Skip to main content

Advertisement

SpringerLink
Log in

The metabolic syndrome and endothelial dysfunction: Common highway to type 2 diabetes and CVD?

  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Due to global lifestyle changes, obesity (the main driver of type 2 diabetes [T2D] and cardiovascular disease [CVD]) is reaching pandemic proportions. The metabolic syndrome, which is regarded as a prediabetic state, is characterized by a concurrence of interrelated cardiovascular risk factors, including abdominal obesity, insulin resistance, hypertension, dyslipidemia, and glucose intolerance. Endothelial dysfunction (ED) is common in the metabolic syndrome and is associated with increased risk for T2D and CVD. This review focuses on the mechanisms linking ED to the metabolic syndrome, T2D, and CVD, and the possible therapies that may improve ED and reduce T2D and CVD risk.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Yach D, Stuckler D, Brownell KD: Epidemiologic and economic consequences of the global epidemics of obesity and diabetes. Nat Med 2006, 12:62–66.

    Article  PubMed  CAS  Google Scholar 

  2. Roglic G, Unwin N, Bennett PH, et al.: The burden of mortality attributable to diabetes: realistic estimates for the year 2000. Diabetes Care 2005, 28:2130–2135.

    Article  PubMed  Google Scholar 

  3. Hu F, Stampfer MJ, Haffner SM, et al.: Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care 2002, 25:1129–1134.

    Article  PubMed  Google Scholar 

  4. Reaven GM: The role of insulin resistance in human disease. Diabetes 1988, 37:1595–1607.

    Article  PubMed  CAS  Google Scholar 

  5. Reaven GM: Why syndrome X? From Harold Himsworth to the insulin resistance syndrome. Cell Metab 2005, 1:9–14. This paper gives an excellent overview of the development of the etiologic) concept of the metabolic syndrome since it was first published by the same author in 1988.

    Article  PubMed  CAS  Google Scholar 

  6. Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) [no authors listed]. JAMA 2001, 285:2486–2497.

  7. Pinkney JH, Stehouwer CD, Coppack SW, Yudkin JS: Endothelial dysfunction: cause of the insulin resistance syndrome. Diabetes 1997, 46(suppl 2):S9-S13.

    PubMed  CAS  Google Scholar 

  8. 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.

    PubMed  CAS  Google Scholar 

  9. Lerman A, Zeiher AM: Endothelial function: cardiac events. Circulation 2005, 111:363–368.

    Article  PubMed  Google Scholar 

  10. Ganz P, Vita JA: Testing endothelial vasomotor function: nitric oxide, a multipotent molecule. Circulation 2003, 108:2049–2053.

    Article  PubMed  Google Scholar 

  11. Herrmann J, Lerman LO, Rodriguez-Porcel M, et al.: Coronary vasa vasorum neovascularization precedes epicardial endothelial dysfunction in experimental hypercholesterolemia. Cardiovasc Res 2001, 51:762–766.

    Article  PubMed  CAS  Google Scholar 

  12. Hill JM, Zalos G, Halcox JP, et al.: Circulating endothelial progenitor cells, vascular function and cardiovascular risk. N Engl J Med 2003, 348:593–600.

    Article  PubMed  Google Scholar 

  13. Nieuwdorp M, Mooij HL, Kroon J, et al.: Progressive glycocalyx perturbation coincides with microvascular complications in patients with type 1 diabetes. Diabetes 2006, 55:1127–1132. The glycocalyx was previously extensively investigated in various experimental models. This paper shows for the first time the in vivo relevance of the glycocalyx in the development of diabetes-related vascular complications in type 1 diabetes.

    Article  PubMed  CAS  Google Scholar 

  14. Saltiel AR, Kahn CR: Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001, 414:799–806.

    Article  PubMed  CAS  Google Scholar 

  15. Steinberg HO, Brechtel G, Johnson A, et al.: Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent: a novel action of insulin to increase nitric oxide release. J Clin Invest 1994, 94:1172–1179.

    Article  PubMed  CAS  Google Scholar 

  16. Hsueh WA, Quiñones MJ: Role of endothelial dysfunction in insulin resistance. Am J Cariol 2003, 92(suppl):10J-17J.

    Article  CAS  Google Scholar 

  17. 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 TNF-alpha dependence of c-Jun N-terminal kinase. Arterioscl Thromb Vasc Biol 2006, 26:274–280.

    Article  PubMed  CAS  Google Scholar 

  18. Hirosumi J, Tuneman G, Chang L, et al.: A central role for JNK in obesity and insulin resistance. Nature 2002, 420:333–336.

    Article  PubMed  CAS  Google Scholar 

  19. Cusi K, Maezono K, Osman A, et al.: Insulin resistance differentially affects the PI3K- and MAPK-mediated signaling in human muscle. J Clin Invest 2000, 105:311–320.

    PubMed  CAS  Google Scholar 

  20. Dandona P, Aljada A, Mohanty P: The anti-inflammatory and potential anti-atherogenic effect of insulin: a new paradigm. Diabetologia 2002, 45:924–930.

    Article  PubMed  CAS  Google Scholar 

  21. Cai H, Harrison DG: Endothelial dysfunction in cardiovascular disease: the role of oxidant stress. Circ Res 2000, 87:840–844.

    PubMed  CAS  Google Scholar 

  22. Ceriello A, Motz E: Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes and cardiovascular disease? The common soil hypothesis revisited. Arterioscl Thromb Vasc Biol 2004, 24:816–823.

    Article  PubMed  CAS  Google Scholar 

  23. Houstis N, Rosen ED, Lander ES: Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 2006, 440:944–948. Using a varied approach to alter ROS levels, the authors elegantly show the involvement of ROS in TNF-á- and glucocorticoidinduced insulin resistance in vitro and in obese insulin-resistant mice. Collectively, the data show that increased oxidative stress induces insulin resistance in different settings.

    Article  PubMed  CAS  Google Scholar 

  24. Wajchenberg BL: Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000, 21:697–738.

    Article  PubMed  CAS  Google Scholar 

  25. Berg AH, Sherer PE: Adipose tissue, inflammation and cardiovascular disease. Circ Res 2005, 96:939–949.

    Article  PubMed  CAS  Google Scholar 

  26. Yudkin JS, Stehouwer CD, Emis JJ, Coppack SW: C-reactive protein in healthy subjects: association with obesity, insulin resistance and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscl Thromb Vasc Biol 1999, 19:972–978.

    PubMed  CAS  Google Scholar 

  27. Schindhelm RK, Diamant M, Van Dijk RAJM, et al.: Elevated liver alanine transferase, insulin resistance and endothelial dysfunction in normotriglyceridemic subjects with type 2 diabetes mellitus. Eur J Clin Invest 2005, 35:369–374.

    Article  PubMed  CAS  Google Scholar 

  28. Yudkin JS, Eringa E, Stehouwer CD: Vasocrine signalling from perivascular fat: a mechanism linking insulin resistance to vascular disease. Lancet 2005, 365:1817–1820.

    Article  PubMed  Google Scholar 

  29. Lowell BB, Shulman GI: Mitochondrial dysfunction and type 2 diabetes. Science 2005, 307:384–387.

    Article  PubMed  CAS  Google Scholar 

  30. Evans JL, Gold.ne ID, Maddux BA, Grodsky GM: Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes 2003, 52:1–8.

    Article  PubMed  CAS  Google Scholar 

  31. Du X, Edelstein D, Obici S, et al.: Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation. J Clin Invest 2006, 116:1071–1080.

    Article  PubMed  CAS  Google Scholar 

  32. Meigs JB, Hu FB, Rifai N, Manson JE: Biomarkers of endothelial dysfunction and risk of type 2 diabetes. JAMA 2004, 291:1978–1986.

    Article  PubMed  CAS  Google Scholar 

  33. Rossi R, Cioni E, Nuzzo A, et al.: Endothelial-dependent vasodilation and incidence of type 2 diabetes in a population of healthy postmenopausal women. Diabetes Care 2005, 28:702–707.

    Article  PubMed  Google Scholar 

  34. Meigs JB, O'Donnell CJ, Tofler GH, et al.: Hemostatic markers of endothelial dysfunction and risk of incident type 2 diabetes: the Framingham offspring study. Diabetes 2006, 55:530–537.

    Article  PubMed  CAS  Google Scholar 

  35. Tushuizen ME, Diamant M, Heine RJ: Postprandial dysmetabolism and atherosclerosis in type 2 diabetes. Postgrad Med 2005, 81:1–6.

    Article  CAS  Google Scholar 

  36. Brownlee M: The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005, 54:1615–1625. An excellent review describing the pathophysiologic mechanisms that seem to converge on a single process (ie, mitochondrial dysfunction and subsequent oxidative stress) by which hyperglycemia causes (micro)vascular complications in diabetes.

    Article  PubMed  CAS  Google Scholar 

  37. Unger RH: Lipotoxic diseases. Annu Rev Med 2002, 53:319–336.

    Article  PubMed  CAS  Google Scholar 

  38. Nappo F, Esposito K, Ciof M, et al.: Postprandial endothelial activation in healthy subjects and in type 2 diabetic patients: role of fat and carbohydrate meals. J Am Coll Cardiol 2002, 39:1145–1150.

    Article  PubMed  CAS  Google Scholar 

  39. Tushuizen ME, Nieuwland R, Scheffer PG, et al.: Two consecutive high-fat meals affect endothelial-dependent vasodilation, oxidative stress and cellular microparticles in healthy men. J Thromb Haemost 2006, 4:1003–1010.

    Article  PubMed  CAS  Google Scholar 

  40. Zilversmit DB: Atherogenesis: a postprandial phenomenon. Circulation 1979, 60:473–485.

    PubMed  CAS  Google Scholar 

  41. Frühbeck G, Gómez-Ambrosi J, Muruzábal FJ, Burrell MA: The adipocyte: a model for integration of endocrine and metabolic signaling in energy regulation. Am J Physiol Endocrinol Metab 2001, 280:E827-E847.

    PubMed  Google Scholar 

  42. Kougias P, Chai H, Lin PH, et al.: Effects of adipocyte-derived cytokines on endothelial functions: implication of vascular disease. J Surg Res 2005, 126:121–129.

    Article  PubMed  CAS  Google Scholar 

  43. Xu H, Barnes GT, Yang Q, et al.: Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003, 112:1821–1830.

    Article  PubMed  CAS  Google Scholar 

  44. Klein J, Perwitz N, Kraus D, Fasshauer M: Adipose tissue as source and target for novel therapies. Trends Endocrinol Metab 2006, 17:26–32.

    Article  PubMed  CAS  Google Scholar 

  45. Lyon CJ, Hsueh WA: Effect of plasminogen activator inhibitor-1 in diabetes mellitus and cardiovascular disease. Am J Med 2003, 115(suppl 8A):62S-68S.

    Article  PubMed  CAS  Google Scholar 

  46. Diamant M, Lamb HJ, Van der Ree MA, et al.: The association between abdominal visceral fat and carotid stiffness is mediated by circulating inflammatory markers in uncomplicated type 2 diabetes. J Clin Endocrinol Metab 2005, 90:1495–1501.

    Article  PubMed  CAS  Google Scholar 

  47. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH: Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000, 101:1767–1772.

    PubMed  CAS  Google Scholar 

  48. Willerson JT, Ridker PM: Inflammation as a cardiovascular risk factor Circulation 2004, 109(suppl II):II2-II10.

    PubMed  Google Scholar 

  49. Widlansky ME, Gokce N, Keaney JF, Vita JA: The clinical implications of endothelial dysfunction. J Am Coll Cardiol 2003, 42:1149–1160.

    Article  PubMed  CAS  Google Scholar 

  50. Tuomilehto J, Lindstrom J, Eriksson JT, et al.: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001, 344:1343–1350.

    Article  PubMed  CAS  Google Scholar 

  51. Yki-Järvinen H: Insulin resistance and endothelial dysfunction. Best Pract Res Clin Endocrinol Metab 2003, 17:411–430.

    Article  PubMed  CAS  Google Scholar 

  52. Lonn E, Bosch J, Yusuf S, et al.: Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 2005, 293:1338–1347.

    Article  PubMed  Google Scholar 

  53. Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002, 360:23–33.

    Article  Google Scholar 

  54. Lonn E, Yusuf S, Arnold MJ, et al.: Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006, 354:1567–1577.

    Article  PubMed  CAS  Google Scholar 

  55. Bonaa KH, Njolstad I, Ueland PM, et al.: Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006, 354:1578–1588.

    Article  PubMed  CAS  Google Scholar 

  56. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group [no authors listed]. Lancet 1998, 352:854–865.

  57. Zhou G, Myers R, Li Y, et al.: Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001, 108:1167–1174.

    Article  PubMed  CAS  Google Scholar 

  58. Kukidome D, Nishikawa T, Sonoda K, et al.: Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial ROS production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes 2006, 55:120–127.

    Article  PubMed  CAS  Google Scholar 

  59. Davis BJ, Xie Z, Viollet B, Zou MH: Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. Diabetes 2006, 55:496–505.

    Article  PubMed  CAS  Google Scholar 

  60. Caballero AE, Delgado A, Aguilar-Salinas CA, et al.: The differential effects of metformin on markers of endothelial activation and inflammation in subjects with impaired glucose tolerance: a placebo-controlled, randomized clinical trial. J Clin Endocrinol Metab 2004, 89:3943–3948.

    Article  PubMed  CAS  Google Scholar 

  61. De Jager J, Kooy A, Lehert P, et al.: Effects of short-term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: a randomized, placebo-controlled trial. J Intern Med 2005, 257:100–109.

    Article  PubMed  Google Scholar 

  62. Knowler WC, Barrett-Connor E, Fowler SE, et al.: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002, 346:393–403.

    Article  PubMed  CAS  Google Scholar 

  63. Diamant M, Heine RJ: Thiazolidinediones in type 2 diabetes mellitus: current clinical evidence. Drugs 2003, 63:1373–1405.

    Article  PubMed  CAS  Google Scholar 

  64. Campia U, Matuskey LA, Panza JA: Peroxisome proliferator-activated receptor-gamma activation with pioglitazone improves endothelium-dependent dilation in nondiabetic patients with major cardiovascular risk factors. Circulation 2006, 113:867–875.

    Article  PubMed  CAS  Google Scholar 

  65. Sidhu JS, Cowan D, Kaski JC: The effects of rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, on markers of endothelial cell activation, C-reactive protein, and fibrinogen levels in non-diabetic coronary artery disease patients. J Am Coll Cardiol 2003, 42:1757–1763.

    Article  PubMed  CAS  Google Scholar 

  66. Dormandy JA, Charbonnel B, Eckland DJ, et al.: Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005, 366:1279–1289. First randomized-controlled outcome study evaluating the effects of a TZD, pioglitazone, in a high-risk population. Although pioglitazone did not significant improve the predefined primary end point, it significantly reduced the risk of the predefined secondary end point by 16%.

    Article  PubMed  CAS  Google Scholar 

  67. Buchanan T, Xiang AH, Peters RK, et al.: Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002, 51:2796–2803.

    Article  PubMed  CAS  Google Scholar 

  68. Gerstein HC, Yusuf S, Holman R, et al.: Rationale, design and recruitment characteristics of a large, simple international trial of diabetes prevention: the DREAM trial. Diabetologia 2004, 47:1519–1527.

    Article  PubMed  CAS  Google Scholar 

  69. Viberti G, Kahn SE, Greene DA, et al.: A diabetes outcome progression trial (ADOPT): an international multicenter study of the comparative efficacy of rosiglitazone, glyburide, and metformin in recently diagnosed type 2 diabetes. Diabetes Care 2002, 25:1737–1743.

    Article  PubMed  CAS  Google Scholar 

  70. LaRosa JC, Grundy SM, Waters DD, et al.: Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005, 352:1425–1435.

    Article  PubMed  CAS  Google Scholar 

  71. Landmesser U, Bahlmann F, Mueller M, et al.: Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation 2005, 111:2356–2363.

    Article  PubMed  CAS  Google Scholar 

  72. Van Venrooij FV, Van de Ree MA, Bots ML, et al.: Aggressive lipid lowering does not improve endothelial function in type 2 diabetes: the Diabetes Atorvastatin Lipid Intervention (DALI) Study: a randomized, double-blind, placebo-controlled trial. Diabetes Care 2002, 25:1211–1216.

    Article  PubMed  Google Scholar 

  73. Yusuf S, Sleight P, Pogue J, et al.: Effects of an angiotensin-converting enzyme inhibitor ramipril, on cardiovascular events in high-risk patients: the Heart Outcomes Prevention Evaluation study investigators. N Engl J Med 2000, 342:145–153.

    Article  PubMed  CAS  Google Scholar 

  74. Dzau V: Tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension 2001, 37:1047–1052.

    PubMed  CAS  Google Scholar 

  75. Scheen AJ: Prevention of type 2 diabetes by inhibition of the renin-angiotensin system. Drugs 2004, 64:2537–2565.

    Article  PubMed  CAS  Google Scholar 

  76. Strazzullo P, Galletti F: Impact of the renin-angiotensin system on lipid and carbohydrate metabolism. Curr Opin Nephrol Hypertens 2004, 13:325–332.

    Article  PubMed  Google Scholar 

  77. Tikellis C, Wookey PJ, Candido R, et al.: Improved islet morphology after blockade of the renin-angiotensin system in the ZDF rat. Diabetes 2004, 53:989–997.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Endocrinology/Diabetes Center, VU University Medical Center, PO Box 7057, 1007, MB Amsterdam, The Netherlands

    Michaela Diamant MD, PhD

Authors
  1. Michaela Diamant MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maarten E. Tushuizen MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michaela Diamant MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Diamant, M., Tushuizen, M.E. The metabolic syndrome and endothelial dysfunction: Common highway to type 2 diabetes and CVD?. Curr Diab Rep 6, 279–286 (2006). https://doi.org/10.1007/s11892-006-0061-4

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-006-0061-4

Keywords

Search

Navigation