Advertisement

Microvascular Changes in the Diabetic Foot

  • Matthieu Roustit
  • Jordan Loader
  • Dimitrios Baltzis
  • Wanni Zhao
  • Aristidis Veves
Chapter
Part of the Contemporary Diabetes book series (CDI)

Abstract

Diabetes affects the microcirculation through many different pathological mechanisms, including endothelial dysfunction and abnormal neurovascular control. These functional changes in microvascular function have a compounding relationship with structural changes in the cutaneous microcirculation of the diabetic foot. Ultimately, such adverse adaptations in function and structure contribute to the formation of diabetic foot complications such as ulceration, and in more severe circumstances to amputation. Indeed, diabetes and its associated complications place an enormous economic burden on public health systems, globally, highlighting the need for early intervention and prevention. In recent decades, several noninvasive imaging techniques and tests of microvascular reactivity have evolved that may have the potential to allow clinicians to more accurately predict the risk of foot ulceration in those with diabetes, as well as provide the ability to monitor wound healing rates and determine the success of therapeutic interventions. This chapter will summarize these methods used to assess the cutaneous microcirculation while also describing the respective roles of hyperglycemia, insulin resistance, and inflammation in endothelial dysfunction and its complex relationship with neurovascular function.

Keywords

Microcirculation Endothelium Diabetic foot ulcers Neurovascular Skin blood flow Axon-reflex Neuropathy Wound healing Laser Doppler Iontophoresis 

References

  1. 1.
    McMillan DE. Deterioration of the microcirculation in diabetes. Diabetes. 1975;24(10):944–57.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Flynn M d., Tooke J e. Aetiology of diabetic foot ulceration: a role for the microcirculation? Diabet Med. 1992;9(4):320–9.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Tooke JE. Microvascular function in human diabetes: a physiological perspective. Diabetes. 1995;44(7):721–6.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Thijssen DH, Black MA, Pyke KE, Padilla J, Atkinson G, Harris RA, et al. Assessment of flow-mediated dilation in humans: a methodological and physiological guideline. Am J Physiol Heart Circ Physiol. 2011;300:H2–12.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Braverman IM. The cutaneous microcirculation. J Investig Dermatol Symp Proc. 2000;5:3–9.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Mulvany MJ, Aalkjaer C. Structure and function of small arteries. Physiol Rev. 1990;70(4):921–61.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Oaklander AL, Siegel SM. Cutaneous innervation: form and function. J Am Acad Dermatol. 2005;53(6):1027–37.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Roustit M, Cracowski J-L. Assessment of endothelial and neurovascular function in human skin microcirculation. Trends Pharmacol Sci. 2013;34(7):373–84.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Karaca Ü, Schram MT, Houben AJHM, Muris DMJ, Stehouwer CDA. Microvascular dysfunction as a link between obesity, insulin resistance and hypertension. Diabetes Res Clin Pract. 2014;103(3):382–7.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Hellsten Y, Nyberg M, Jensen LG, Mortensen SP. Vasodilator interactions in skeletal muscle blood flow regulation. J Physiol. 2012;590(24):6297–305.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Gutiérrez E, Flammer AJ, Lerman LO, Elízaga J, Lerman A, Fernández-Avilés F. Endothelial dysfunction over the course of coronary artery disease. Eur Heart J. 2013;34(41):3175–81.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Rajendran P, Rengarajan T, Thangavel J, Nishigaki Y, Sakthisekaran D, Sethi G, et al. The vascular endothelium and human diseases. Int J Biol Sci. 2013;9(10):1057–69.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Jia G, Aroor AR, DeMarco VG, Martinez-Lemus LA, Meininger GA, Sowers JR. Vascular stiffness in insulin resistance and obesity. Front Physiol. 2015;6:231.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999;399(6736):601–5.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Geiger M, Stone A, Mason SN, Oldham KT, Guice KS. Differential nitric oxide production by microvascular and macrovascular endothelial cells. Am J Phys. 1997;273(1 Pt 1):L275–81.Google Scholar
  16. 16.
    Fleming I, Busse R. Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am J Physiol Regul Integr Comp Physiol. 2003;284(1):R1–12.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Félétou M, Huang Y, Vanhoutte PM. Endothelium-mediated control of vascular tone: COX-1 and COX-2 products. Br J Pharmacol. 2011;164(3):894–912.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Bellien J, Joannides R, Richard V, Thuillez C. Modulation of cytochrome-derived epoxyeicosatrienoic acids pathway: a promising pharmacological approach to prevent endothelial dysfunction in cardiovascular diseases? Pharmacol Ther. 2011;131:1–17.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Forsythe RO, Hinchliffe RJ. Assessment of foot perfusion in patients with a diabetic foot ulcer. Diabetes Metab Res Rev. 2016;32:232–8.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Stern MD. In vivo evaluation of microcirculation by coherent light scattering. Nature. 1975;254(5495):56–8.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Roustit M, Cracowski JL. Non-invasive assessment of skin microvascular function in humans: an insight into methods. Microcirculation. 2012;19(1):47–64.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Allen J, Howell K. Microvascular imaging: techniques and opportunities for clinical physiological measurements. Physiol Meas. 2014;35(7):R91.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Carpentier PH. New techniques for clinical assessment of the peripheral microcirculation. Drugs. 1999;59 Spec No:17–22.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Yip WL. Evaluation of the clinimetrics of transcutaneous oxygen measurement and its application in wound care. Int Wound J. 2015;12(6):625–9.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Williams DT, Price P, Harding KG. The influence of diabetes and lower limb arterial disease on cutaneous foot perfusion. J Vasc Surg. 2006;44(4):770–5.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Scheeren TWL. Journal of clinical monitoring and computing 2015 end of year summary: tissue oxygenation and microcirculation. J Clin Monit Comput. 2016;30(2):141–6.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Pedersen BL, Baekgaard N, Quistorff B. Muscle mitochondrial function in patients with type 2 diabetes mellitus and peripheral arterial disease: implications in vascular surgery. Eur J Vasc Endovasc Surg. 2009;38(3):356–64.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Boezeman RPE, Moll FL, Ünlü Ç, de Vries J-PPM. Systematic review of clinical applications of monitoring muscle tissue oxygenation with near-infrared spectroscopy in vascular disease. Microvasc Res. 2016;104:11–22.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Weingarten MS, Samuels JA, Neidrauer M, Mao X, Diaz D, McGuire J, et al. Diffuse near-infrared spectroscopy prediction of healing in diabetic foot ulcers: a human study and cost analysis. Wound Repair Regen. 2012;20(6):911–7.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Neidrauer M, Zubkov L, Weingarten MS, Pourrezaei K, Papazoglou ES. Near infrared wound monitor helps clinical assessment of diabetic foot ulcers. J Diabetes Sci Technol. 2010;4(4):792–8.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Rizzoni D, Porteri E, Guelfi D, Muiesan ML, Valentini U, Cimino A, et al. Structural alterations in subcutaneous small arteries of normotensive and hypertensive patients with non–insulin-dependent diabetes mellitus. Circulation. 2001;103(9):1238–44.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    MÅrin P, Andersson B, Krotkiewski M, Björntorp P. Muscle fiber composition and capillary density in women and men with NIDDM. Diabetes Care. 1994;17(5):382–6.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Malik RA, Newrick PG, Sharma AK, Jennings A, Ah-See AK, Mayhew TM, et al. Microangiopathy in human diabetic neuropathy: relationship between capillary abnormalities and the severity of neuropathy. Diabetologia. 1989;32(2):92–102.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Malik RA, Metcalfe J, Sharma AK, Day JL, Rayman G. Skin epidermal thickness and vascular density in type 1 diabetes. Diabet Med. 1992;9(3):263–7.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Khodabandehlou T, Zhao H, Vimeux M, Le Dévéhat C. The autoregulation of the skin microcirculation in healthy subjects and diabetic patients with and without vascular complications. Clin Hemorheol Microcirc. 1997;17(5):357–62.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Raskin P, Pietri AO, Unger R, Shannon WAJ. The effect of diabetic control on the width of skeletal-muscle capillary basement membrane in patients with type I diabetes mellitus. N Engl J Med. 1983;309(25):1546–50.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Walløe L. Arterio-venous anastomoses in the human skin and their role in temperature control. Temperature. 2016;3(1):92–103.CrossRefGoogle Scholar
  38. 38.
    Kenny GP, Stapleton JM, Yardley JE, Boulay P, Sigal RJ. Older adults with type 2 diabetes store more heat during exercise. Med Sci Sports Exerc. 2013;45(10):1906–14.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Carter MR, McGinn R, Barrera-Ramirez J, Sigal RJ, Kenny GP. Impairments in local heat loss in type 1 diabetes during exercise in the heat. Med Sci Sports Exerc. 2014;46(12):2224–33.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    McNally PG, Watt PAC, Rimmer T, Burden AC, Hearnshaw JR, Thurston H. Impaired contraction and endothelium-dependent relaxation in isolated resistance vessels from patients with insulin-dependent diabetes mellitus. Clin Sci. 1994;87(1):31–6.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Makimattila S, Virkamaki A, Groop P-H, Cockcroft J, Utriainen T, Fagerudd J, et al. Chronic hyperglycemia impairs endothelial function and insulin sensitivity via different mechanisms in insulin-dependent diabetes mellitus. Circulation. 1996;94(6):1276–82.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Hogikyan RV, Galecki AT, Pitt B, Halter JB, Greene DA, Supiano MA. Specific impairment of endothelium-dependent vasodilation in subjects with type 2 diabetes independent of obesity. J Clin Endocrinol Metab. 1998;83(6):1946–52.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Tibiriçá E, Rodrigues E, Cobas R, Gomes MB. Increased functional and structural skin capillary density in type 1 diabetes patients with vascular complications. Diabetol Metab Syndr. 2009;1:24.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Rayman G, Williams SA, Spencer PD, Smaje LH, Wise PH, Tooke JE. Impaired microvascular hyperaemic response to minor skin trauma in type I diabetes. Br Med J (Clin Res Ed). 1986;292(6531):1295.CrossRefGoogle Scholar
  45. 45.
    Khan F, Elhadd TA, Greene SA, Belch JJ. Impaired skin microvascular function in children, adolescents, and young adults with type 1 diabetes. Diabetes Care. 2000;23(2):215–20.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Krishnan STM, Baker NR, Carrington AL, Rayman G. Comparative roles of microvascular and nerve function in foot ulceration in type 2 diabetes. Diabetes Care. 2004;27(6):1343–8.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Jaap AJ, Hammersley MS, Shore AC, Tooke JE. Reduced microvascular hyperaemia in subjects at risk of developing type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1994;37(2):214–6.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Veves A, Akbari CM, Primavera J, Donaghue VM, Zacharoulis D, Chrzan JS, et al. Endothelial dysfunction and the expression of endothelial nitric oxide synthetase in diabetic neuropathy, vascular disease, and foot ulceration. Diabetes. 1998;47(3):457–63.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Krishnan STM, Rayman G. The LDIflare: a novel test of C-fiber function demonstrates early neuropathy in type 2 diabetes. Diabetes Care. 2004;27(12):2930–5.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Tomešová J, Gruberova J, Lacigova S, Cechurova D, Jankovec Z, Rusavy Z. Differences in skin microcirculation on the upper and lower extremities in patients with diabetes mellitus: relationship of diabetic neuropathy and skin microcirculation. Diabetes Technol Ther. 2013;15(11):968–75.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Caballero AE, Arora S, Saouaf R, Lim SC, Smakowski P, Park JY, et al. Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes. 1999;48(9):1856–62.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Dinh T, Tecilazich F, Kafanas A, Doupis J, Gnardellis C, Leal E, et al. Mechanisms involved in the development and healing of diabetic foot ulceration. Diabetes. 2012;61(11):2937–47.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Vinik AI, Erbas T, Park TS, Stansberry KB, Scanelli JA, Pittenger GL. Dermal neurovascular dysfunction in type 2 diabetes. Diabetes Care. 2001;24(8):1468–75.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Szolcsányi J, Sándor Z. Multisteric TRPV1 nocisensor: a target for analgesics. Trends Pharmacol Sci. 2012;33(12):646–55.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Tóth BI, Oláh A, Szöllősi AG, Bíró T. TRP channels in the skin. Br J Pharmacol. 2014;171(10):2568–81.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Johnson JM, Minson CT, Kellogg DL. Cutaneous vasodilator and vasoconstrictor mechanisms in temperature regulation. In: Terjung R, editor. Comprehensive physiology [Internet]. Hoboken, NJ: John Wiley & Sons, Inc.; 2014. p. 33–89. [cited 2016 Jul 26]. http://doi.wiley.com/10.1002/cphy.c130015.CrossRefGoogle Scholar
  57. 57.
    Vas PRJ, Green AQ, Rayman G. Small fibre dysfunction, microvascular complications and glycaemic control in type 1 diabetes: a case–control study. Diabetologia. 2011;55(3):795–800.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Caselli A, Uccioli L, Khaodhiar L, Veves A. Local anesthesia reduces the maximal skin vasodilation during iontophoresis of sodium nitroprusside and heating. Microvasc Res. 2003;66(2):134–9.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Gibbons CH, Freeman R, Tecilazich F, Dinh T, Lyons TE, Gnardellis C, et al. The evolving natural history of neurophysiologic function in patients with well-controlled diabetes. J Peripher Nerv Syst. 2013;18(2):153–61.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Rutkove SB, Veves A, Mitsa T, Nie R, Fogerson PM, Garmirian LP, et al. Impaired distal thermoregulation in diabetes and diabetic polyneuropathy. Diabetes Care. 2009;32(4):671–6.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Charkoudian N. Mechanisms and modifiers of reflex induced cutaneous vasodilation and vasoconstriction in humans. J Appl Physiol. 2010;109:1221–8.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Strom NA, Meuchel LW, Mundy DW, Sawyer JR, Roberts SK, Kingsley-Berg SM, et al. Cutaneous sympathetic neural responses to body cooling in type 2 diabetes mellitus. Auton Neurosci. 2011;159(1–2):15–9.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Quattrini C, Jeziorska M, Boulton AJM, Malik RA. Reduced vascular endothelial growth factor expression and intra-epidermal nerve fiber loss in human diabetic neuropathy. Diabetes Care. 2008;31(1):140–5.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Shah AS, Gao Z, Dolan LM, Dabelea D, D’Agostino RB, Urbina EM. Assessing endothelial dysfunction in adolescents and young adults with type 1 diabetes mellitus using a non-invasive heat stimulus. Pediatr Diabetes. 2015;16(6):434–40.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Heimhalt-El Hamriti M, Schreiver C, Noerenberg A, Scheffler J, Jacoby U, Haffner D, et al. Impaired skin microcirculation in paediatric patients with type 1 diabetes mellitus. Cardiovasc Diabetol. 2013;12:115.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Kilo S, Berghoff M, Hilz M, Freeman R. Neural and endothelial control of the microcirculation in diabetic peripheral neuropathy. Neurology. 2000;54(6):1246–52.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Gomes MB, Matheus AS, Tibirica E. Evaluation of microvascular endothelial function in patients with type 1 diabetes using laser-Doppler perfusion monitoring: which method to choose? Microvasc Res. 2008;76(2):132–3.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Durand S, Tartas M, Bouye P, Koitka A, Saumet JL, Abraham P. Prostaglandins participate in the late phase of the vascular response to acetylcholine iontophoresis in humans. J Physiol. 2004;561(Pt 3):811–9.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Morris SJ, Shore AC, Tooke JE. Responses of the skin microcirculation to acetylcholine and sodium nitroprusside in patients with NIDDM. Diabetologia. 1995;38(11):1337–44.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Beer S, Feihl F, Ruiz J, Juhan-Vague I, Aillaud M-F, Wetzel SG, et al. Comparison of skin microvascular reactivity with hemostatic markers of endothelial dysfunction and damage in type 2 diabetes. Vasc Health Risk Manag. 2008;4(6):1449–58.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Arora S, Smakowski P, Frykberg RG, Simeone LR, Freeman R, LoGerfo FW, et al. Differences in foot and forearm skin microcirculation in diabetic patients with and without neuropathy. Diabetes Care. 1998;21(8):1339–44.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Saad MI, Abdelkhalek TM, Saleh MM, Kamel MA, Youssef M, Tawfik SH, et al. Insights into the molecular mechanisms of diabetes-induced endothelial dysfunction: focus on oxidative stress and endothelial progenitor cells. Endocrine. 2015;50(3):537–67.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Szabo C. Role of nitrosative stress in the pathogenesis of diabetic vascular dysfunction. Br J Pharmacol. 2009;156(5):713–27.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Kizub IV, Klymenko KI, Soloviev AI. Protein kinase C in enhanced vascular tone in diabetes mellitus. Int J Cardiol. 2014;174(2):230–42.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Rask-Madsen C, King GL. Vascular complications of diabetes: mechanisms of injury and protective factors. Cell Metab. 2013;17(1):20–33.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Tuttle KR, McGill JB, Bastyr EJ III, Poi KK, Shahri N, Anderson PW. Effect of ruboxistaurin on albuminuria and estimated GFR in people with diabetic peripheral neuropathy: results from a randomized trial. Am J Kidney Dis. 2015;65(4):634–6.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Sheetz MJ, Aiello LP, Davis MD, Danis R, Bek T, Cunha-Vaz J, et al. The effect of the oral PKC β inhibitor ruboxistaurin on vision loss in two phase 3 studies. Invest Opthalmol Vis Sci. 2013;54(3):1750.CrossRefGoogle Scholar
  78. 78.
    Khamaisi M, Katagiri S, Keenan H, Park K, Maeda Y, Li Q, et al. PKCδ inhibition normalizes the wound-healing capacity of diabetic human fibroblasts. J Clin Invest. 2016;126(3):837–53.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414(6865):813–20.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Bedard K, Krause K-H. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 2007;87(1):245–313.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products. Circulation. 2006;114(6):597–605.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Garcia Soriano F, Virág L, Jagtap P, Szabó É, Mabley JG, Liaudet L, et al. Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nat Med. 2001;7(1):108–13.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Zhou X, Patel D, Sen S, Shanmugam V, Sidawy A, Mishra L, et al. Poly-ADP-ribose polymerase inhibition enhances ischemic and diabetic wound healing by promoting angiogenesis. J Vasc Surg. 2016;65(4):1161–9.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Ziegler D, Strom A, Brüggemann J, Ziegler I, Ringel B, Püttgen S, et al. Overexpression of cutaneous mitochondrial superoxide dismutase in recent-onset type 2 diabetes. Diabetologia. 2015;58(7):1621–5.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Kimura F, Hasegawa G, Obayashi H, Adachi T, Hara H, Ohta M, et al. Serum extracellular superoxide dismutase in patients with type 2 diabetes. Diabetes Care. 2003;26(4):1246–50.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Al-Kateb H, Boright AP, Mirea L, Xie X, Sutradhar R, Mowjoodi A, et al. Multiple superoxide dismutase 1/splicing factor serine alanine 15 variants are associated with the development and progression of diabetic nephropathy. Diabetes. 2008;57(1):218–28.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Mohammedi K, Bellili-Muñoz N, Driss F, Roussel R, Seta N, Fumeron F, et al. Manganese superoxide dismutase ( SOD2 ) polymorphisms, plasma advanced oxidation protein products (AOPP) concentration and risk of kidney complications in subjects with type 1 diabetes. PLoS One. 2014;9(5):e96916.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Roche C, Guerrot D, Harouki N, Duflot T, Besnier M, Rémy-Jouet I, et al. Impact of soluble epoxide hydrolase inhibition on early kidney damage in hyperglycemic overweight mice. Prostaglandins Other Lipid Mediat. 2015;120:148–54.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Lorthioir A, Guerrot D, Joannides R, Bellien J. Diabetic CVD—soluble epoxide hydrolase as a target. Cardiovasc Hematol Agents Med Chem. 2012;10(3):212–22.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Kim J, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction. Circulation. 2006;113(15):1888–904.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Rask-Madsen C, Li Q, Freund B, Feather D, Abramov R, Wu I-H, et al. Loss of insulin signaling in vascular endothelial cells accelerates atherosclerosis in apolipoprotein E null mice. Cell Metab. 2010;11(5):379–89.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest. 1996;97(11):2601–10.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Natali A, Toschi E, Baldeweg S, Ciociaro D, Favilla S, Saccà L, et al. Clustering of insulin resistance with vascular dysfunction and low-grade inflammation in type 2 diabetes. Diabetes. 2006;55(4):1133–40.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    de Jongh RT, Serné EH, Ijzerman RG, de Vries G, Stehouwer CDA. Free fatty acid levels modulate microvascular function. Diabetes. 2004;53(11):2873–82.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Paneni F, Beckman JA, Creager MA, Cosentino F. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Eur Heart J. 2013;34(31):2436–43.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Tellechea A, Leal EC, Kafanas A, Auster ME, Kuchibhotla S, Ostrovsky Y, et al. Mast cells regulate wound healing in diabetes. Diabetes. 2016;65(7):2006–19.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Vincent AM, Callaghan BC, Smith AL, Feldman EL. Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat Rev Neurol. 2011;7(10):573–83.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Hao W, Tashiro S, Hasegawa T, Sato Y, Kobayashi T, Tando T, et al. Hyperglycemia promotes Schwann cell de-differentiation and de-myelination via sorbitol accumulation and Igf1 protein down-regulation. J Biol Chem. 2015;290(28):17106–15.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Malik RA, Tesfaye S, Thompson SD, Veves A, Sharma AK, Boulton AJM, et al. Endoneurial localisation of microvascular damage in human diabetic neuropathy. Diabetologia. 1993;36(5):454–9.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Chapouly C, Yao Q, Vandierdonck S, Larrieu-Lahargue F, Mariani JN, Gadeau A-P, et al. Impaired Hedgehog signalling-induced endothelial dysfunction is sufficient to induce neuropathy: implication in diabetes. Cardiovasc Res. 2016;109(2):217–27.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Roustit M, Loader J, Deusenbery C, Baltzis D, Veves A. Endothelial dysfunction as a link between cardiovascular risk factors and peripheral neuropathy in diabetes. J Clin Endocrinol Metab. 2016;101(9):3401–8.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Suri A, Szallasi A. The emerging role of TRPV1 in diabetes and obesity. Trends Pharmacol Sci. 2008;29(1):29–36.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Koitka A, Abraham P, Bouhanick B, Sigaudo-Roussel D, Demiot C, Saumet JL. Impaired pressure-induced vasodilation at the foot in young adults with type 1 diabetes. Diabetes. 2004;53(3):721–5.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Fromy B, Abraham P, Bouvet C, Bouhanick B, Fressinaud P, Saumet JL. Early decrease of skin blood flow in response to locally applied pressure in diabetic subjects. Diabetes. 2002;51(4):1214–7.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Fromy B, Lingueglia E, Sigaudo-Roussel D, Saumet JL, Lazdunski M. Asic3 is a neuronal mechanosensor for pressure-induced vasodilation that protects against pressure ulcers. Nat Med. 2012;18(8):1205–7.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Crawford F, Cezard G, Chappell FM, Murray GD, Price JF, Sheikh A, et al. A systematic review and individual patient data meta-analysis of prognostic factors for foot ulceration in people with diabetes: the international research collaboration for the prediction of diabetic foot ulcerations (PODUS). Health Technol Assess. 2015;19(57):1–210.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Monteiro-Soares M, Boyko EJ, Ribeiro J, Ribeiro I, Dinis-Ribeiro M. Predictive factors for diabetic foot ulceration: a systematic review. Diabetes Metab Res Rev. 2012;28(7):574–600.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Chabbert-Buffet N, LeDevehat C, Khodabandhelou T, Allaire E, Gaitz JP, Tribout L, et al. Evidence for associated cutaneous microangiopathy in diabetic patients with neuropathic foot ulceration. Diabetes Care. 2003;26(3):960–1.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Wang Z, Hasan R, Firwana B, Elraiyah T, Tsapas A, Prokop L, et al. A systematic review and meta-analysis of tests to predict wound healing in diabetic foot. J Vasc Surg. 2016;63(2 Suppl):29S–36S.e2.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Hingorani A, LaMuraglia GM, Henke P, Meissner MH, Loretz L, Zinszer KM, et al. The management of diabetic foot: a clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine. J Vasc Surg. 2016;63(2 Suppl):3S–21S.PubMedCrossRefGoogle Scholar
  111. 111.
    Vouillarmet J, Bourron O, Gaudric J, Lermusiaux P, Millon A, Hartemann A. Lower-extremity arterial revascularization: is there any evidence for diabetic foot ulcer-healing? Diabetes Metab. 2016;42(1):4–15.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Arora S, Pomposelli F, LoGerfo FW, Veves A. Cutaneous microcirculation in the neuropathic diabetic foot improves significantly but not completely after successful lower extremity revascularization. J Vasc Surg. 2002;35(3):501–5.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Brunt VE, Fujii N, Minson CT. Endothelial-derived hyperpolarization contributes to acetylcholine-mediated vasodilation in human skin in a dose-dependent manner. J Appl Physiol. 2015;119(9):1015–22.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Jeffcoate WJ, Clark DJ, Savic N, Rodmell PI, Hinchliffe RJ, Musgrove A, et al. Use of HSI to measure oxygen saturation in the lower limb and its correlation with healing of foot ulcers in diabetes. Diabet Med. 2015;32(6):798–802.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Khaodhiar L, Dinh T, Schomacker KT, Panasyuk SV, Freeman JE, Lew R, et al. The use of medical hyperspectral technology to evaluate microcirculatory changes in diabetic foot ulcers and to predict clinical outcomes. Diabetes Care. 2007;30(4):903–10.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Roustit M, Millet C, Blaise S, Dufournet B, Cracowski JL. Excellent reproducibility of laser speckle contrast imaging to assess skin microvascular reactivity. Microvasc Res. 2010;80(3):505–11.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Nakagami G, Sari Y, Nagase T, Iizaka S, Ohta Y, Sanada H. Evaluation of the usefulness of skin blood flow measurements by laser speckle flowgraphy in pressure-induced ischemic wounds in rats. Ann Plast Surg. 2010;64(3):351–4.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Minniti CP, Gorbach AM, Xu D, Hon YY, Delaney K-M, Seidel M, et al. Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia: a phase 1 dose-finding safety and tolerability trial. Lancet Haematol. 2014;1(3):e95.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Sangiorgi S, Manelli A, Reguzzoni M, Ronga M, Protasoni M, Dell’Orbo C. The cutaneous microvascular architecture of human diabetic toe studied by corrosion casting and scanning electron microscopy analysis. Anat Rec Adv Integr Anat Evol Biol. 2010;293(10):1639–45.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Matthieu Roustit
    • 1
  • Jordan Loader
    • 1
  • Dimitrios Baltzis
    • 1
  • Wanni Zhao
    • 1
  • Aristidis Veves
    • 2
  1. 1.Microcirculatory Lab, Rongxiang Xu, MD, Center for Regenerative Therapeutics, Joslin-Beth Israel Deaconess Foot Center, Beth Israel Deaconess Medical Center, Harvard Medical SchoolBostonUSA
  2. 2.The Rongxiang Xu, MD, Center for Regenerative Therapeutics Research Director, Joslin-Beth Israel Deaconess Foot CenterBeth Israel Deaconess Medical CenterBostonUSA

Personalised recommendations