Current Diabetes Reports

, Volume 2, Issue 5, pp 396–402 | Cite as

Role of inflammatory pathways in the development and cardiovascular complications of type 2 diabetes

  • Milagros G. Huerta
  • Jerry L. Nadler


Experimental and epidemiologic studies support the role of inflammation in the development of type 2 diabetes and atherosclerosis. Serum levels of inflammatory markers, in particular highly sensitive C-reactive protein, have been found to be strong predictors of increased risk for type 2 diabetes and cardiovascular disease independent of traditional risk factors. A beneficial effect of thiazolidinediones, angiotensin-converting enzyme inhibitors, and statins in the prevention of type 2 diabetes and cardiovascular events has recently been reported, and potential anti-inflammatory mechanisms of action for these compounds have been described. Prospective, randomized clinical trials are currently underway to confirm these initial findings and define indications for treatment of patients at risk.


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References and Recommended Reading

  1. 1.
    Ross R: Atherosclerosis: an inflammatory disease. N Engl J Med 1999, 340:115–126. Review of the inflammatory mechanisms that contribute to the development and progression of atherosclerosis.PubMedCrossRefGoogle Scholar
  2. 2.
    Stern MP: Diabetes and cardiovascular disease: the "common soil" hypothesis. Diabetes 1995, 44:369–374.PubMedCrossRefGoogle Scholar
  3. 3.
    Pradhan AD, Manson JE, Rifai N, et al.: C-reactive protein, interleukin 6 and risk of developing type 2 diabetes mellitus. JAMA 2001, 286:327–334. Demonstrated that elevated CRP is a powerful independent predictor of risk for T2DM.PubMedCrossRefGoogle Scholar
  4. 4.
    Fröhlich M, Imhof A, Berg G, et al.: Association between C-reactive protein and features of the metabolic syndrome. Diabetes Care 2000, 23:1835–1839.PubMedCrossRefGoogle Scholar
  5. 5.
    Kern PA, Ranganathan S, Li C, et al.: Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 2001, 280:E745-E751.PubMedGoogle Scholar
  6. 6.
    Bastard JP, Jardel C, Bruckert E, et al.: Elevated levels of interleukin 6 are reduced in serum and adipose tissue of obese women after weight loss. J Clin Endocrinol Metabol 2000, 85:3338–3342.CrossRefGoogle Scholar
  7. 7.
    Visser M, Bouter LM, McQuillan GM, et al.: Elevated C-reactive protein levels in overweight and obese adults. JAMA 2000, 282:2131–2135.CrossRefGoogle Scholar
  8. 8.
    Yudkin JS, Stehouwer CDA, Emeis JJ, et al.: C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction. Arterioscler Thromb Vasc Biol 1999, 19:972–978.PubMedGoogle Scholar
  9. 9.
    Festa A, D'Agostino RJ, Howard G, et al.: Chronic subclinical inflammation as part of insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 2000, 102:42–47.PubMedGoogle Scholar
  10. 10.
    Girard J: Is leptin the link between obesity and insulin resistance? Diabetes Metab 1997, 23(suppl 3):16–24.PubMedGoogle Scholar
  11. 11.
    Uysal KT, Wiesbrock SM, Marino MW, et al.: Protection from obesity-induced insulin resistance in mice lacking TNF alpha function. Nature 1997, 389:610–614.PubMedCrossRefGoogle Scholar
  12. 12.
    Straczkowski M, Kowalska I, Dzienis-Straczkowska S, et al.: Changes in tumor necrosis factor-alpha system and insulin sensitivity during an exercise training program in obese women with normal and impaired glucose tolerance. Eur J Endocrinol 2001, 145:273–280.PubMedCrossRefGoogle Scholar
  13. 13.
    Schmidt MI, Duncan BB, Sharrett AR, et al.: Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities Study): a cohort study. Lancet 1999, 353:1649–1652.PubMedCrossRefGoogle Scholar
  14. 14.
    O'Riordain MG, Ross JA, Fearon KC, et al.: Insulin and counterregulatory hormones influence acute-phase protein production in human hepatocytes. Am J Physiol 1995, 269:E323-E330.PubMedGoogle Scholar
  15. 15.
    Barzilay JI, Abraham L, Heckbert SR, et al.: The relation of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. Diabetes 2001, 50:2384–2389.PubMedCrossRefGoogle Scholar
  16. 16.
    Festa A, D'Agostino RJ, Tracy RP, Haffner SM: Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the Insulin Resistance Atherosclerosis Study. Diabetes 2002, 51:1131–1137. Demonstrated that elevated PAI-1 is a good predictor of T2DM independent of IR and other known risk factors.PubMedCrossRefGoogle Scholar
  17. 17.
    Libby P, Ridker P: Novel inflammatory markers of coronary risk: theory versus practice. Circulation 1999, 100:1148–1150.PubMedGoogle Scholar
  18. 18.
    Freeman DJ, Norrie J, Sattar N, et al.: Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 2001, 103:357–362.PubMedGoogle Scholar
  19. 19.
    Rosenson RS, Tangney CC, Casey LC: Inhibition of proinflammatory cytokine production by pravastatin. Lancet 1999, 353:983–984.PubMedCrossRefGoogle Scholar
  20. 20.
    Yusuf S, Gerstein H, Hoogwerf B, et al.: Ramipril and the development of diabetes. JAMA 2001, 286:1882–1885. Showed a 34% risk reduction for new-onset T2DM in the group treated with ramipril compared with placebo.PubMedCrossRefGoogle Scholar
  21. 21.
    Henriksen EJ, Jacob S, Kinnick TR, et al.: ACE inhibition and glucose transport in insulin resistant muscle: roles of bradykinin and nitric oxide. A J Physiol 1999, 277:R332-R336.Google Scholar
  22. 22.
    Torlone E, Rambotti AM, Perriello G, et al.: ACE-inhibition increases hepatic and extrahepatic sensitivity to insulin in patients with type 2 (non-insulin-dependent) diabetes mellitus and arterial hypertension. Diabetologia 1991, 34:119–125.PubMedCrossRefGoogle Scholar
  23. 23.
    Buchanan T, Xiang A, Peters R, et al.: Prevention of type 2 diabetes by treatment of insulin resistance: comparison of early vs. late intervention in the TRIPOD study. Diabetes 2002, 51(suppl 2):A35.Google Scholar
  24. 24.
    Chu JW, Abbasi F, Lamendola C, et al.: Rosiglitazone enhances insulin sensitivity and decreases cardiovascular risk factors in insulin-resistant subjects without diabetes mellitus. Diabetes 2002, 51(suppl 2):A137.Google Scholar
  25. 25.
    Konrad T, Vicini P, Kusterer K, et al.: alpha-lipoic acid treatment decreases serum lactate and pyruvate concentrations and improves glucose effectiveness in lean and obese type 2 diabetes. Diabetes Care 1999, 22:280–287.PubMedCrossRefGoogle Scholar
  26. 26.
    Yang Z, Chen M, Fialkow LB, et al.: Protection of cytokinemediated apoptosis in human pancreatic islets by lisofylline. Diabetes 2002, 51(suppl 2):A386.Google Scholar
  27. 27.
    Huang ES, Meigs JB, Singer DE: The effect of interventions to prevent cardiovascular disease in patient with type 2 diabetes mellitus. Am J Med 2001, 111:633–642.PubMedCrossRefGoogle Scholar
  28. 28.
    Khaw KT, Wareham N, Luben R, et al.: Glycated hemoglobin, diabetes, and mortality in men in Norfolk cohort of European Prospective Investigation of Cancer and Nutrition (EPIC-Norfolk). BMJ 2001, 322:1–6. Demonstrated that a lower value of hemoglobin A1c is associated with a lower CV risk even within the normal range for hemoglobin A1c.CrossRefGoogle Scholar
  29. 29.
    Pasceri V, Wilkerson JT, Yeh ET: Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 2000, 102:2165–2168.PubMedGoogle Scholar
  30. 30.
    Ridker PM: High sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 2001, 103:1813–1818.PubMedGoogle Scholar
  31. 31.
    Danesh J, Whincup P, Walker M, et al.: Low-grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ 2000, 321:199–204.PubMedCrossRefGoogle Scholar
  32. 32.
    Stehouwer C, Gall MA, Twisk JWR, et al.: Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: progressive, interrelated and independently associated with risk of death. Diabetes 2002, 51:1157–1165.PubMedCrossRefGoogle Scholar
  33. 33.
    Ridker PM, Hennekens CH, Buring JE, et al.: C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000, 342:836–843.PubMedCrossRefGoogle Scholar
  34. 34.
    Ridker PM: Physician's Health Study. Ann Intern Med 1999, 130:933–937.PubMedGoogle Scholar
  35. 35.
    Albert MA, Danielson E, Rifai N, et al.: Effect of statin therapy on C-reactive protein levels. The Pravastatin Inflammation/ CRP Evaluation (PRINCE): a randomized clinical trial and cohort study. JAMA 2001, 286:64–70. Found significant reductions in CRP during pravastatin treatment of patients with no prior history of CVD and LDL-C levels of at least 130 mg/dL; this effect was not significantly related to pravastatin-induced changes in LDL-C.PubMedCrossRefGoogle Scholar
  36. 36.
    Antonipillai A, Nadler J, Jost-Vu E, et al.: A 12-lipoxygenase product, 12-hydroxyeicosatetranoic acid is increased in diabetes with incipient and early renal disease. J Clin Endocrinol Metab 1996, 81:1940–1945.PubMedCrossRefGoogle Scholar
  37. 37.
    Hedrick CC, Kim MD, Natarajan R, Nadler JL: 12-lipoxygenase products increase monocyte:endothelial interactions. Adv Exp Med Biol 1999, 469:455–460.PubMedGoogle Scholar
  38. 38.
    Natarajan R, Gerrity RG, Gu JL, et al.: Role of 12-lipoxygenase and oxidant stress in hyperglycemia-induced acceleration of atherosclerosis in a diabetic pig model. Diabetologia 2002, 45:125–133.PubMedCrossRefGoogle Scholar
  39. 39.
    Chinetti G, Fruchart JC, Staels B: Peroxisome proliferatoractivated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm Res 2000, 49:497–505.PubMedCrossRefGoogle Scholar
  40. 40.
    Marx N, Kehrle B, Kohlhammer K, et al.: PPAR activators as anti-inflammatory mediators in human t lymphocytes. Implications for atherosclerosis and transplantationassociated atherosclerosis. Circ Res 2002, 90:703–710.PubMedCrossRefGoogle Scholar
  41. 41.
    Robins SJ: PPAR-alpha ligands and clinical trials: cardiovascular risk reduction with fibrates. J Cardiovasc Risk 2001, 4:203–210.Google Scholar
  42. 42.
    Collins AR, Meehan WP, Kintscher U, et al.: Troglitazone inhibits formation of early atherosclerotic lesions in diabetic and nondiabetic low density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol 2001, 21:365–371.PubMedGoogle Scholar
  43. 43.
    Rosenblatt S, Miskin B, Glazer NB, et al.: The impact of pioglitazone on glycemic control and atherogenic dyslipidemia in patients with type 2 diabetes mellitus. Coron Artery Dis 2001, 12:413–423.PubMedCrossRefGoogle Scholar
  44. 44.
    Caballero AE, Saquaf R, Lim SC, et al.: The effects of troglitazone on the endothelial function of the micro and macrocirculation in patients with early or late type 2 diabetes. Diabetes 2001, 50:A149.Google Scholar
  45. 45.
    Pasceri V, Chang J, Willerson JT, Yeh ETH: Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by antiatherosclerosis drugs. Circulation 2001, 103:2531–2534.PubMedGoogle Scholar
  46. 46.
    Goldberg RB, Mellies MJ, Sacks FM, et al.: Cardiovascular events and their reduction with pravastatin in diabetic and glucoseintolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the Cholesterol and Recurrent Events (CARE) trial. Circulation 1998, 98:2513–2519.PubMedGoogle Scholar
  47. 47.
    Ridker PM, Rifai N, Pfeffer MA, et al.: Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Circulation 1998, 98:839–844.PubMedGoogle Scholar
  48. 48.
    Downs JR, Clearfield M, Weis S, et al.: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998, 279:1615–1622.PubMedCrossRefGoogle Scholar
  49. 49.
    Shepard J, Cobb SM, Ford I, et al.: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995, 333:1301–1307.CrossRefGoogle Scholar
  50. 50.
    Schieffer B, Schieffer E, Hilfiker-Kleiner D, et al.: Expression of angiotensin ii and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability. Circulation 2000, 101:1372–1378.PubMedGoogle Scholar
  51. 51.
    Ruiz-Ortega M, Lorenzo O, Suzuki Y, et al.: Proinflammatory actions of angiotensins. Curr Opin Nephrol Hypertens 2001, 10:321–329. Discusses the molecular mechanisms by which angiotensin II contributes to the proinflammatory pathways involved in the development of atherosclerosis, hypertension, and renal damage.PubMedCrossRefGoogle Scholar
  52. 52.
    Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fraction. The SOLVD Investigators [no authors listed]. N Engl J Med 1992, 327:725-727.Google Scholar
  53. 53.
    Pfeffer M, Braunwald E, Moye L, et al.: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial. N Engl J Med 1992, 327:669–677.PubMedCrossRefGoogle Scholar
  54. 54.
    Effects of ramipril on cardiovascular and microvascular complications outcomes in people with diabetes mellitus: results of the HOPE Study and MICRO-HOPE Study. Heart Outcomes Prevention Evaluation Study Investigators [no authors listed]. Lancet 2000, 355:253-259.Demonstrated that ramipril treatment in patients with diabetes is associated with a reduction in CV events and mortality. This finding was only partially related to blood-pressure reduction, suggesting a direct vascular protective effect of ramipril.Google Scholar
  55. 55.
    Lonn E, Yusuf S, Dzavik V, et al.: Effects of ramipril and vitamin E on atherosclerosis: the Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Ramipril and Vitamin E (SECURE). Circulation 2001, 103:919–925.PubMedGoogle Scholar
  56. 56.
    Lindholm LH, Ibsen H, Dahlöf B, et al.: Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002, 359:1004–1010.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc. 2002

Authors and Affiliations

  • Milagros G. Huerta
    • 1
  • Jerry L. Nadler
    • 1
  1. 1.Division of Endocrinology and MetabolismUniversity of VirginiaCharlottesvilleUSA

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