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Introduction of hyperglycemia and dyslipidemia in the pathogenesis of diabetic vascular complications

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Abstract

Hyperglycemia and dyslipidemia are significant and independent risk factors for the vascular complications in patients with diabetes. They have been suggested to cause cardiovascular pathologic changes in diabetic states through the following molecular mechanisms: formation and accumulation of advanced glycation end products; increased oxidative stress; activation of protein kinase C pathway; increased activity of hexosamine pathway; and vascular inflammation and the impairment of insulin action in the vascular tissues.

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References and Recommended Reading

  1. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group [no authors listed]. N Engl J Med 1993, 329:977–986.

  2. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group [no authors listed]. Lancet 1998, 352:837–853.

  3. Nathan DM, Lachin J, Cleary P, et al.: Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med 2003, 348:2294–2303.

    Article  PubMed  Google Scholar 

  4. Renard CB, Kramer F, Johansson F, et al.: Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions. J Clin Invest 2004, 114:659–668.

    Article  PubMed  CAS  Google Scholar 

  5. Park L, Raman KG, Lee KJ, et al.: Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation end products. Nat Med 1998, 4:1025–1031.

    Article  PubMed  CAS  Google Scholar 

  6. Goldberg RB, Capuzzi D: Lipid disorders in type 1 and type 2 diabetes. Clin Lab Med 2001, 21:147–72, vii.

    PubMed  CAS  Google Scholar 

  7. Beckman JA, Creager MA, Libby P: Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 2002, 287:2570–2581.

    Article  PubMed  CAS  Google Scholar 

  8. Krolewski AS, Kosinski EJ, Warram JH, et al.: Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus. Am J Cardiol 1987, 59:750–755.

    Article  PubMed  CAS  Google Scholar 

  9. Garg A: Management of dyslipidemia in IDDM patients. Diabetes Care 1994, 17:224–234.

    Article  PubMed  CAS  Google Scholar 

  10. Larsson LI, Alm A, Lithner F, et al.: The association of hyperlipidemia with retinopathy in diabetic patients aged 15–50 years in the county of Umea. Acta Ophthalmol Scand 1999, 77:585–591.

    Article  PubMed  CAS  Google Scholar 

  11. Jenkins AJ, Lyons TJ, Zheng D, et al.: Lipoproteins in the DCCT/EDIC cohort: associations with diabetic nephropathy. Kidney Int 2003, 64:817–828.

    Article  PubMed  CAS  Google Scholar 

  12. Tarnow L, Rossing P, Nielsen FS, et al.: Increased plasma apolipoprotein (a) levels in IDDM patients with diabetic nephropathy. Diabetes Care 1996, 19:1382–1387.

    Article  PubMed  CAS  Google Scholar 

  13. Kozek E, Gorska A, Fross K, et al.: Chronic complications and risk factors in patients with type 1 diabetes mellitus—retrospective analysis [in Polish]. Przegl Lek 2003, 60:773–777.

    PubMed  Google Scholar 

  14. Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature 2001, 414:813–820. Describes four major molecular mechanisms that have recently been proposed in glucose-mediated vascular damages, including oxidative stress, activation of PKC, hexosamine pathway, and AGE formation.

    Article  PubMed  CAS  Google Scholar 

  15. He Z, Rask-Madesen C, King GL: Pathogenesis of diabetic microvascular complications. In International Textbook of Diabetes Mellitus, edn 3, vol 2. Edited by De Fronzo R, et al. John Wiley & Sons; 2004:1135–1159. Illustrates the pathologic changes of macro- and microvascular diseases in diabetes and their possible mechanisms.

  16. He Z, King GL: Microvascular complications of diabetes. Endocrinol Metab Clin North Am 2004, 33:215-xii. Introduces the possible mechanisms involved in the pathogenesis of diabetic vascular complications.

    Article  PubMed  CAS  Google Scholar 

  17. Rask-Madsen C, He Z, King GL: Mechanisms of diabetic microvascular complications. In Joslin's Diabetes Mellitus. Edited by Kahn RC, et al. Philadelphia, PA: Lippincott, Williams & Wilkins; 2004:823–837. Presents the potential mechanisms contributing to the pathogenesis of diabetic microvascular complications.

    Google Scholar 

  18. Yegin A, Ozben T, Yegin H: Glycation of lipoproteins and accelerated atherosclerosis in non-insulin-dependent diabetes mellitus. Int J Clin Lab Res 1995, 25:157–161.

    Article  PubMed  CAS  Google Scholar 

  19. Numano F, Tanaka A, Makita T, et al.: Glycated lipoprotein and atherosclerosis. Ann N Y Acad Sci 1997, 811:100–113.

    Article  PubMed  CAS  Google Scholar 

  20. Shen GX: Impact and mechanism for oxidized and glycated lipoproteins on generation of fibrinolytic regulators from vascular endothelial cells. Mol Cell Biochem 2003, 246:69–74.

    Article  PubMed  CAS  Google Scholar 

  21. Januszewski AS, Alderson NL, Metz TO, et al.: Role of lipids in chemical modification of proteins and development of complications in diabetes. Biochem Soc Trans 2003, 31:1413–1416.

    Article  PubMed  CAS  Google Scholar 

  22. Yan SF, Ramasamy R, Naka Y, et al.: Glycation, inflammation, and RAGE: a scaffold for the macrovascular complications of diabetes and beyond. Circ Res 2003, 93:1159–1169.

    Article  PubMed  CAS  Google Scholar 

  23. Bucala R, Makita Z, Vega G, et al.: Modification of low density lipoprotein by advanced glycation end products contributes to the dyslipidemia of diabetes and renal insufficiency. Proc Natl Acad Sci U S A 1994, 91:9441–9445.

    Article  PubMed  CAS  Google Scholar 

  24. Basta G, Schmidt AM, De Caterina R: Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res 2004, 63:582–592.

    Article  PubMed  CAS  Google Scholar 

  25. Soulis-Liparota T, Cooper M, Papazoglou D, et al.: Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocininduced diabetic rat. Diabetes 1991, 40:1328–1334.

    Article  PubMed  CAS  Google Scholar 

  26. Hammes HP, Martin S, Federlin K, et al.: Aminoguanidine treatment inhibits the development of experimental diabetic retinopathy. Proc Natl Acad Sci U S A 1991, 88:11555–11558.

    Article  PubMed  CAS  Google Scholar 

  27. Cooper ME: Importance of advanced glycation end products in diabetes-associated cardiovascular and renal disease. Am J Hypertens 2004, 17:31S-38S.

    Article  PubMed  CAS  Google Scholar 

  28. Goova MT, Li J, Kislinger T, et al.: Blockade of receptor for advanced glycation end-products restores effective wound healing in diabetic mice. Am J Pathol 2001, 159:513–525.

    PubMed  CAS  Google Scholar 

  29. Wendt TM, Tanji N, Guo J, et al.: RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol 2003, 162:1123–1137.

    PubMed  CAS  Google Scholar 

  30. Kuroki T, Isshiki K, King GL: Oxidative stress: the lead or supporting actor in the pathogenesis of diabetic complications. J Am Soc Nephrol 2003, 14:S216-S220.

    Article  PubMed  CAS  Google Scholar 

  31. Lee IK, Kim HS, Bae JH: Endothelial dysfunction: its relationship with acute hyperglycaemia and hyperlipidemia. Int J Clin Pract Suppl 2002, 129:59–64.

    PubMed  Google Scholar 

  32. Maytin M, Leopold J, Loscalzo J: Oxidant stress in the vasculature. Curr Atheroscler Rep 1999, 1:156–164.

    PubMed  CAS  Google Scholar 

  33. Erciyas F, Taneli F, Arslan B, et al.: Glycemic control, oxidative stress, and lipid profile in children with type 1 diabetes mellitus. Arch Med Res 2004, 35:134–140.

    Article  PubMed  CAS  Google Scholar 

  34. Flores L, Rodela S, Abian J, et al.: F2 isoprostane is already increased at the onset of type 1 diabetes mellitus: effect of glycemic control. Metabolism 2004, 53:1118–1120.

    Article  PubMed  CAS  Google Scholar 

  35. Zhang Z, Apse K, Pang J, Stanton RC: High glucose inhibits glucose-6-phosphate dehydrogenase via cAMP in aortic endothelial cells. J Biol Chem 2000, 275:40042–40047.

    Article  PubMed  CAS  Google Scholar 

  36. Giugliano D, Ceriello A, Paolisso G: Oxidative stress and diabetic vascular complications. Diabetes Care 1996, 19:257–267.

    Article  PubMed  CAS  Google Scholar 

  37. Baynes JW, Thorpe SR: Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 1999, 48:1–9.

    Article  PubMed  CAS  Google Scholar 

  38. Yusuf S, Dagenais G, Pogue J, et al.: Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000, 342:154–160.

    Article  PubMed  CAS  Google Scholar 

  39. Lonn E, Yusuf S, Hoogwerf B, et al.: Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes: results of the HOPE study and MICRO-HOPE substudy. Diabetes Care 2002, 25:1919–1927.

    Article  PubMed  CAS  Google Scholar 

  40. Rask-Madsen C, King GL: Proatherosclerotic mechanisms involving protein kinase C in diabetes and insulin resistance. Arterioscler Thromb Vasc Biol 2005, Jan 6; [Epub ahead of print]. Describes proatherosclerostic mechanisms that PKC is involved in diabetes and insulin resistance.

  41. Way KJ, Katai N, King GL: Protein kinase C and the development of diabetic vascular complications. Diabet Med 2001, 18:945–959.

    Article  PubMed  CAS  Google Scholar 

  42. Way KJ, Chou E, King GL: Identification of PKC-isoform-specific biological actions using pharmacological approaches. Trends Pharmacol Sci 2000, 21:181–187.

    Article  PubMed  CAS  Google Scholar 

  43. Sheetz MJ, King GL: Molecular understanding of hyperglycemia's adverse effects for diabetic complications. JAMA 2002, 288:2579–2588.

    Article  PubMed  CAS  Google Scholar 

  44. Aiello LP, Bursell SE, Clermont A, et al.: Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor. Diabetes 1997, 46:1473–1480.

    Article  PubMed  CAS  Google Scholar 

  45. Koya D, Haneda M, Kikkawa R, et al.: d-alpha-tocopherol treatment prevents glomerular dysfunctions in diabetic rats through inhibition of protein kinase C-diacylglycerol pathway. Biofactors 1998, 7:69–76.

    PubMed  CAS  Google Scholar 

  46. Koya D, Haneda M, Nakagawa H, et al.: Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. FASEB J 2000, 14:439–447.

    PubMed  CAS  Google Scholar 

  47. Kim H, Sasaki T, Maeda K, et al.: Protein kinase C-beta selective inhibitor LY333531 attenuates diabetic hyperalgesia through ameliorating cGMP level of dorsal root ganglion neurons. Diabetes 2003, 52:2102–2109.

    Article  PubMed  CAS  Google Scholar 

  48. Nakamura J, Kato K, Hamada Y, et al.: A protein kinase C-betaselective inhibitor ameliorates neural dysfunction in streptozotocin-induced diabetic rats. Diabetes 1999, 48:2090–2095.

    Article  PubMed  CAS  Google Scholar 

  49. Marshall S, Bacote V, Traxinger RR: Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance. J Biol Chem 1991, 266:4706–4712.

    PubMed  CAS  Google Scholar 

  50. Hawkins M, Barzilai N, Liu R, et al.: Role of the glucosamine pathway in fat-induced insulin resistance. J Clin Invest 1997, 99:2173–2182.

    PubMed  CAS  Google Scholar 

  51. Daniels MC, Ciaraldi TP, Nikoulina S, et al.: Glutamine:fructose-6-phosphate amidotransferase activity in cultured human skeletal muscle cells: relationship to glucose disposal rate in control and non-insulin-dependent diabetes mellitus subjects and regulation by glucose and insulin. J Clin Invest 1996, 97:1235–1241.

    Article  PubMed  CAS  Google Scholar 

  52. Buse MG, Robinson KA, Gettys TW, et al.: Increased activity of the hexosamine synthesis pathway in muscles of insulinresistant ob/ob mice. Am J Physiol 1997, 272:E1080-E1088.

    PubMed  CAS  Google Scholar 

  53. Yki-Jarvinen H, Daniels MC, Virkamaki A, et al.: Increased glutamine:fructose-6-phosphate amidotransferase activity in skeletal muscle of patients with NIDDM. Diabetes 1996, 45:302–307.

    Article  PubMed  CAS  Google Scholar 

  54. Akimoto Y, Kreppel LK, Hirano H, et al.: Increased O-GlcNAc transferase in pancreas of rats with streptozotocin-induced diabetes. Diabetologia 2000, 43:1239–1247.

    Article  PubMed  CAS  Google Scholar 

  55. Nerlich AG, Sauer U, Kolm-Litty V, et al.: Expression of glutamine:fructose-6-phosphate amidotransferase in human tissues: evidence for high variability and distinct regulation in diabetes. Diabetes 1998, 47:170–178.

    Article  PubMed  CAS  Google Scholar 

  56. James LR, Tang D, Ingram A, et al.: Flux through the hexosamine pathway is a determinant of nuclear factor kappaB-dependent promoter activation. Diabetes 2002, 51:1146–1156.

    Article  PubMed  CAS  Google Scholar 

  57. Kolm-Litty V, Sauer U, Nerlich A, et al.: High glucose-induced transforming growth factor beta1 production is mediated by the hexosamine pathway in porcine glomerular mesangial cells. J Clin Invest 1998, 101:160–169.

    PubMed  CAS  Google Scholar 

  58. Burt DJ, Gruden G, Thomas SM, et al.: P38 mitogen-activated protein kinase mediates hexosamine-induced TGFbeta1 mRNA expression in human mesangial cells. Diabetologia 2003, 46:531–537.

    PubMed  CAS  Google Scholar 

  59. Du XL, Edelstein D, Dimmeler S, et al.: Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest 2001, 108:1341–1348.

    Article  PubMed  CAS  Google Scholar 

  60. Federici M, Menghini R, Mauriello A, et al.: Insulindependent activation of endothelial nitric oxide synthase is impaired by O-linked glycosylation modification of signaling proteins in human coronary endothelial cells. Circulation 2002, 106:466–472.

    Article  PubMed  CAS  Google Scholar 

  61. Hammes HP, Du X, Edelstein D, et al.: Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 2003, 9:294–299.

    Article  PubMed  CAS  Google Scholar 

  62. Dandona P: Endothelium, inflammation, and diabetes. Curr Diab Rep 2002, 2:311–315.

    PubMed  Google Scholar 

  63. Schram MT, Chaturvedi N, Schalkwijk C, et al.: Vascular risk factors and markers of endothelial function as determinants of inflammatory markers in type 1 diabetes: the EURODIAB Prospective Complications Study. Diabetes Care 2003, 26:2165–2173.

    Article  PubMed  Google Scholar 

  64. Ben Mahmud BM, Mann GE, Datti A, et al.: Tumor necrosis factor-alpha in diabetic plasma increases the activity of core 2 GlcNAc-T and adherence of human leukocytes to retinal endothelial cells: significance of core 2 GlcNAc-T in diabetic retinopathy. Diabetes 2004, 53:2968–2976.

    Article  Google Scholar 

  65. Doganay S, Evereklioglu C, Er H, et al.: Comparison of serum NO, TNF-alpha, IL-1beta, sIL-2R, IL-6 and IL-8 levels with grades of retinopathy in patients with diabetes mellitus. Eye 2002, 16:163–170.

    Article  PubMed  CAS  Google Scholar 

  66. Limb GA, Chignell AH, Green W, et al.: Distribution of TNF alpha and its reactive vascular adhesion molecules in fibrovascular membranes of proliferative diabetic retinopathy. Br J Ophthalmol 1996, 80:168–173.

    PubMed  CAS  Google Scholar 

  67. Limb GA, Soomro H, Janikoun S, et al.: Evidence for control of tumour necrosis factor-alpha (TNF-alpha) activity by TNF receptors in patients with proliferative diabetic retinopathy. Clin Exp Immunol 1999, 115:409–414.

    Article  PubMed  CAS  Google Scholar 

  68. Cybulsky MI, Gimbrone MA Jr: Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 1991, 251:788–791.

    Article  PubMed  CAS  Google Scholar 

  69. Jager A, van Hinsbergh VW, Kostense PJ, et al.: Increased levels of soluble vascular cell adhesion molecule 1 are associated with risk of cardiovascular mortality in type 2 diabetes: the Hoorn study. Diabetes 2000, 49:485–491.

    Article  PubMed  CAS  Google Scholar 

  70. Dardik R, Varon D, Tamarin I, et al.: Homocysteine and oxidized low density lipoprotein enhanced platelet adhesion to endothelial cells under flow conditions: distinct mechanisms of thrombogenic modulation. Thromb Haemost 2000, 83:338–344.

    PubMed  CAS  Google Scholar 

  71. Cosentino F, Eto M, De Paolis P, et al.: High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species. Circulation 2003, 107:1017–1023.

    Article  PubMed  CAS  Google Scholar 

  72. Pickup JC: Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 2004, 27:813–823.

    Article  PubMed  Google Scholar 

  73. Kislinger T, Fu C, Huber B, et al.: N(epsilon)-(carboxymethyl) lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. J Biol Chem 1999, 274:31740–31749.

    Article  PubMed  CAS  Google Scholar 

  74. Hofmann MA, Drury S, Hudson BI, et al.: RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response. Genes Immun 2002, 3:123–135.

    Article  PubMed  CAS  Google Scholar 

  75. Yan SS, Wu ZY, Zhang HP, et al.: Suppression of experimental autoimmune encephalomyelitis by selective blockade of encephalitogenic T-cell infiltration of the central nervous system. Nat Med 2003, 9:287–293.

    Article  PubMed  CAS  Google Scholar 

  76. Medzhitov R, Janeway CJr: Innate immunity. N Engl J Med 2000, 343:338–344.

    Article  PubMed  CAS  Google Scholar 

  77. Pickup JC, Crook MA: Is type II diabetes mellitus a disease of the innate immune system? Diabetologia 1998, 41:1241–1248.

    Article  PubMed  CAS  Google Scholar 

  78. Pickup JC, Mattock MB: Activation of the innate immune system as a predictor of cardiovascular mortality in type 2 diabetes mellitus. Diabet Med 2003, 20:723–726.

    Article  PubMed  CAS  Google Scholar 

  79. Mather K, Anderson TJ, Verma S: Insulin action in the vasculature: physiology and pathophysiology. J Vasc Res 2001, 38:415–422.

    Article  PubMed  CAS  Google Scholar 

  80. Kuboki K, Jiang ZY, Takahara N, et al.: Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo: a specific vascular action of insulin. Circulation 2000, 101:676–681.

    PubMed  CAS  Google Scholar 

  81. Montagnani M, Chen H, Barr VA, et al.: Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser(1179). J Biol Chem 2001, 276:30392–30398.

    Article  PubMed  CAS  Google Scholar 

  82. Federici M, Pandolfi A, De Filippis EA, et al.: G972R IRS-1 variant impairs insulin regulation of endothelial nitric oxide synthase in cultured human endothelial cells. Circulation 2004, 109:399–405.

    Article  PubMed  CAS  Google Scholar 

  83. Vicent D, Ilany J, Kondo T, et al.: The role of endothelial insulin signaling in the regulation of vascular tone and insulin resistance. J Clin Invest 2003, 111:1373–1380.

    Article  PubMed  CAS  Google Scholar 

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  1. Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Room 4504, 02215, Boston, MA, USA

    George L. King MD

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  1. Yizhen Xu MD, PhD
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Xu, Y., He, Z. & King, G.L. Introduction of hyperglycemia and dyslipidemia in the pathogenesis of diabetic vascular complications. Curr Diab Rep 5, 91–97 (2005). https://doi.org/10.1007/s11892-005-0034-z

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