Vascular Complications in Diabetes

  • Louise L. DunnEmail author
  • Kim Hoe Chan
  • Martin K. C. Ng
  • Roland Stocker


The vascular complications of diabetes mellitus are accountable for significant morbidity and mortality of the disease worldwide. A striking feature of diabetes is the heterogeneity in the dysregulation of angiogenesis. Excessive and disordered angiogenesis predominate in microvessels, leading to retinopathy and nephropathy. Insufficient neovascularization features heavily in the diabetic wound. This is aggravated by neuropathy and poor nutritive blood flow due to peripheral vascular disease. These complications can converge leading to amputation. Failure of neovascularization or collateralization in atheroocclusive diseased macrovessels can precipitate myocardial infarction and stroke. In this chapter, the features and mechanisms underlying the various vascular complications associated with diabetes will be reviewed.


Diabetes mellitus Angiogenesis Neovascularization Diabetic vasculopathies 



Advanced glycation end products


Coronary artery disease




Endothelial nitric oxide synthase


Endothelial progenitor cell


Mitogen activated protein kinase


Peripheral artery disease


Protein kinase C


Receptor for advanced glycation end products


Type 1 diabetes mellitus


Type 2 diabetes mellitus


Vascular endothelial growth factor




A global term used to define the growth of new blood vessels from pre-existing ones


An adaptive process referring to the growth and widening of existing blood vessels to increase blood flow to inadequately served vascular beds

Carbonyl stress

An increase in reactive carbonyl species

Endothelial dysfunction

The inability of blood vessels to appropriately dilate as a result of decreased bioavailability of nitric oxide


Inadequate oxygen supply


Insufficient blood supply to an organ


The process of new blood vessel growth in response to stress, injury or disease such as ischemia, tissue damage and cancer


Disease of the nephrons within the kidney


Diseases of the nerves

Oxidative stress

A net increased in reactive oxygen species


Disease of the retina within the eye

Type 1 diabetes mellitus

A disease characterized by high blood glucose levels due to the destruction of insulin secreting pancreatic beta cells that is responsible for ~10 % diabetes cases

Type 2 diabetes mellitus

A disease characterized by high blood glucose levels, elevated insulin levels, and tissue resistance to insulin, which is responsible for ~90 % of diabetes cases

Vascular tone

The ability of blood vessels to dilate and constrict


De novo production of new endothelial cells and blood vessels, a process in which EPC are involved.


  1. 1.
    WHO (2011) The top 10 causes of death | Fact sheet No. 310. World Health Organization. Accessed 12 Aug 2013
  2. 2.
    UKPDS (1998) 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. Lancet 352:837–853CrossRefGoogle Scholar
  3. 3.
    Holman RR, Paul SK, Bethel MA et al (2008) 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359:1577–1589PubMedCrossRefGoogle Scholar
  4. 4.
    Nathan DM, Cleary PA, Backlund JY et al (2005) Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 353:2643–2653PubMedCrossRefGoogle Scholar
  5. 5.
    Patel A, MacMahon S, Chalmers J et al (2008) Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358:2560–2572PubMedCrossRefGoogle Scholar
  6. 6.
    Shichiri M, Kishikawa H, Ohkubo Y et al (2000) Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 23(Suppl 2):B21–B29PubMedGoogle Scholar
  7. 7.
    Stratton IM, Adler AI, Neil HA et al (2000) Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321:405–412PubMedCrossRefGoogle Scholar
  8. 8.
    UKPDS (1998) 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. Lancet 352:854–865CrossRefGoogle Scholar
  9. 9.
    Schalkwijk CG, Stehouwer CD (2005) Vascular complications in diabetes mellitus: the role of endothelial dysfunction. Clin Sci (Lond) 109:143–159CrossRefGoogle Scholar
  10. 10.
    Le Brocq M, Leslie SJ, Milliken P et al (2008) Endothelial dysfunction: from molecular mechanisms to measurement, clinical implications, and therapeutic opportunities. Antioxid Redox Signal 10:1631–1674PubMedCrossRefGoogle Scholar
  11. 11.
    Kolluru GK, Bir SC, Kevil CG (2012) Endothelial dysfunction and diabetes: effects on angiogenesis, vascular remodeling, and wound healing. Int J Vasc Med 2012(918267):1–30CrossRefGoogle Scholar
  12. 12.
    Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54:1615–1625PubMedCrossRefGoogle Scholar
  13. 13.
    Baynes JW, Thorpe SR (1999) Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48:1–9PubMedCrossRefGoogle Scholar
  14. 14.
    Baynes JW (1991) Role of oxidative stress in development of complications in diabetes. Diabetes 40:405–412PubMedCrossRefGoogle Scholar
  15. 15.
    Brownlee M, Cerami A, Vlassara H (1988) Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 318:1315–1321PubMedCrossRefGoogle Scholar
  16. 16.
    Ramasamy R, Yan SF, Schmidt AM (2011) Receptor for AGE (RAGE): signaling mechanisms in the pathogenesis of diabetes and its complications. Ann N Y Acad Sci 1243:88–102PubMedCrossRefGoogle Scholar
  17. 17.
    Farmer DG, Kennedy S (2009) RAGE, vascular tone and vascular disease. Pharmacol Ther 124:185–194PubMedCrossRefGoogle Scholar
  18. 18.
    Klein RL, Laimins M, Lopes-Virella MF (1995) Isolation, characterization, and metabolism of the glycated and nonglycated subfractions of low-density lipoproteins isolated from type I diabetic patients and nondiabetic subjects. Diabetes 44:1093–1098PubMedCrossRefGoogle Scholar
  19. 19.
    Kawamura N, Ookawara T, Suzuki K et al (1992) Increased glycated Cu, Zn-superoxide dismutase levels in erythrocytes of patients with insulin-dependent diabetis mellitus. J Clin Endocrinol Metab 74:1352–1354PubMedGoogle Scholar
  20. 20.
    Morgan PE, Dean RT, Davies MJ (2002) Inactivation of cellular enzymes by carbonyls and protein-bound glycation/glycoxidation products. Arch Biochem Biophys 403:259–269PubMedCrossRefGoogle Scholar
  21. 21.
    Kathir K, Dennis JM, Croft KD et al (2010) Equivalent lipid oxidation profiles in advanced atherosclerotic lesions of carotid endarterectomy plaques obtained from symptomatic type 2 diabetic and nondiabetic subjects. Free Radic Biol Med 49:481–486PubMedCrossRefGoogle Scholar
  22. 22.
    Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438:932–936PubMedCrossRefGoogle Scholar
  23. 23.
    Asahara T, Murohara T, Sullivan A et al (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967PubMedCrossRefGoogle Scholar
  24. 24.
    Chen YH, Lin SJ, Lin FY et al (2007) High glucose impairs early and late endothelial progenitor cells by modifying nitric oxide-related but not oxidative stress-mediated mechanisms. Diabetes 56:1559–1568PubMedCrossRefGoogle Scholar
  25. 25.
    Waltenberger J (2001) Impaired collateral vessel development in diabetes: potential cellular mechanisms and therapeutic implications. Cardiovasc Res 49:554–560PubMedCrossRefGoogle Scholar
  26. 26.
    Gallagher KA, Liu ZJ, Xiao M et al (2007) Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1 alpha. J Clin Invest 117:1249–1259PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Liu ZJ, Velazquez OC (2008) Hyperoxia, endothelial progenitor cell mobilization, and diabetic wound healing. Antioxid Redox Signal 10:1869–1882PubMedCrossRefGoogle Scholar
  28. 28.
    Resnikoff S, Pascolini D, Etya’ale D et al (2004) Global data on visual impairment in the year 2002. Bull World Health Organ 82:844–851PubMedCentralPubMedGoogle Scholar
  29. 29.
    Henricsson M, Nilsson A, Janzon L et al (1997) The effect of glycaemic control and the introduction of insulin therapy on retinopathy in non-insulin-dependent diabetes mellitus. Diabet Med 14:123–131PubMedCrossRefGoogle Scholar
  30. 30.
    Schrier RW, Estacio RO, Esler A et al (2002) Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int 61:1086–1097PubMedCrossRefGoogle Scholar
  31. 31.
    UKPDS (1998) Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 317:703–713CrossRefGoogle Scholar
  32. 32.
    Keech AC, Mitchell P, Summanen PA et al (2007) Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 370:1687–1697PubMedCrossRefGoogle Scholar
  33. 33.
    Garner A (1993) Histopathology of diabetic retinopathy in man. Eye (Lond) 7:250–253CrossRefGoogle Scholar
  34. 34.
    Cai J, Boulton M (2002) The pathogenesis of diabetic retinopathy: old concepts and new questions. Eye (Lond) 16:242–260CrossRefGoogle Scholar
  35. 35.
    Dokken BB (2008) The pathophysiology of cardiovascular disease and diabetes: beyond blood pressure and lipids. Diabetes Spectr 2008:160–165CrossRefGoogle Scholar
  36. 36.
    Lorenzi M (2007) The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient. Exp Diabetes Res 2007(61038):1–10CrossRefGoogle Scholar
  37. 37.
    Tang WH, Martin KA, Hwa J (2012) Aldose reductase, oxidative stress, and diabetic mellitus. Front Pharmacol 3:1–8CrossRefGoogle Scholar
  38. 38.
    Williamson JR, Chang K, Frangos M et al (1993) Hyperglycemic pseudohypoxia and diabetic complications. Diabetes 42:801–813PubMedCrossRefGoogle Scholar
  39. 39.
    Goldin A, Beckman JA, Schmidt AM et al (2006) Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation 114:597–605PubMedCrossRefGoogle Scholar
  40. 40.
    Behl Y, Krothapalli P, Desta T et al (2008) Diabetes-enhanced tumor necrosis factor-alpha production promotes apoptosis and the loss of retinal microvascular cells in type 1 and type 2 models of diabetic retinopathy. Am J Pathol 172:1411–1418PubMedCrossRefGoogle Scholar
  41. 41.
    Antonetti DA, Barber AJ, Bronson SK et al (2006) Diabetic retinopathy: seeing beyond glucose-induced microvascular disease. Diabetes 55:2401–2411PubMedCrossRefGoogle Scholar
  42. 42.
    Lu M, Perez VL, Ma N et al (1999) VEGF increases retinal vascular ICAM-1 expression in vivo. Invest Ophthalmol Vis Sci 40:1808–1812PubMedGoogle Scholar
  43. 43.
    Miyamoto K, Khosrof S, Bursell SE et al (1999) Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. Proc Natl Acad Sci USA 96:10836–10841PubMedCrossRefGoogle Scholar
  44. 44.
    Vinores SA, Xiao WH, Shen J et al (2007) TNF-alpha is critical for ischemia-induced leukostasis, but not retinal neovascularization nor VEGF-induced leakage. J Neuroimmunol 182:73–79PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Xia P, Aiello LP, Ishii H et al (1996) Characterization of vascular endothelial growth factor’s effect on the activation of protein kinase C, its isoforms, and endothelial cell growth. J Clin Invest 98:2018–2026PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Ting RD, Keech AC, Drury PL et al (2012) Benefits and safety of long-term fenofibrate therapy in people with type 2 diabetes and renal impairment: the FIELD Study. Diabetes Care 35:218–225PubMedCrossRefGoogle Scholar
  47. 47.
    Saito A, Takeda T, Sato K et al (2005) Significance of proximal tubular metabolism of advanced glycation end products in kidney diseases. Ann N Y Acad Sci 1043:637–643PubMedCrossRefGoogle Scholar
  48. 48.
    Cooper ME, Vranes D, Youssef S et al (1999) Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes. Diabetes 48:2229–2239PubMedCrossRefGoogle Scholar
  49. 49.
    Iglesias-de la Cruz MC, Ziyadeh FN, Isono M et al (2002) Effects of high glucose and TGF-beta1 on the expression of collagen IV and vascular endothelial growth factor in mouse podocytes. Kidney Int 62:901–913PubMedCrossRefGoogle Scholar
  50. 50.
    Wendt TM, Tanji N, Guo J et al (2003) RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol 162:1123–1137PubMedCrossRefGoogle Scholar
  51. 51.
    Wolf G (2004) New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology. Eur J Clin Invest 34:785–796PubMedCrossRefGoogle Scholar
  52. 52.
    Chung SS, Ho EC, Lam KS et al (2003) Contribution of polyol pathway to diabetes-induced oxidative stress. J Am Soc Nephrol 14:S233–S236PubMedCrossRefGoogle Scholar
  53. 53.
    Brem H, Tomic-Canic M (2007) Cellular and molecular basis of wound healing in diabetes. J Clin Invest 117:1219–1222PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Singh N, Armstrong DG, Lipsky BA (2005) Preventing foot ulcers in patients with diabetes. JAMA 293:217–228PubMedCrossRefGoogle Scholar
  55. 55.
    Iversen MM, Tell GS, Riise T et al (2009) History of foot ulcer increases mortality among individuals with diabetes: ten-year follow-up of the Nord-Trondelag Health Study, Norway. Diabetes Care 32:2193–2199PubMedCrossRefGoogle Scholar
  56. 56.
    Izumi Y, Satterfield K, Lee S et al (2006) Risk of reamputation in diabetic patients stratified by limb and level of amputation: a 10-year observation. Diabetes Care 29:566–570PubMedCrossRefGoogle Scholar
  57. 57.
    Sharma KR, Cross J, Farronay O et al (2002) Demyelinating neuropathy in diabetes mellitus. Arch Neurol 59:758–765PubMedCrossRefGoogle Scholar
  58. 58.
    Greene DA, Sima AA, Stevens MJ et al (1992) Complications: neuropathy, pathogenetic considerations. Diabetes Care 15:1902–1925PubMedCrossRefGoogle Scholar
  59. 59.
    Gurtner GC, Werner S, Barrandon Y et al (2008) Wound repair and regeneration. Nature 453:314–321PubMedCrossRefGoogle Scholar
  60. 60.
    Grochot-Przeczek A, Lach R, Mis J et al (2009) Heme oxygenase-1 accelerates cutaneous wound healing in mice. PLoS One 4:e5803PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Deshane J, Chen S, Caballero S et al (2007) Stromal cell-derived factor 1 promotes angiogenesis via a heme oxygenase 1-dependent mechanism. J Exp Med 204:605–618PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Dulak J, Deshane J, Jozkowicz A et al (2008) Heme oxygenase-1 and carbon monoxide in vascular pathobiology: focus on angiogenesis. Circulation 117:231–241PubMedCrossRefGoogle Scholar
  63. 63.
    Niu Y, Xie T, Ge K et al (2008) Effects of extracellular matrix glycosylation on proliferation and apoptosis of human dermal fibroblasts via the receptor for advanced glycosylated end products. Am J Dermatopathol 30:344–351PubMedCrossRefGoogle Scholar
  64. 64.
    Lerman OZ, Galiano RD, Armour M et al (2003) Cellular dysfunction in the diabetic fibroblast: impairment in migration, vascular endothelial growth factor production, and response to hypoxia. Am J Pathol 162:303–312PubMedCrossRefGoogle Scholar
  65. 65.
    Burrow JW, Koch JA, Chuang HH et al (2007) Nitric oxide donors selectively reduce the expression of matrix metalloproteinases-8 and -9 by human diabetic skin fibroblasts. J Surg Res 140:90–98PubMedCrossRefGoogle Scholar
  66. 66.
    Wall SJ, Sampson MJ, Levell N et al (2003) Elevated matrix metalloproteinase-2 and -3 production from human diabetic dermal fibroblasts. Br J Dermatol 149:13–16PubMedCrossRefGoogle Scholar
  67. 67.
    Li H, Zhang X, Guan X et al (2012) Advanced glycation end products impair the migration, adhesion and secretion potentials of late endothelial progenitor cells. Cardiovasc Diabetol 11:137–146CrossRefGoogle Scholar
  68. 68.
    Bucala R, Tracey KJ, Cerami A (1991) Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest 87:432–438PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Liao H, Zakhaleva J, Chen W (2009) Cells and tissue interactions with glycated collagen and their relevance to delayed diabetic wound healing. Biomaterials 30:1689–1696PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Wear-Maggitti K, Lee J, Conejero A et al (2004) Use of topical sRAGE in diabetic wounds increases neovascularization and granulation tissue formation. Ann Plast Surg 52:519–522PubMedCrossRefGoogle Scholar
  71. 71.
    Gerstein HC, Miller ME, Byington RP et al (2008) Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358:2545–2559PubMedCrossRefGoogle Scholar
  72. 72.
    Laakso M (2011) Heart in diabetes: a microvascular disease. Diabetes Care 34(Suppl 2):S145–S149PubMedCrossRefGoogle Scholar
  73. 73.
    Carr ME (2001) Diabetes mellitus: a hypercoagulable state. J Diabetes Complications 15:44–54PubMedCrossRefGoogle Scholar
  74. 74.
    Sniderman A, Michel C, Racine N (1992) Heart disease in patients with diabetes mellitus. J Clin Epidemiol 45:1357–1370PubMedCrossRefGoogle Scholar
  75. 75.
    Ceradini DJ, Yao D, Grogan RH et al (2008) Decreasing intracellular superoxide corrects defective ischemia-induced new vessel formation in diabetic mice. J Biol Chem 283:10930–10938PubMedCrossRefGoogle Scholar
  76. 76.
    Taniguchi N, Arai K, Kinoshita N (1989) Glycation of copper/zinc superoxide dismutase and its inactivation: identification of glycated sites. Methods Enzymol 179:570–581PubMedCrossRefGoogle Scholar
  77. 77.
    Wolffenbuttel BH, Boulanger CM, Crijns FR et al (1998) Breakers of advanced glycation end products restore large artery properties in experimental diabetes. Proc Natl Acad Sci USA 95:4630–4634PubMedCrossRefGoogle Scholar
  78. 78.
    Abaci A, Oguzhan A, Kahraman S et al (1999) Effect of diabetes mellitus on formation of coronary collateral vessels. Circulation 99:2239–2242PubMedCrossRefGoogle Scholar
  79. 79.
    Sasso FC, Torella D, Carbonara O et al (2005) Increased vascular endothelial growth factor expression but impaired vascular endothelial growth factor receptor signaling in the myocardium of type 2 diabetic patients with chronic coronary heart disease. J Am Coll Cardiol 46:827–834PubMedCrossRefGoogle Scholar
  80. 80.
    Johannesson A, Larsson GU, Ramstrand N et al (2009) Incidence of lower-limb amputation in the diabetic and nondiabetic general population: a 10-year population-based cohort study of initial unilateral and contralateral amputations and reamputations. Diabetes Care 32:275–280PubMedCrossRefGoogle Scholar
  81. 81.
    Bakker K, van Houtum WH, Riley PC (2005) 2005: the International Diabetes Federation focuses on the diabetic foot. Curr Diab Rep 5:436–440PubMedCrossRefGoogle Scholar
  82. 82.
    Tongers J, Roncalli JG, Losordo DW (2008) Therapeutic angiogenesis for critical limb ischemia: microvascular therapies coming of age. Circulation 118:9–16PubMedCrossRefGoogle Scholar
  83. 83.
    Stamler J, Vaccaro O, Neaton JD et al (1993) Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 16:434–444PubMedCrossRefGoogle Scholar
  84. 84.
    Tsang TS, Petty GW, Barnes ME et al (2003) The prevalence of atrial fibrillation in incident stroke cases and matched population controls in Rochester, Minnesota: changes over three decades. J Am Coll Cardiol 42:93–100PubMedCrossRefGoogle Scholar
  85. 85.
    Rosenson RS, Fioretto P, Dodson PM (2011) Does microvascular disease predict macrovascular events in type 2 diabetes? Atherosclerosis 218:13–18PubMedCrossRefGoogle Scholar
  86. 86.
    O’Donnell MJ, Xavier D, Liu L et al (2010) Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet 376:112–123PubMedCrossRefGoogle Scholar
  87. 87.
    Hyvarinen M, Tuomilehto J, Mahonen M et al (2009) Hyperglycemia and incidence of ischemic and hemorrhagic stroke-comparison between fasting and 2-hour glucose criteria. Stroke 40:1633–1637PubMedCrossRefGoogle Scholar
  88. 88.
    Plate KH, Beck H, Danner S et al (1999) Cell type specific upregulation of vascular endothelial growth factor in an MCA-occlusion model of cerebral infarct. J Neuropathol Exp Neurol 58:654–666PubMedCrossRefGoogle Scholar
  89. 89.
    Issa R, Krupinski J, Bujny T et al (1999) Vascular endothelial growth factor and its receptor, KDR, in human brain tissue after ischemic stroke. Lab Invest 79:417–425PubMedGoogle Scholar
  90. 90.
    Romanic AM, White RF, Arleth AJ et al (1998) Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke 29:1020–1030PubMedCrossRefGoogle Scholar
  91. 91.
    de Courten-Myers GM, Kleinholz M, Holm P et al (1992) Hemorrhagic infarct conversion in experimental stroke. Ann Emerg Med 21:120–126PubMedCrossRefGoogle Scholar
  92. 92.
    Li PA, Shuaib A, Miyashita H et al (2000) Hyperglycemia enhances extracellular glutamate accumulation in rats subjected to forebrain ischemia. Stroke 31:183–192PubMedCrossRefGoogle Scholar
  93. 93.
    Bright R, Steinberg GK, Mochly-Rosen D (2007) DeltaPKC mediates microcerebrovascular dysfunction in acute ischemia and in chronic hypertensive stress in vivo. Brain Res 1144:146–155PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Liang W, Chuan-Zhen L, Qiang D et al (2004) Reductions in mRNA of the neuroprotective agent, neuroserpin, after cerebral ischemia/reperfusion in diabetic rats. Brain Res 1015:175–180PubMedCrossRefGoogle Scholar
  95. 95.
    Rajamani K, Colman PG, Li LP et al (2009) Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. Lancet 373:1780–1788PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Keech A, Simes RJ, Barter P et al (2005) Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366:1849–1861PubMedCrossRefGoogle Scholar
  97. 97.
    Gross JL, de Azevedo MJ, Silveiro SP et al (2005) Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care 28:164–176PubMedCrossRefGoogle Scholar
  98. 98.
    Aiello LP, Vignati L, Sheetz MJ et al (2011) Oral protein kinase c beta inhibition using ruboxistaurin: efficacy, safety, and causes of vision loss among 813 patients (1,392 eyes) with diabetic retinopathy in the Protein kinase C beta inhibitor-diabetic retinopathy study and the Protein kinase C beta inhibitor-diabetic retinopathy study 2. Retina 31:2084–2094PubMedCrossRefGoogle Scholar
  99. 99.
    Simo R, Hernandez C (2009) Advances in the medical treatment of diabetic retinopathy. Diabetes Care 32:1556–1562PubMedCrossRefGoogle Scholar
  100. 100.
    Gupta R, Tongers J, Losordo DW (2009) Human studies of angiogenic gene therapy. Circ Res 105:724–736PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Leeper NJ, Hunter AL, Cooke JP (2010) Stem cell therapy for vascular regeneration: adult, embryonic, and induced pluripotent stem cells. Circulation 122:517–526PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2013

Authors and Affiliations

  • Louise L. Dunn
    • 1
    • 2
    Email author
  • Kim Hoe Chan
    • 3
  • Martin K. C. Ng
    • 3
  • Roland Stocker
    • 1
    • 2
  1. 1.Victor Chang Cardiac Research InstituteDarlinghurstAustralia
  2. 2.Faculty of MedicineThe University of New South WalesKensingtonAustralia
  3. 3.Department of CardiologyRoyal Prince Alfred HospitalCamperdownAustralia

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