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Inflammatory mechanisms of diabetic complications

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Abstract

Activation of inflammatory processes may contribute to the development of type 2 diabetes mellitus. In addition, inflammation appears to be a major mechanism responsible for vascular damage leading to the clinically well-recognized complications of diabetes. Inflammatory cytokine and chemokine mediators released from visceral fat contribute to atherosclerotic plaque formation and increased risk for myocardial infarction and stroke. Activation of growth factors and adhesion molecules may promote the movement of inflammatory cells into the renal microvasculature, predisposing to the development of diabetic nephropathy. Emerging evidence also indicates that markers of inflammation are associated with the more severe forms of diabetic retinopathy. Future approaches to the treatment of diabetic complications may involve regulation of inflammatory processes, specifically targeting factors that contribute to vascular damage.

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References and Recommended Reading

  1. Centers for Disease Control and Prevention: National Diabetes Fact Sheet: General Information and National Estimates on Diabetes in the United States, 2005. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2005.

    Google Scholar 

  2. Ogden CL, Carroll MD, Curtin LR, et al.: Prevalence of overweight and obesity in the United States, 1999–2004. JAMA 2006, 295:1549–1555.

    Article  PubMed  CAS  Google Scholar 

  3. Brownlee M: The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005, 54:1615–1625.

    Article  PubMed  CAS  Google Scholar 

  4. Rask-Madsen C, King G: Mechanisms of disease: endothelial dysfunction in insulin resistance and diabetes. Nat Clin Pract Endocrinol Metab 2007, 3:46–56.

    Article  PubMed  CAS  Google Scholar 

  5. Yan S, Yan S, Herold K, et al.: Receptor for advanced glycation end products and the cardiovascular complications of diabetes and beyond: lessons from AGEing. Endocrinol Metab Clin North Am 2006, 35:511–524.

    Article  PubMed  CAS  Google Scholar 

  6. 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.

    PubMed  CAS  Google Scholar 

  7. Yudkin JS, Stehouwer CDA, Emeis JJ, Coppack SW: C-Reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 1999, 19:972–978.

    PubMed  CAS  Google Scholar 

  8. Trujillo ME, Scherer PE: Adipose tissue-derived factors: impact on health and disease. Endocr Rev 2006, 27:762–778.

    PubMed  CAS  Google Scholar 

  9. Maedler K, Sergeev P, Ris F, et al.: Glucose-induced beta cell production of IL-1 beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest 2002, 110:851–860.

    Article  PubMed  CAS  Google Scholar 

  10. Robertson RP: Oxidative stress and impaired insulin secretion in type 2 diabetes. Curr Opin Pharmacol 2006, 6:615–619.

    Article  PubMed  CAS  Google Scholar 

  11. Kahn SE, Haffner SM, Heise MA, et al.: Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006, 355:2427–2443.

    Article  PubMed  CAS  Google Scholar 

  12. Cooper R, Cutler J, Desvigne-Nickens P, et al.: Trends and disparities in coronary heart disease, stroke, and other cardiovascular diseases in the United States: findings of the National Conference on Cardiovascular Disease Prevention. Circulation 2000, 102:3137–3147.

    PubMed  CAS  Google Scholar 

  13. Grundy SM, Benjamin IJ, Burke GL, et al.: Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 1999, 100:1134–1146.

    PubMed  CAS  Google Scholar 

  14. 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) Final Report [no authors listed]. Circulation 2002, 106:3143–3421.

  15. Boring L, Gosling J, Cleary M, Charo IF: Decreased lesion formation in CCR2-/-mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 1998, 394:894–897.

    Article  PubMed  CAS  Google Scholar 

  16. Min JK, Kim YM, Kim SW, et al.: TNF-related activation-induced cytokine enhances leukocyte adhesiveness: induction of ICAM-1 and VCAM-1 via TNF receptor-associated factor and protein kinase C-dependent NF-kappaB activation in endothelial cells. J Immunol 2005, 175:531–540.

    PubMed  CAS  Google Scholar 

  17. Berliner JA, Navab M, Fogelman AM, et al.: Atherosclerosis: basic mechanisms: oxidation, inflammation, and genetics. Circulation 1995, 91:2488–2496.

    PubMed  CAS  Google Scholar 

  18. Zhao L, Funk CD: Lipoxygenase pathways in atherogenesis. Trends Cardiovasc Med 2004, 14:191–195.

    Article  PubMed  CAS  Google Scholar 

  19. Funk CD: Lipoxygenase pathways as mediators of early inflammatory events in atherosclerosis. Arterioscler Thromb Vasc Biol 2006, 26:1204–1206.

    Article  PubMed  CAS  Google Scholar 

  20. Natarajan R, Nadler JL: Lipid inflammatory mediators in diabetic vascular disease. Arterioscler Thromb Vasc Biol 2004, 24:1542–1548.

    Article  PubMed  CAS  Google Scholar 

  21. Honda HM, Leitinger N, Frankel M, et al.: Induction of monocyte binding to endothelial cells by MM-LDL: role of lipoxygenase metabolites. Arterioscler Thromb Vasc Biol 1999, 19:680–686.

    PubMed  CAS  Google Scholar 

  22. Reddy MA, Thimmalapura PR, Lanting L, et al.: The oxidized lipid and lipoxygenase product 12(S)-hydroxyeicosatetraenoic acid induces hypertrophy and fibronectin transcription in vascular smooth muscle cells via p38 MAPK and cAMP response element-binding protein activation. mediation of angiotensin II effects. J Biol Chem 2002, 277:9920–9928.

    Article  PubMed  CAS  Google Scholar 

  23. Parthasarathy S, Wieland E, Steinberg D: A role for endothelial cell lipoxygenase in the oxidative modification of low density lipoprotein. Proc Natl Acad Sci U S A 1989, 86:1046–1050.

    Article  PubMed  CAS  Google Scholar 

  24. Pei H, Gu J, Thimmalapura PR, et al.: Activation of the 12-lipoxygenase and signal transducer and activator of transcription pathway during neointima formation in a model of the metabolic syndrome. Am J Physiol Endocrinol Metab 2006, 290:E92–E102.

    Article  PubMed  CAS  Google Scholar 

  25. George J, Afek A, Shaish A, et al.: 12/15-Lipoxygenase gene disruption attenuates atherogenesis in LDL receptor-deficient mice. Circulation 2001, 104:1646–1650.

    PubMed  CAS  Google Scholar 

  26. Huo Y, Zhao L, Hyman MC, et al.: Critical role of macrophage 12/15-lipoxygenase for atherosclerosis in apolipoprotein E-deficient mice. Circulation 2004, 110:2024–2031.

    Article  PubMed  CAS  Google Scholar 

  27. Reilly KB, Srinivasan S, Hatley ME, et al.: 12/15-Lipoxygenase activity mediates inflammatory monocyte/endothelial interactions and atherosclerosis in vivo. J Biol Chem 2004, 279:9440–9450.

    Article  PubMed  CAS  Google Scholar 

  28. Wen Y, Gu J, Li SL, et al.: Elevated glucose and diabetes promote interleukin-12 cytokine gene expression in mouse macrophages. Endocrinology 2006, 147:2518–2525.

    Article  PubMed  CAS  Google Scholar 

  29. Antonipillai I, Nadler J, Vu EJ, et al.: A 12-lipoxygenase product, 12-hydroxyeicosatetraenoic acid, is increased in diabetics with incipient and early renal disease. J Clin Endocrinol Metab 1996, 81:1940–1945.

    Article  PubMed  CAS  Google Scholar 

  30. Natarajan R, Gu J, Rossi J, et al.: Elevated glucose and angiotensin ii increase 12-lipoxygenase activity and expression in porcine aortic smooth muscle cells. Proc Natl Acad Sci U S A 1993, 90:4947–4951.

    Article  PubMed  CAS  Google Scholar 

  31. Patricia MK, Kim JA, Harper CM, et al.: Lipoxygenase products increase monocyte adhesion to human aortic endothelial cells. Arterioscler Thromb Vasc Biol 1999, 19:2615–2622.

    PubMed  CAS  Google Scholar 

  32. Chen M, Yang ZD, Smith KM, et al.: Activation of 12-lipoxygenase in proinflammatory cytokine-mediated beta cell toxicity. Diabetologia 2005, 48:486–495.

    Article  PubMed  CAS  Google Scholar 

  33. Weisberg SP, McCann D, Desai M, et al.: Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003, 112:1796–1808.

    Article  PubMed  CAS  Google Scholar 

  34. Cancello R, Henegar C, Viguerie N, et al.: Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 2005, 54:2277–2286.

    Article  PubMed  CAS  Google Scholar 

  35. Di Gregorio GB, Yao-Borengasser A, Rasouli N, et al.: Expression of CD68 and macrophage chemoattractant protein-1 genes in human adipose and muscle tissues: association with cytokine expression, insulin resistance, and reduction by pioglitazone. Diabetes 2005, 54:2305–2313.

    Article  PubMed  Google Scholar 

  36. Takahashi K, Mizuarai S, Araki H, et al.: Adiposity elevates plasma MCP-1 levels leading to the increased CD11b-positive monocytes in mice. J Biol Chem 2003, 278:46654–46660.

    Article  PubMed  CAS  Google Scholar 

  37. Kamei N, Tobe K, Suzuki R, et al.: Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem 2006, 281:26602–26614.

    Article  PubMed  CAS  Google Scholar 

  38. Sartipy P, Loskutoff DJ: Monocyte chemoattractant protein in obesity and insulin resistance. Proc Natl Acad Sci U S A 2003, 100:7265–7270.

    Article  PubMed  CAS  Google Scholar 

  39. de Lemos JA, Morrow DA, Sabatine MS, et al.: Association between plasma levels of monocyte chemoattractant protein-1 and long-term clinical outcomes in patients with acute coronary syndromes. Circulation 2003, 107:690–695.

    Article  PubMed  CAS  Google Scholar 

  40. Dwarakanath RS, Sahar S, Reddy MA, et al.: Regulation of monocyte chemoattractant protein-1 by the oxidized lipid, 13-hydroperoxyoctadecadienoic acid, in vascular smooth muscle cells via nuclear factor-kappa B (NF-kB). J Mol Cell Cardiol 2004, 36:585–595.

    Article  PubMed  CAS  Google Scholar 

  41. Nadler JL, Pei H, Bevard M, Bruce A: Reduced macrophage infiltration in visceral adipose tissue of 12-Lipoxygenase knockout mice. Paper presented at the Arteriosclerosis, Thrombosis and Vascular Biology Annual Conference 2007. Chicago, IL; April 19–21, 2007.

  42. Wen Y, Gu J, Chakrabarti SK, et al.: The role of 12/15-lipoxygenase in the expression of IL-6 and TNF-alpha in macrophages. Endocrinology 2007, 148:1313–1322.

    Article  PubMed  CAS  Google Scholar 

  43. Finne P, Reunanen A, Stenman S, et al.: Incidence of endstage renal disease in patients with type 1 diabetes. JAMA 2005, 294:1782–1787.

    Article  PubMed  CAS  Google Scholar 

  44. Hohenstein B, Hausknecht B, Boehmer K, et al.: Local VEGF activity but not VEGF expression is tightly regulated during diabetic nephropathy in man. Kidney Int 2006, 69:1654–1661.

    Article  PubMed  CAS  Google Scholar 

  45. Jandeleit-Dahm K, Cooper M: Hypertension and diabetes: role of the renin-angiotensin system. Endocrinol Metab Clin North Am 2006, 35:469–490.

    Article  PubMed  CAS  Google Scholar 

  46. Xu S, Jiang B, Maitland KA, et al.: The thromboxane receptor antagonist S18886 attenuates renal oxidant stress and proteinuria in diabetic apolipoprotein E-deficient mice. Diabetes 2006, 55:110–119.

    Article  PubMed  CAS  Google Scholar 

  47. Gomez-Garre D, Largo R, Tejera N, et al.: Activation of NF-kappaB in tubular epithelial cells of rats with intense proteinuria: role of angiotensin II and endothelin-1. Hypertension 2001, 37:1171–1178.

    PubMed  CAS  Google Scholar 

  48. Mezzano S, Aros C, Droguett A, et al.: NF-kappa B activation and overexpression of regulated genes in human diabetic nephropathy. Nephrol Dial Transplant 2004, 19:2505–2512.

    Article  PubMed  CAS  Google Scholar 

  49. Banba N, Nakamura T, Matsumura M, et al.: Possible relationship of monocyte chemoattractant protein-1 with diabetic nephropathy. Kidney Int 2000, 58:684–690.

    Article  PubMed  CAS  Google Scholar 

  50. Young B, Johnson R, Alpers C, et al.: Cellular events in the evolution of experimental diabetic nephropathy. Kidney Int 1995, 47:935–944.

    Article  PubMed  CAS  Google Scholar 

  51. Chow F, Ozols E, Nikolic-Paterson DJ, et al.: Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury. Kidney Int 2004, 65:116–128.

    Article  PubMed  CAS  Google Scholar 

  52. Coimbra TM, Janssen U, Grone HJ, et al.: Early events leading to renal injury in obese Zucker (fatty) rats with type II diabetes. Kidney Int 2000, 57:167–182.

    Article  PubMed  CAS  Google Scholar 

  53. Park CW, Kim JH, Lee JW, et al.: High glucose-induced intercellular adhesion molecule-1 (ICAM-1) expression through an osmotic effect in rat mesangial cells is PKC-NF-kappaB-dependent. Diabetologia 2000, 43:1544–1553.

    Article  PubMed  CAS  Google Scholar 

  54. Okouchi M, Okayama N, Shimizu M, et al.: High insulin exacerbates neutrophil-endothelial cell adhesion through endothelial surface expression of intercellular adhesion molecule-1 via activation of protein kinase C and mitogen-activated protein kinase. Diabetologia 2002, 45:556–559.

    Article  PubMed  CAS  Google Scholar 

  55. Yokoyama H, Takaeda M, Wada T, et al.: Glomerular ICAM-1 expression related to circulating TNF-alpha in human glomerulonephritis. Nephron 1997, 76:425–433.

    Article  PubMed  CAS  Google Scholar 

  56. Chow FY, Nikolic-Paterson DJ, Ozols E, et al.: Intercellular adhesion molecule-1 deficiency is protective against nephropathy in type 2 diabetic db/db mice. J Am Soc Nephrol 2005, 16:1711–1722.

    Article  PubMed  CAS  Google Scholar 

  57. Congdon NG, Friedman DS, Lietman T: Important causes of visual impairment in the world today. JAMA 2003, 290:2057–2060.

    Article  PubMed  CAS  Google Scholar 

  58. Frank RN: Diabetic retinopathy. N Engl J Med 2004, 350:48–58.

    Article  PubMed  CAS  Google Scholar 

  59. Nguyen TT, Wong TY: Retinal vascular manifestations of metabolic disorders. Trends Endocrinol Metab 2006, 17:262–268.

    Article  PubMed  CAS  Google Scholar 

  60. Orchard TJ, Dorman JS, Maser RE, et al.: Prevalence of complications in IDDM by sex and duration. Pittsburgh Epidemiology of Diabetes Complications Study II. Diabetes 1990, 39:1116–1124.

    Article  PubMed  CAS  Google Scholar 

  61. Wong TY, Klein R, Sharrett AR, et al.: Retinal arteriolar narrowing and risk of coronary heart disease in men and women: the Atherosclerosis Risk in Communities Study. JAMA 2002, 287:1153–1159.

    Article  PubMed  Google Scholar 

  62. Wong TY, Shankar A, Klein R, et al.: Prospective cohort study of retinal vessel diameters and risk of hypertension. BMJ 2004, 329:79.

    Article  PubMed  Google Scholar 

  63. Wong TY, Klein R, Sharrett AR, et al.: Retinal arteriolar narrowing and risk of diabetes mellitus in middle-aged persons. JAMA 2002, 287:2528–2533.

    Article  PubMed  Google Scholar 

  64. Ikram MK, de Jong FJ, Vingerling JR, et al.: Are retinal arteriolar or venular diameters associated with markers for cardiovascular disorders? The Rotterdam Study. Invest Ophthalmol Vis Sci 2004, 45:2129–2134.

    Article  PubMed  Google Scholar 

  65. Klein R, Klein BEK, Knudtson MD, et al.: Are inflammatory factors related to retinal vessel caliber? The Beaver Dam Eye Study. Arch Ophthalmol 2006, 124:87–94.

    Article  PubMed  Google Scholar 

  66. Demircan N, Safran B, Soylu M, et al.: Determination of vitreous interleukin-1 (IL-1) and tumour necrosis factor (TNF) levels in proliferative diabetic retinopathy. Eye 2006, 20:1366–1369.

    Article  PubMed  CAS  Google Scholar 

  67. Meleth AD, Agron E, Chan CC, et al.: Serum inflammatory markers in diabetic retinopathy. Invest Ophthalmol Vis Sci 2005, 46:4295–4301.

    Article  PubMed  Google Scholar 

  68. Joussen AM, Poulaki V, Le ML, et al.: A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB J 2004, 18:1450–1452.

    PubMed  CAS  Google Scholar 

  69. Natarajan R, Bai W, Lanting L, et al.: Effects of high glucose on vascular endothelial growth factor expression in vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 1997, 273:H2224–H2231.

    CAS  Google Scholar 

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  1. Division of Endocrinology and Metabolism, University of Virginia, P.O. Box 801405, 450 Ray C. Hunt Drive, Room 1220, Charlottesville, VA, 22908-1405, USA

    Michael D. Williams MD

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  1. Michael D. Williams MD
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  2. Jerry L. Nadler MD
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Correspondence to Michael D. Williams MD.

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Williams, M.D., Nadler, J.L. Inflammatory mechanisms of diabetic complications. Curr Diab Rep 7, 242–248 (2007). https://doi.org/10.1007/s11892-007-0038-y

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