Microcirculation of the Diabetic Foot

  • Osama Hamdy
  • K. Abuelenin
  • Aristidis Veves
Part of the Contemporary Cardiology book series (CONCARD)


There is now general acceptance that the abnormalities of the microcirculation are one of the early changes that occur in diabetes (1–7). Such abnormalities, which manifest during the course of diabetes as the triopathy of retinopathy, nephropathy, and neuropathy, have been found to be related to the duration and severity of diabetes (8–10). The pattern of these abnormalities, however, may be different between the two main types of diabetes, as is evident in the higher prevalence of proliferative retinopathy in type 1 diabetic patients and of maculopathy in type 2 diabetic patients (11). Intensive glycemic control, as shown in the Diabetes Control and Complications Trial (DCCT), was found to delay significantly the development and progression of these microvascular complications in type 1 diabetic patients (10). Similar results were also reported in type 2 diabetic patients (12,13). In this context, the capillary microcirculation to foot skin is not an exception and has shown signs of significant impairment in diabetic patients, especially when metabolic control is poor (14). This chapter focuses on the changes that occur in the microcirculation of the diabetic foot and the different methods used for their evaluation.


Diabetic Patient Sodium Nitroprusside Small Vessel Disease Hyperemic Response Baseline Flow 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Malik RA, Tesfaye S, Thompson SD, et al. Endothelial localization of microvascular damage in human diabetic neuropathy. Diabetologia 1993;36:454–459.PubMedCrossRefGoogle Scholar
  2. 2.
    Tesfaye S, Harris N, Jakubowski JJ, et al. Impaired blood flow and arterio-venous shunting in human diabetic neuropathy: a novel technique of nerve photography and fluorescein angiography. Diabetologia 1993;36:1266–1274.PubMedCrossRefGoogle Scholar
  3. 3.
    Tesfaye S, Malik R, Ward JD. Vascular factors in diabetic neuropathy. Diabetologia 1994;37:847–854.PubMedCrossRefGoogle Scholar
  4. 4.
    Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 1993;88:2510–2516.PubMedCrossRefGoogle Scholar
  5. 5.
    Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993;362:801–809.PubMedCrossRefGoogle Scholar
  6. 6.
    Stevens MJ, Dananberg J, Feldman EL, et al. The linked roles of nitric oxide, aldose reductase and (Na+, K+)-ATPase in the slowing of nerve conduction in the streptozotocin diabetic rat. J Clin Invest 1994; 94:853–859.PubMedCrossRefGoogle Scholar
  7. 7.
    Stevens MJ, Feldman EL, Greene DA. The etiology of diabetic neuropathy: the combined roles of metabolic and vascular defects. Diabetes Med 1995;12:566–579.CrossRefGoogle Scholar
  8. 8.
    Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of 4400 patients observed between 1947 and 1973. Diabetes Metab 1977;3:97–107.Google Scholar
  9. 9.
    PalmbergP,SmithM,WaltmanS,etal.Thenaturalhistoryofretinopathyininsulin-dependentjuvenileonset diabetes. Opthalmology 1981;88:613–618.Google Scholar
  10. 10.
    Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986.CrossRefGoogle Scholar
  11. 11.
    Jaap AJ, Tooke JE. The pathophysiology of microvascular disease in type 2 diabetes. Clin Sci 1995;89: 3–12.PubMedGoogle Scholar
  12. 12.
    UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–853.CrossRefGoogle Scholar
  13. 13.
    Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995;28:103–117.PubMedCrossRefGoogle Scholar
  14. 14.
    Jorneskog G, Brismar K, Fagrell B. Skin capillary circulation severely impaired in toes of patients with IDDM, with and without late diabetic complications. Diabetologia 1995;38:474–480.PubMedCrossRefGoogle Scholar
  15. 15.
    Goldenberg SG, Alex M, Joshi RA, Blumenthal HT. Nonatheromatous peripheral vascular disease of the lower extremity in diabetes mellitus. Diabetes 1959;8:261–273.PubMedGoogle Scholar
  16. 16.
    Barner HB, Kaiser GC, Willman VL. Blood flow in the diabetic leg. Circulation 1971;43:391–394.PubMedCrossRefGoogle Scholar
  17. 17.
    Strandness DE Jr, Priest RE, Gibbons GE. Combined clinical and pathologic study of diabetic and nondiabetic peripheral arterial disease. Diabetes 1964;13:366–372.PubMedGoogle Scholar
  18. 18.
    LoGerfo FW, Coffman JD. Vascular and microvascular disease of the foot in diabetes. N Engl J Med 1984;311:1615–1619.PubMedCrossRefGoogle Scholar
  19. 19.
    Nathan DM. Long-term complications of diabetes mellitus. N Engl J Med 1993;328:1676–1685.PubMedCrossRefGoogle Scholar
  20. 20.
    Vanhoutte PM. The endothelium modulator of vascular smooth-muscle tone. N Engl J Med 1988;319: 512–513.PubMedCrossRefGoogle Scholar
  21. 21.
    Cohen RA. Dysfunction of vascular endothelium in diabetes mellitus. Circulation 1993;87:V67–V76.Google Scholar
  22. 22.
    Jaap AJ, Shore AC, Stockman AJ, Tooke JE. Skin capillary density in subjects with impaired glucose tolerance and patients with type 2 diabetes. Diabetes Med 1996;13:160–164.CrossRefGoogle Scholar
  23. 23.
    Rayman G, Malik RA, Sharma AK, Day JL. Microvascular response to tissue injury and capillary ultrastructure in the foot skin of type I diabetic patients. Clin Sci 1995;89:467–474.PubMedGoogle Scholar
  24. 24.
    Malik RA, Metcalf I, Sharma AK, Day JL, Rayman G. Skin epidermal thickness and vascular density in type 1 diabetes. Diabetes Med 1992;9:263–267.CrossRefGoogle Scholar
  25. 25.
    Williamson JR, Kilo C. Basement membrane physiology and pathophysiology. In: Alberti KGMM, DeFronzo RA, Keen H, Zimmet P, eds. International Textbook of Diabetes Mellitus, vol. 2. John Wiley, Chichester, 1992, pp. 1245–1265.Google Scholar
  26. 26.
    Raskin P, Pietri A, Unger R, Shannon WA Jr. The effect of diabetic control on skeletal muscle capillary basement membrane width in patients with type 1 diabetes mellitus. N Engl J Med 1983;309:1546–1550.PubMedCrossRefGoogle Scholar
  27. 27.
    Ajjam ZS, Barton S, Corbett M, et al. Quantitative evaluation of the dermal vasculature of diabetics. Q J Med 1985;215:229–239.Google Scholar
  28. 28.
    Tilton RG, Faller AM, Burkhardt JK, et al. Pericyte degeneration and acellular capillaries are increased in the feet of human diabetes. Diabetologia 1985;28:895–900.PubMedCrossRefGoogle Scholar
  29. 29.
    Rayman G, Williams SA, Spencer PD, Smaje LH, Wise PH, Tooke JE. Impaired microvascular hyperaemic response to minor skin trauma in type 1 diabetes. BMJ 1986;292:1295–1298.PubMedCrossRefGoogle Scholar
  30. 30.
    Flynn MD, Tooke JE. Aetiology of diabetic foot ulceration: a role for the microcirculation? Diabetes Med 1992;8:320–329.CrossRefGoogle Scholar
  31. 31.
    Tooke JE. Microvascular function in human diabetes: a physiological perspective. Diabetes 1995;44: 721–726.PubMedCrossRefGoogle Scholar
  32. 32.
    Parving HH, Viberti GC, Keen H, Christiansen JS, Lassen NA. Hemodynamic factors in the genesis of diabetic microangiopathy. Metabolism 1983;32:. 943–949.Google Scholar
  33. 33.
    Mullarkey CJ, Brownlee M. Biochemical basis of microvascular disease. In: Pickup JC, Williams G, eds. Chronic complications of diabetes. Blackwell Scientific Publications, Oxford, 1994, pp. 20–29.Google Scholar
  34. 34.
    Schmidt AM, Hori O, Brett J, Yan SD, Wautier JL, Stern D. Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions. Arterioscler Thromb 1994;14:1521–1528.PubMedCrossRefGoogle Scholar
  35. 35.
    Makita Z, Radoff S, Rayfield EJ, et al. Advanced glycosylation end products in patients with diabetic nephropathy. N Engl J Med 1991;325:836–842.PubMedCrossRefGoogle Scholar
  36. 36.
    Bucala R, Tracey KJ, Cerami A. Advanced glycosylation end products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest 1991;87:432–438.PubMedCrossRefGoogle Scholar
  37. 37.
    Sandeman DD, Shore AC, Tooke JE. Relation of skin capillary pressure in patients with insulindependent diabetes to complications and metabolic control. N Engl J Med 1992;327:760–764.PubMedCrossRefGoogle Scholar
  38. 38.
    ShoreAC,PriceHJ,SandemanDD,GreenEM,TrippJH,TookeJE.Impairedmicrovascularhyperaemic response in children with diabetes mellitus. Diabetes Med 1991;8:619–623.CrossRefGoogle Scholar
  39. 39.
    Flynn MD, Williams SA, Tooke AE. Clinical television microscopy. J Med Eng Technol 1989;13: 278–284.PubMedCrossRefGoogle Scholar
  40. 40.
    Rendell M, Bergman T, O’Donnell G, Drobny E, Borgos J, Bonner RF. Microvascular blood flow, volume, and velocity measured by laser doppler techniques in IDDM. Diabetes 1989;38:819–824.PubMedCrossRefGoogle Scholar
  41. 41.
    TookeJE,OstergrenJ,FagrellB.Synchronousassessmentofhumanskinmicrocirculationbylaserpoppler flowmetry and dynamic capillaroscopy. Int J Microcirc Clin Exp 1983;2:277–284.Google Scholar
  42. 42.
    Rayman G, Williams SA, Spencer PD, Smaje LH, Wise PH, Tooke JE. Impaired microvascular hyperaemic response to minor skin trauma in type I diabetes. BMJ 1986;292:1295–1298.PubMedCrossRefGoogle Scholar
  43. 43.
    Boulton AJM, Scarpello JHB, Ward JD. Venous oxygenation in the diabetic neuropathic foot: evidence of arteriovenous shunting? Diabetologia 1982;22:6–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Murray HJ, Boulton A. The pathophysiology of diabetic foot ulceration. Clin Podiatr Med Surg 1995; 12:1–17.PubMedGoogle Scholar
  45. 45.
    Conrad MC. Functional Anatomy of the Circulation to the Lower Extremities. Year Book Medical Publishers, Chicago, 1971, pp. 60–75.Google Scholar
  46. 46.
    Watkins PJ, Edmonds ME. Sympathetic nerve failure in diabetes. Diabetologia 1983;25:75–77.CrossRefGoogle Scholar
  47. 47.
    Malik RA, Newrick PG,Sharma AK, et al. Microangiopathy in human diabetic neuropathy: relationship between capillary abnormalities and the severity of neuropathy. Diabetologia 1989;32:92–102.PubMedCrossRefGoogle Scholar
  48. 48.
    Flynn MD, Tooke JE. Diabetic neuropathy and the microcirculation. Diabetes Med 1995;12:298–301.CrossRefGoogle Scholar
  49. 49.
    Edmonds ME, Roberts VC, Watkins PJ. Blood flow in the diabetic neuropathic foot. Diabetologia 1982; 22:141–147.CrossRefGoogle Scholar
  50. 50.
    Williams SB, Cusco JA, Roddy M, Johnstone MY, Creager MA. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1996;27:567–574.PubMedCrossRefGoogle Scholar
  51. 51.
    Stehouwer CDA, Fischer HRA, Van Kuijk AWR, Polak BCP, Donker AJM. Endothelial dysfunction precedes development of microalbuminuria in IDD. Diabetes 1995;44:561–564.PubMedCrossRefGoogle Scholar
  52. 52.
    Caballero AE, Arora S, Saouaf R, et al. Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes 1999;48:1856–1862.PubMedCrossRefGoogle Scholar
  53. 53.
    Veves A, Akbari CA, Primavera J, et al. Endothelial dysfunction and the expression of endothelial nitric oxide synthetase in diabetic neuropathy, vascular disease, and foot ulceration. Diabetes 1998;47:457–463.PubMedCrossRefGoogle Scholar
  54. 54.
    Parkhouse N, LeQueen PM. Impaired neurogenic vascular response in patients with diabetes and neuropathic foot lesions. N Engl J Med 1988;318:1306–1309.PubMedCrossRefGoogle Scholar
  55. 55.
    Walmsley D, Wiles PG. Early loss of neurogenic inflammation in the human diabetic foot. Clin Sci 1991; 80:605–610.PubMedGoogle Scholar
  56. 56.
    Arora S, Smakowski P, Frykberg RG, et al. Differences in foot and forearm skin microcirculation in diabetic patients with and without neuropathy. Diabetes Care 1998;21:1339–1344.PubMedCrossRefGoogle Scholar
  57. 57.
    Stansberry KB, Peppard HR, Babyak LM, Popp G, McNitt PM, Vinik AI. Primary nociceptive afferents mediate the blood flow dysfunction in non-glabrous (hairy) skin of type 2 diabetes. Diabetes Care 1999; 22:1549–1554.PubMedCrossRefGoogle Scholar
  58. 58.
    Hamdy O, Abou-Elenin K, LoGerfo FW, Horton ES, Veves A. Contribution of nerve-axon reflexrelated vasodilation to the total skin vasodilation in diabetic patients with and without neuropathy. Diabetes Care 2001;24:344–349.PubMedCrossRefGoogle Scholar
  59. 59.
    Veves A, Uccioli L, Manes C, et al. Comparisons of risk factors for foot problems in diabetic patients attending teaching hospitals outpatient clinics in four different European states. Diabetes Med 1994; 11:709–713.CrossRefGoogle Scholar
  60. 60.
    Ward JD. Upright posture and the microvasculature in human diabetic neuropathy: a hypothesis. Diabetes 1997;46(Supp12):S94–S97.Google Scholar
  61. 61.
    Jude EB, Boulton AJ, Ferguson MW, Appleton I. Therole of nitric oxide synthase isoforms and arginase in the pathogenesis of diabetic foot ulcers: possible modulatory effects by transforming growth factor beta 1. Diabetologia 1999;42:748–757.PubMedCrossRefGoogle Scholar
  62. 62.
    Frykberg RG, Kozak GP. The diabetic Charcot foot. In: Kozak GP, Campbell DR, Frykberg RG, HaberShaw GM, eds. Management of Diabetic Foot Problems, 2nd ed. WB Saunders, Philadelphia, 1995, pp. 88–97.Google Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Osama Hamdy
  • K. Abuelenin
  • Aristidis Veves

There are no affiliations available

Personalised recommendations