Nijveldt R, De Vries G, Evertz R, et al. Direct evidence for insulin-induced capillary recruitment in skin of healthy subjects during physiological hyperinsulinemia. Diabetes. 2002;51(5):1515–22.PubMedCrossRefGoogle Scholar
  73. 73.
    Newman JM, Dwyer RM, St-Pierre P, Richards SM, Clark MG, Rattigan S. Decreased microvascular vasomotion and myogenic response in rat skeletal muscle in association with acute insulin resistance. J Physiol. 2009;587(Pt 11):2579–88.PubMedCrossRefGoogle Scholar
  74. 74.
    Vincent MA, Barrett EJ, Lindner JR, Clark MG, Rattigan S. Inhibiting NOS blocks microvascular recruitment and blunts muscle glucose uptake in response to insulin. Am J Physiol Endocrinol Metab. 2003;285:E123–9.PubMedGoogle Scholar
  75. 75.
    Wallis MG, Wheatley CM, Rattigan S, Barrett EJ, Clark AD, Clark MG. Insulin-mediated hemodynamic changes are impaired in muscle of Zucker obese rats. Diabetes. 2002;51(12):3492–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Han KA, Patel Y, Lteif AA, Chisholm R, Mather KJ. Contributions of dysglycaemia, obesity, and insulin resistance to impaired endothelium-dependent vasodilation in humans. Diabetes Metab Res Rev. 2011;27(4):354–61.PubMedCrossRefGoogle Scholar
  77. 77.
    de Jongh RT, Serne EH, Ijzerman RG, Jorstad HT, Stehouwer CD. Impaired local microvascular vasodilatory effects of insulin and reduced skin microvascular vasomotion in obese women. Microvasc Res. 2008;75(2):256–62.PubMedCrossRefGoogle Scholar
  78. 78.
    Ketel IJ, Serne EH, Ijzerman RG, Korsen TJ, Twisk JW, Hompes PG, et al. Insulin-induced capillary recruitment is impaired in both lean and obese women with PCOS. Hum Reprod. 2011;26(11):3130–7.PubMedCrossRefGoogle Scholar
  79. 79.
    Ketel IJ, Stehouwer CD, Serne EH, Korsen TJ, Hompes PG, Smulders YM, et al. Obese but not normal-weight women with polycystic ovary syndrome are characterized by metabolic and microvascular insulin resistance. J Clin Endocrinol Metab. 2008;93(9):3365–72.PubMedCrossRefGoogle Scholar
  80. 80.
    de Jongh RT, Serne EH, Ijzerman RG, de Vries G, Stehouwer CD. Free fatty acid levels modulate microvascular function: relevance for obesity-associated insulin resistance, hypertension, and microangiopathy. Diabetes. 2004;53(11):2873–82.PubMedCrossRefGoogle Scholar
  81. 81.
    Brantsma AH, Bakker SJ, Hillege HL, de Zeeuw D, de Jong PE, Gansevoort RT. Urinary albumin excretion and its relation with C-reactive protein and the metabolic syndrome in the prediction of type 2 diabetes. Diabetes Care. 2005;28:2525–30.PubMedCrossRefGoogle Scholar
  82. 82.
    Friedman AN, Marrero D, Ma Y, Ackermann R, Narayan KM, Barrett-Connor E, et al. Value of urinary albumin-to-creatinine ratio as a predictor of type 2 diabetes in pre-diabetic individuals. Diabetes Care. 2008;31:2344–8.PubMedCrossRefGoogle Scholar
  83. 83.
    Ikram MK, Janssen JA, Roos AM, Rietveld I, Witteman JC, Breteler MM, et al. Retinal vessel diameters and risk of impaired fasting glucose or diabetes: the Rotterdam study. Diabetes. 2006;55:506–10.PubMedCrossRefGoogle Scholar
  84. 84.
    Kifley A, Wang JJ, Cugati S, Wong TY, Mitchell P. Retinal vascular caliber and the long-term risk of diabetes and impaired fasting glucose: the Blue Mountains Eye Study. Microcirculation. 2008;15:373–7.PubMedCrossRefGoogle Scholar
  85. 85.
    Krakoff J, Funahashi T, Stehouwer CD, Schalkwijk CG, Tanaka S, Matsuzawa Y, et al. Inflammatory markers, adiponectin, and risk of type 2 diabetes in the Pima Indian. Diabetes Care. 2003;26:1745–51.PubMedCrossRefGoogle Scholar
  86. 86.
    Meigs JB, O’Donnell CJ, Tofler GH, Benjamin EJ, Fox CS, Lipinska I, et al. Hemostatic markers of endothelial dysfunction and risk of incident type 2 diabetes: the Framingham offspring study. Diabetes. 2006;55:530–7.PubMedCrossRefGoogle Scholar
  87. 87.
    Nguyen TT, Wang JJ, Islam FM, Mitchell P, Tapp RJ, Zimmet PZ, et al. Retinal arteriolar narrowing predicts incidence of diabetes: the Australian Diabetes, Obesity and Lifestyle (AusDiab) study. Diabetes. 2008;57:536–9.PubMedCrossRefGoogle Scholar
  88. 88.
    Perticone F, Maio R, Sciacqua A, Andreozzi F, Iemma G, Perticone M, et al. Endothelial dysfunction and c-reactive protein are risk factors for diabetes in essential hypertension. Diabetes. 2008;57:167–71.PubMedCrossRefGoogle Scholar
  89. 89.
    Sattar N, Murray HM, Welsh P, Blauw GJ, Buckley BM, de Craen AJ, et al. Are elevated circulating intercellular adhesion molecule 1 levels more strongly predictive of diabetes than vascular risk? Outcome of a prospective study in the elderly. Diabetologia. 2009;52:235–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Song Y, Manson JE, Tinker L, Rifai N, Cook NR, Hu FB, et al. Circulating levels of endothelial adhesion molecules and risk of diabetes in an ethnically diverse cohort of women. Diabetes. 2007;56:1898–904.PubMedCrossRefGoogle Scholar
  91. 91.
    Wang Z, Hoy WE. Albuminuria as a marker of the risk of developing type 2 diabetes in non-diabetic Aboriginal Australians. Int J Epidemiol. 2006;35:1331–5.PubMedCrossRefGoogle Scholar
  92. 92.
    Wong TY, Klein R, Sharrett AR, Schmidt MI, Pankow JS, Couper DJ, et al. Retinal arteriolar narrowing and risk of diabetes mellitus in middle-aged persons. JAMA. 2002;287:2528–33.PubMedCrossRefGoogle Scholar
  93. 93.
    Wong TY, Shankar A, Klein R, Klein BE, Hubbard LD. Retinal arteriolar narrowing, hypertension, and subsequent risk of diabetes mellitus. Arch Intern Med. 2005;165:1060–5.PubMedCrossRefGoogle Scholar
  94. 94.
    Muris DM, Houben AJ, Schram MT, Stehouwer CD. Microvascular dysfunction is associated with a higher incidence of type 2 diabetes mellitus: a systematic review and meta-analysis. Arterioscler Thromb Vasc Biol. 2012;32(12):3082–94.PubMedCrossRefGoogle Scholar
  95. 95.
    To SS, Newman PM, Hyland VJ, Robinson BG, Schrieber L. Regulation of adhesion molecule expression by human synovial microvascular endothelial cells in vitro. Arthritis Rheum. 1996;39:467–77.PubMedCrossRefGoogle Scholar
  96. 96.
    Kim F, Pham M, Maloney E, Rizzo NO, Morton GJ, Wisse BE, et al. Vascular inflammation, insulin resistance, and reduced nitric oxide production precede the onset of peripheral insulin resistance. Arterioscler Thromb Vasc Biol. 2008;28(11):1982–8.PubMedCrossRefGoogle Scholar
  97. 97.
    Bonner, JS, Lantier L, Hasenour CM, James FD, Bracy DP, Wasserman DH (2012) Muscle-specific vascular endothelial growth factor deletion induces muscle capillary rarefaction creating muscle insulin resistance. Diabetes.Google Scholar
  98. 98.
    Chittari MV, McTernan P, Bawazeer N, Constantinides K, Ciotola M, O’Hare JP, et al. Impact of acute hyperglycaemia on endothelial function and retinal vascular reactivity in patients with Type 2 diabetes. Diabet Med. 2011;28(4):450–4.PubMedCrossRefGoogle Scholar
  99. 99.
    Giugliano D, Marfella R, Coppola L, Verrazzo G, Acampora R, Giunta R, et al. Vascular effects of acute hyperglycemia in humans are reversed by L-arginine. Evidence for reduced availability of nitric oxide during hyperglycemia. Circulation. 1997;95(7):1783–90.PubMedCrossRefGoogle Scholar
  100. 100.
    Watanabe K, Oba K, Suzuki T, Ouchi M, Suzuki K, Futami-Suda S, et al. Oral glucose loading attenuates endothelial function in normal individual. Eur J Clin Invest. 2011;41(5):465–73.PubMedCrossRefGoogle Scholar
  101. 101.
    Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. Obesity/Insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest. 1996;47(2):310–3.Google Scholar
  102. 102.
    Costa RR, Villela NR, Souza MG, Boa BC, Cyrino FZ, Silva SV, et al. High fat diet induces central obesity, insulin resistance and microvascular dysfunction in hamsters. Microvasc Res. 2011;82(3):416–22.PubMedCrossRefGoogle Scholar
  103. 103.
    de Jongh RT, Ijzerman RG, Serne EH, Voordouw JJ, Yudkin JS, de Waal HA, et al. Visceral and truncal subcutaneous adipose tissue are associated with impaired capillary recruitment in healthy individuals. J Clin Endocrinol Metab. 2006;91(12):5100–6.PubMedCrossRefGoogle Scholar
  104. 104.
    Jiang ZY, Lin YW, Clemont A, Feener EP, Hein KD, Igarashi M, et al. Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest. 1999;104(4):447–57.PubMedCrossRefGoogle Scholar
  105. 105.
    Rizzo NO, Maloney E, Pham M, Luttrell I, Wessells H, Tateya S, et al. Reduced NO-cGMP signaling contributes to vascular inflammation and insulin resistance induced by high-fat feeding. Arterioscler Thromb Vasc Biol. 2010;30(4):758–65.PubMedCrossRefGoogle Scholar
  106. 106.
    Tsuchiya K, Sakai H, Suzuki N, Iwashima F, Yoshimoto T, Shichiri M, et al. Chronic blockade of nitric oxide synthesis reduces adiposity and improves insulin resistance in high fat-induced obese mice. Endocrinology. 2007;148(10):4548–56.PubMedCrossRefGoogle Scholar
  107. 107.
    Eringa EC, Stehouwer CD, Roos MH, Westerhof N, Sipkema P. Selective resistance to vasoactive effects of insulin in muscle resistance arteries of obese Zucker (fa/fa) rats. Am J Physiol Endocrinol Metab. 2007;293(5):E1134–9.PubMedCrossRefGoogle Scholar
  108. 108.
    Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun. 1999;257(1):79–83.PubMedCrossRefGoogle Scholar
  109. 109.
    Liu J, Jahn LA, Fowler DE, Barrett EJ, Cao W, Liu Z. Free fatty acids induce insulin resistance in both cardiac and skeletal muscle microvasculature in humans. J Clin Endocrinol Metab. 2011;96(2):438–46.PubMedCrossRefGoogle Scholar
  110. 110.
    Liu Z, Liu J, Jahn LA, Fowler DE, Barrett EJ. Infusing lipid raises plasma free fatty acids and induces insulin resistance in muscle microvasculature. J Clin Endocrinol Metab. 2009;94:3543–9.PubMedCrossRefGoogle Scholar
  111. 111.
    Clerk LH, Rattigan S, Clark MG. Lipid infusion impairs physiologic insulin-mediated capillary recruitment and muscle glucose uptake in vivo. Diabetes. 2002;51(4):1138–45.PubMedCrossRefGoogle Scholar
  112. 112.
    Watanabe S, Tagawa T, Yamakawa K, Shimabukuro M, Ueda S. Inhibition of the renin-angiotensin system prevents free fatty acid-induced acute endothelial dysfunction in humans. Arterioscler Thromb Vasc Biol. 2005;25(11):2376–80.PubMedCrossRefGoogle Scholar
  113. 113.
    Chai W, Liu J, Jahn LA, Fowler DE, Barrett EJ, Liu Z. Salsalate attenuates free fatty acid-induced microvascular and metabolic insulin resistance in humans. Diabetes Care. 2011;34(7):1634–8.PubMedCrossRefGoogle Scholar
  114. 114.
    Li H, Bao Y, Zhang X, Yu Y. Free fatty acids induce endothelial dysfunction and activate protein kinase C and nuclear factor-kappaB pathway in rat aorta. Int J Cardiol. 2011;152(2):218–24.PubMedCrossRefGoogle Scholar
  115. 115.
    Steinberg HO, Paradisi G, Hook G, Crowder K, Cronin J, Baron AD. Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production. Diabetes. 2000;49(7):1231–8.PubMedCrossRefGoogle Scholar
  116. 116.
    Steinberg HO, Tarshoby M, Monestel R, Hook G, Cronin J, Johnson A, et al. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest. 1997;100(5):1230–9.PubMedCrossRefGoogle Scholar
  117. 117.
    Inyard AC, Chong DG, Klibanov AL, Barrett EJ. Muscle contraction, but not insulin, increases microvascular blood volume in the presence of free fatty acid-induced insulin resistance. Diabetes. 2009;58(11):2457–63.PubMedCrossRefGoogle Scholar
  118. 118.
    Bakker W, Sipkema P, Stehouwer CD, Serne EH, Smulders YM, van Hinsbergh VW, et al. Protein kinase C theta activation induces insulin-mediated constriction of muscle resistance arteries. Diabetes. 2008;57(3):706–13.PubMedCrossRefGoogle Scholar
  119. 119.
    Youd JM, Rattigan S, Clark MG. Acute impairment of insulin-mediated capillary recruitment and glucose uptake in rat skeletal muscle in vivo by TNF-alpha. Diabetes. 2000;49(11):1904–9.PubMedCrossRefGoogle Scholar
  120. 120.
    Zhang L, Wheatley CM, Richards SM, Barrett EJ, Clark MG, Rattigan S. TNF-alpha acutely inhibits vascular effects of physiological but not high insulin or contraction. Am J Physiol Endocrinol Metab. 2003;285(3):E654–60.PubMedGoogle Scholar
  121. 121.
    Eringa EC, Stehouwer CD, Walburg K, Clark AD, van Nieuw Amerongen GP, Westerhof N, 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(2):274–80.PubMedCrossRefGoogle Scholar
  122. 122.
    Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, et al. A central role for JNK in obesity and insulin resistance. Nature. 2002;420(6913):333–6.PubMedCrossRefGoogle Scholar
  123. 123.
    Li G, Barrett EJ, Barrett MO, Cao W, Liu Z. Tumor necrosis factor-alpha induces insulin resistance in endothelial cells via a p38 mitogen-activated protein kinase-dependent pathway. Endocrinology. 2007;148(7):3356–63.PubMedCrossRefGoogle Scholar
  124. 124.
    Meijer RI, Bakker W, Alta CL, Sipkema P, Yudkin JS, Viollet B, et al. (2012). Perivascular adipose tissue control of insulin-induced vasoreactivity in muscle is impaired in db/db Mice. Diabetes.Google Scholar
  125. 125.
    Koenig W, Khuseyinova N, Baumert J, Meisinger C, Lowel H. Serum concentrations of adiponectin and risk of type 2 diabetes mellitus and coronary heart disease in apparently healthy middle-aged men: results from the 18-year follow-up of a large cohort from southern Germany. J Am Coll Cardiol. 2006;48(7):1369–77.PubMedCrossRefGoogle Scholar
  126. 126.
    Chen H, Montagnani M, Funahashi T, Shimomura I, Quon MJ. Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem. 2003;278(45):45021–6.PubMedCrossRefGoogle Scholar
  127. 127.
    Zheng Q, Yuan Y, Yi W, Lau WB, Wang Y, Wang X, et al. C1q/TNF-related proteins, a family of novel adipokines, induce vascular relaxation through the adiponectin receptor-1/AMPK/eNOS/nitric oxide signaling pathway. Arterioscler Thromb Vasc Biol. 2011;31(11):2616–23.PubMedCrossRefGoogle Scholar
  128. 128.
    Luo N, Liu J, Chung BH, Yang Q, Klein RL, Garvey WT, et al. Macrophage adiponectin expression improves insulin sensitivity and protects against inflammation and atherosclerosis. Diabetes. 2010;59(4):791–9.PubMedCrossRefGoogle Scholar
  129. 129.
    Meijer RI, Serne EH, Smulders YM, van Hinsbergh VW, Yudkin JS, Eringa EC. Perivascular adipose tissue and its role in type 2 diabetes and cardiovascular disease. Curr Diab Rep. 2011;11(3):211–7.PubMedCrossRefGoogle Scholar
  130. 130.
    Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol. 2006;6(10):772–83.PubMedCrossRefGoogle Scholar
  131. 131.
    Karlsson C, Lindell K, Ottosson M, Sjostrom L, Carlsson B, Carlsson LM. Human adipose tissue expresses angiotensinogen and enzymes required for its conversion to angiotensin II. J Clin Endocrinol Metab. 1998;83(11):3925–9.PubMedCrossRefGoogle Scholar
  132. 132.
    Schling P, Mallow H, Trindl A, Loffler G. Evidence for a local renin angiotensin system in primary cultured human preadipocytes. Int J Obes Relat Metab Disord. 1999;23(4):336–41.PubMedCrossRefGoogle Scholar
  133. 133.
    Rahmouni K, Mark AL, Haynes WG, Sigmund CD. Adipose depot-specific modulation of angiotensinogen gene expression in diet-induced obesity. Am J Physiol Endocrinol Metab. 2004;286(6):E891–5.PubMedCrossRefGoogle Scholar
  134. 134.
    Andreozzi F, Laratta E, Sciacqua A, Perticone F, Sesti G. Angiotensin II impairs the insulin signaling pathway promoting production of nitric oxide by inducing phosphorylation of insulin receptor substrate-1 on Ser312 and Ser616 in human umbilical vein endothelial cells. Circ Res. 2004;94(9):1211–8.PubMedCrossRefGoogle Scholar
  135. 135.
    Velloso LA, Folli F, Sun XJ, White MF, Saad MJ, Kahn CR. Cross-talk between the insulin and angiotensin signaling systems. Proc Natl Acad Sci U S A. 1996;93(22):12490–5.PubMedCrossRefGoogle Scholar
  136. 136.
    Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, et al. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest. 1996;97(8):1916–23.PubMedCrossRefGoogle Scholar
  137. 137.
    Zhou MS, Schulman IH, Raij L. Role of angiotensin II and oxidative stress in vascular insulin resistance linked to hypertension. Am J Physiol Heart Circ Physiol. 2009;296(3):H833–9.PubMedCrossRefGoogle Scholar
  138. 138.
    Hong HJ, Chan P, Liu JC, Juan SH, Huang MT, Lin JG, et al. Angiotensin II induces endothelin-1 gene expression via extracellular signal-regulated kinase pathway in rat aortic smooth muscle cells. Cardiovasc Res. 2004;61(1):159–68.PubMedCrossRefGoogle Scholar
  139. 139.
    Imai T, Hirata Y, Emori T, Yanagisawa M, Masaki T, Marumo F. Induction of endothelin-1 gene by angiotensin and vasopressin in endothelial cells. Hypertension. 1992;19(6 Pt 2):753–7.PubMedCrossRefGoogle Scholar
  140. 140.
    Bakker W, Eringa EC, Sipkema P, van Hinsbergh VW. Endothelial dysfunction and diabetes: roles of hyperglycemia, impaired insulin signaling and obesity. Cell Tissue Res. 2009;335(1):165–89.PubMedCrossRefGoogle Scholar
  141. 141.
    Eringa EC, Bakker W, van Hinsbergh VW. Paracrine regulation of vascular tone, inflammation and insulin sensitivity by perivascular adipose tissue. Vascul Pharmacol. 2012;56(5–6):204–9.PubMedCrossRefGoogle Scholar
  142. 142.
    Yudkin JS, Eringa E, Stehouwer CD. “Vasocrine” signalling from perivascular fat: a mechanism linking insulin resistance to vascular disease. Lancet. 2005;365(9473):1817–20.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Dennis M. J. Muris
    • 1
    • 2
  • Alfons J. H. M. Houben
    • 1
    • 2
  • Miranda T. Schram
    • 1
    • 2
  • Coen D. A. Stehouwer
    • 1
    • 2
  1. 1.Department of Internal MedicineMaastricht University Medical Centre (MUMC+)Maastrichtthe Netherlands
  2. 2.Cardiovascular Research Institute Maastricht (CARIM)Maastricht UniversityMaastrichtthe Netherlands

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