Berlanga-Acosta J, López-Mola E, Garcia-Siverio M, Guillen-Nieto G, Lopez-Saura P, Valdez-Pérez C, Puentes-Madera I, Savigne-Gutierrez W, Álvarez-Duarte H, Miranda-Espinosa N, Mir-Benítez AJ, García DD, Mendoza-Mari Y, Martínez-Espina MD, Garcia-Ojalvo A, Subiros-Martinez N, Herrera-Martínez L

Language: English
References: 131
Page: 208-217
PDF size: 284.38 Kb.

ABSTRACT

Type 2 diabetes mellitus comprises a group of non-communicable metabolic diseases with an expanding pandemic magnitude. Diabetes predisposes to lower extremities ulceration and impairs the healing process leading to wounds chronification. Diabetes also dismantles innate immunity favoring wound infection. Amputation is therefore acknowledged as one of the disease’s complications. Hyperglycemia appears as the proximal detonator of toxic effectors including pro-inflammation, spillover of reactive oxygen and nitrogen species. The systemic accumulation of advanced glycation end-products irreversibly impairs the entire physiology from cells-to-organs. Insulin axis deficiency weakens wounds’ anabolism and predisposes to inflammation. These factors converge to hamper fibroblasts and endothelial cells proliferation, migration, homing, secretion and organization of a productive granulation tissue. Diabetic wound bed may turn chronically inflamed, pro-catabolic and a superimposed source of circulating pro-inflammatory cytokines, establishing a self-perpetuating loop. Diabetic toxicity breadth includes mitochondrial damages in fibroblasts and endothelial cells becoming prone to apoptosis thus hindering granulation. Endothelial progenitor cells recruitment and tubulogenesis are also impaired. Failure of wound re-epithelialization remains as a clinical challenge while it appears to be biologically multifactorial. Novel medical interventions as the local intra-ulcer infiltration of epidermal growth factor have emerged to hopefully reduce the current worldwide amputation rates.

REFERENCES

1. 1. Daneman D. Type 1 diabetes. Lancet. 2006;367(9513):847-58.

2. Lamers ML, Almeida ME, Vicente-Manzanares M, Horwitz AF, Santos MF. High glucose-mediated oxidative stress impairs cell migration. PLoS One. 2011;6(8):e22865.

3. Bouche C, Serdy S, Kahn CR, Goldfine AB. The cellular fate of glucose and its relevance in type 2 diabetes. Endocr Rev. 2004;25(5):807-30.

4. Armstrong DG, Cohen K, Courric S, Bharara M, Marston W. Diabetic foot ulcers and vascular insufficiency: our population has changed, but our methods have not. J Diabetes Sci Technol. 2011;5(6):1591-5.

5. Pryce TD. A case of perforating ulcers of both feet associated with diabetes and ataxic symptoms. Lancet. 1887;2(3331):11-12.

6. Nguyen PD, Tutela JP, Thanik VD, Knobel D, Allen RJ, Jr., Chang CC, et al. Improved diabetic wound healing through topical silencing of p53 is associated with augmented vasculogenic mediators. Wound Repair Regen. 2010;18(6):553-9.

7. Berlanga-Acosta J, Valdéz-Pérez C, Savigne-Gutiérrez W, Mendoza-Marí Y, Franco-Pérez N, Vargas-Machiran E, et al. Cellular and molecular insights into the wound healing mechanism in diabetes. Biotecnol Apl. 2010;27(4):255-61.

8. Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J. The global burden of diabetic foot disease. Lancet. 2005;366(9498):1719-24.

9. Gloire G, Legrand-Poels S, Piette J. NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol. 2006;72(11):1493-505.

10. Mitra S, Abraham E. Participation of superoxide in neutrophil activation and cytokine production. Biochim Biophys Acta. 2006;1762(8):732-41.

11. Pubmed [Internet]. Bethesda, MD: National Center for Biotechnology Information, U.S. National Library of Medicine. c2012 [cited 2012 May 18]. Available from: www.ncbi.nlm.nih.gov/pubmed

12. Bioline International [Internet]. Sao Paulo: Reference Center on Environmental Information, CRIA, Brazil. c1989-2012 [cited 2012 May 18]. Available from: www.bioline.org.br

13. Guarino M, Tosoni A, Nebuloni M. Direct contribution of epithelium to organ fibrosis: epithelial-mesenchymal transition. Hum Pathol. 2009;40(10):1365-76.

14. Yevdokimova NY. High glucose-induced alterations of extracellular matrix of human skin fibroblasts are not dependent on TSP-1-TGFbeta1 pathway. J Diabetes Complications. 2003;17(6):355-64.

15. Rowe DW, Starman BJ, Fujimoto WY, Williams RH. Abnormalities in proliferation and protein synthesis in skin fibroblast cultures from patients with diabetes mellitus. Diabetes. 1977;26(4):284-90.

16. Hehenberger K, Hansson A. High glucose-induced growth factor resistance in human fibroblasts can be reversed by antioxidants and protein kinase C-inhibitors. Cell Biochem Funct. 1997;15(3):197-201.

17. Goldstein S, Moerman EJ, Soeldner JS, Gleason RE, Barnett DM. Diabetes mellitus and genetic prediabetes. Decreased replicative capacity of cultured skin fibroblasts. J Clin Invest. 1979;63(3):358-70.

18. Goldstein S. Cellular and molecular biological studies on diabetes mellitus. Pathol Biol (Paris). 1984;32(2):99-106.

19. Hehenberger K, Heilborn JD, Brismar K, Hansson A. Inhibited proliferation of fibroblasts derived from chronic diabetic wounds and normal dermal fibroblasts treated with high glucose is associated with increased formation of l-lactate. Wound Repair Regen. 1998;6(2):135-41.

20. Loots MA, Lamme EN, Mekkes JR, Bos JD, Middelkoop E. Cultured fibroblasts from chronic diabetic wounds on the lower extremity (non-insulin-dependent diabetes mellitus) show disturbed proliferation. Arch Dermatol Res. 1999;291(2-3):93-9.

21. Grazul-Bilska AT, Luthra G, Reynolds LP, Bilski JJ, Johnson ML, Adbullah SA, et al. Effects of basic fibroblast growth factor (FGF-2) on proliferation of human skin fibroblasts in type II diabetes mellitus. Exp Clin Endocrinol Diabetes. 2002;110(4):176-81.

22. Loots MA, Kenter SB, Au FL, van Galen WJ, Middelkoop E, Bos JD, et al. Fibroblasts derived from chronic diabetic ulcers differ in their response to stimulation with EGF, IGF-I, bFGF and PDGF-AB compared to controls. Eur J Cell Biol. 2002;81(3):153-60.

23. Xue SN, Lei J, Yang C, Lin DZ, Yan L. The biological behaviors of rat dermal fibroblasts can be inhibited by high levels of MMP9. Exp Diabetes Res. 2012;2012:494579.

24. Velander P, Theopold C, Hirsch T, Bleiziffer O, Zuhaili B, Fossum M, et al. Impaired wound healing in an acute diabetic pig model and the effects of local hyperglycemia. Wound Repair Regen. 2008;16(2):288-93.

25. Loughlin DT, Artlett CM. 3-Deoxyglucosone-collagen alters human dermal fibroblast migration and adhesion: implications for impaired wound healing in patients with diabetes. Wound Repair Regen. 2009;17(5):739-49.

26. Loughlin DT, Artlett CM. Modification of collagen by 3-deoxyglucosone alters wound healing through differential regulation of p38 MAP kinase. PLoS One. 2011;6(5):e18676.

27. Loughlin DT, Artlett CM. Precursor of advanced glycation end products mediates ER-stress-induced caspase-3 activation of human dermal fibroblasts through NAD(P)H oxidase 4. PLoS One. 2010;5(6):e11093.

28. Alikhani M, Maclellan CM, Raptis M, Vora S, Trackman PC, Graves DT. Advanced glycation end products induce apoptosis in fibroblasts through activation of ROS, MAP kinases, and the FOXO1 transcription factor. Am J Physiol Cell Physiol. 2007;292(2):C850-6.

29. Tong X, Ying J, Pimentel DR, Trucillo M, Adachi T, Cohen RA. High glucose oxidizes SERCA cysteine-674 and prevents inhibition by nitric oxide of smooth muscle cell migration. J Mol Cell Cardiol. 2008;44(2):361-9.

30. Lerman OZ, Galiano RD, Armour M, Levine JP, Gurtner GC. Cellular dysfunction in the diabetic fibroblast: impairment in migration, vascular endothelial growth factor production, and response to hypoxia. Am J Pathol. 2003;162(1):303-12.

31. Wall SJ, Sampson MJ, Levell N, Murphy G. Elevated matrix metalloproteinase-2 and -3 production from human diabetic dermal fibroblasts. Br J Dermatol. 2003;149(1):13-6.

32. Burrow JW, Koch JA, Chuang HH, Zhong W, Dean DD, Sylvia VL. Nitric oxide donors selectively reduce the expression of matrix metalloproteinases-8 and -9 by human diabetic skin fibroblasts. J Surg Res. 2007;140(1):90-8.

33. Sivitz WI, Yorek MA. Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities. Antioxid Redox Signal. 2010;12(4):537-77.

34. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107(9):1058-70.

35. Ponugoti B, Dong G, Graves DT. Role of forkhead transcription factors in diabetes-induced oxidative stress. Exp Diabetes Res. 2012;2012:939751.

36. Storz P. Forkhead homeobox type O transcription factors in the responses to oxidative stress. Antioxid Redox Signal. 2011;14(4):593-605.

37. Siqueira MF, Li J, Chehab L, Desta T, Chino T, Krothpali N, et al. Impaired wound healing in mouse models of diabetes is mediated by TNF-alpha dysregulation and associated with enhanced activation of forkhead box O1 (FOXO1). Diabetologia. 2010;53(2):378-88.

38. Obrenovich ME, Monnier VM. Apoptotic killing of fibroblasts by matrix-bound advanced glycation endproducts. Sci Aging Knowledge Environ. 2005;2005(4):pe3.

39. Lima MH, Caricilli AM, de Abreu LL, Araujo EP, Pelegrinelli FF, Thirone AC, et al. Topical insulin accelerates wound healing in diabetes by enhancing the AKT and ERK pathways: a double-blind placebo-controlled clinical trial. PLoS One. 2012;7(5):e36974.

40. Dandona P, Chaudhuri A, Ghanim H, Mohanty P. Insulin as an anti-inflammatory and antiatherogenic modulator. J Am Coll Cardiol. 2009;53(5 Suppl):S14-20.

41. Pirola L, Balcerczyk A, Okabe J, El-Osta A. Epigenetic phenomena linked to diabetic complications. Nat Rev Endocrinol. 2010;6(12):665-75.

42. Turner RC. The U.K. Prospective Diabetes Study. A review. Diabetes Care. 1998;21 Suppl 3:C35-8.

43. The 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(14):977-86.

44. Sonta T, Inoguchi T, Tsubouchi H, Sekiguchi N, Kobayashi K, Matsumoto S, et al. Evidence for contribution of vascular NAD(P)H oxidase to increased oxidative stress in animal models of diabetes and obesity. Free Radic Biol Med. 2004;37(1):115-23.

45. Waltenberger J, Lange J, Kranz A. Vascular endothelial growth factor-A-induced chemotaxis of monocytes is attenuated in patients with diabetes mellitus: A potential predictor for the individual capacity to develop collaterals. Circulation. 2000;102(2):185-90.

46. Efron DT, Most D, Barbul A. Role of nitric oxide in wound healing. Curr Opin Clin Nutr Metab Care. 2000;3(3):197-204.

47. Epstein SE, Kornowski R, Fuchs S, Dvorak HF. Angiogenesis therapy: amidst the hype, the neglected potential for serious side effects. Circulation. 2001;104(1):115-9.

48. Epstein SE, Fuchs S, Zhou YF, Baffour R, Kornowski R. Therapeutic interventions for enhancing collateral development by administration of growth factors: basic principles, early results and potential hazards. Cardiovasc Res. 2001;49(3):532-42.

49. Khan TA, Sellke FW, Laham RJ. Gene therapy progress and prospects: therapeutic angiogenesis for limb and myocardial ischemia. Gene Ther. 2003;10(4):285-91.

50. Duncan E, Ezzat V, Kearney M. Insulin and endothelial function: physiological environment defines effect on atherosclerotic risk. Curr Diabetes Rev. 2006;2(1):51-61.

51. Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M, et al. Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res. 2001;88(2):E14-22.

52. Jain M, LoGerfo FW, Guthrie P, Pradhan L. Effect of hyperglycemia and neuropeptides on interleukin-8 expression and angiogenesis in dermal microvascular endothelial cells. J Vasc Surg. 2011;53(6):1654-60 e2.

53. Busik JV, Mohr S, Grant MB. Hyperglycemia-induced reactive oxygen species toxicity to endothelial cells is dependent on paracrine mediators. Diabetes. 2008;57(7):1952-65.

54. Rai NK, Suryabhan, Ansari M, Kumar M, Shukla VK, Tripathi K. Effect of glycaemic control on apoptosis in diabetic wounds. J Wound Care. 2005;14(6):277-81.

55. Kageyama S, Yokoo H, Tomita K, Kageyama-Yahara N, Uchimido R, Matsuda N, et al. High glucose-induced apoptosis in human coronary artery endothelial cells involves up-regulation of death receptors. Cardiovasc Diabetol. 2011;10:73.

56. Su D, Coudriet GM, Hyun Kim D, Lu Y, Perdomo G, Qu S, et al. FoxO1 links insulin resistance to proinflammatory cytokine IL-1beta production in macrophages. Diabetes. 2009;58(11):2624-33.

57. Simons M. Angiogenesis, arteriogenesis, and diabetes: paradigm reassessed? J Am Coll Cardiol. 2005;46(5):835-7.

58. Tanii M, Yonemitsu Y, Fujii T, Shikada Y, Kohno R, Onimaru M, et al. Diabetic microangiopathy in ischemic limb is a disease of disturbance of the platelet-derived growth factor-BB/protein kinase C axis but not of impaired expression of angiogenic factors. Circ Res. 2006;98(1):55-62.

59. Tamarat R, Silvestre JS, Huijberts M, Benessiano J, Ebrahimian TG, Duriez M, et al. Blockade of advanced glycation end-product formation restores ischemia-induced angiogenesis in diabetic mice. Proc Natl Acad Sci USA. 2003;100(14):8555-60.

60. Magnusson PU, Looman C, Ahgren A, Wu Y, Claesson-Welsh L, Heuchel RL. Platelet-derived growth factor receptor-beta constitutive activity promotes angiogenesis in vivo and in vitro. Arterioscler Thromb Vasc Biol. 2007;27(10):2142-9.

61. Davidson SM, Duchen MR. Endothelial mitochondria: contributing to vascular function and disease. Circ Res. 2007;100(8):1128-41.

62. Fosslien E. Mitochondrial medicine-molecular pathology of defective oxidative phosphorylation. Ann Clin Lab Sci. 2001;31(1):25-67.

63. Martin A, Komada MR, Sane DC. Abnormal angiogenesis in diabetes mellitus. Med Res Rev. 2003;23(2):117-45.

64. Altavilla D, Saitta A, Cucinotta D, Galeano M, Deodato B, Colonna M, et al. Inhibition of lipid peroxidation restores impaired vascular endothelial growth factor expression and stimulates wound healing and angiogenesis in the genetically diabetic mouse. Diabetes. 2001;50(3):667-74.

65. Cooke JP, Losordo DW. Nitric oxide and angiogenesis. Circulation. 2002;105(18):2133-5.

66. Leo CH, Hart JL, Woodman OL. Impairment of both nitric oxide-mediated and EDHF-type relaxation in small mesenteric arteries from rats with streptozotocin-induced diabetes. Br J Pharmacol. 2011;162(2):365-77.

67. Kampfer H, Pfeilschifter J, Frank S. Expression and activity of arginase isoenzymes during normal and diabetes-impaired skin repair. J Invest Dermatol. 2003;121(6):1544-51.

68. Cooke CL, Davidge ST. Peroxynitrite increases iNOS through NF-kappaB and decreases prostacyclin synthase in endothelial cells. Am J Physiol Cell Physiol. 2002;282(2):C395-402.

69. Higashi Y, Noma K, Yoshizumi M, Kihara Y. Endothelial function and oxidative stress in cardiovascular diseases. Circ J. 2009;73(3):411-8.

70. Tamarat R, Silvestre JS, Le Ricousse-Roussanne S, Barateau V, Lecomte-Raclet L, Clergue M, et al. Impairment in ischemia-induced neovascularization in diabetes: bone marrow mononuclear cell dysfunction and therapeutic potential of placenta growth factor treatment. Am J Pathol. 2004;164(2):457-66.

71. Saito H, Yamamoto Y, Yamamoto H. Diabetes alters subsets of endothelial progenitor cells that reside in blood, bone marrow, and spleen. Am J Physiol Cell Physiol. 2012;302(6):C892-901.

72. Loomans CJ, de Koning EJ, Staal FJ, Rookmaaker MB, Verseyden C, de Boer HC, et al. Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes. 2004;53(1):195-9.

73. Shen C, Li Q, Zhang YC, Ma G, Feng Y, Zhu Q, et al. Advanced glycation endproducts increase EPC apoptosis and decrease nitric oxide release via MAPK pathways. Biomed Pharmacother. 2010;64(1):35-43.

74. Reinhard H, Jacobsen PK, Lajer M, Pedersen N, Billestrup N, Mandrup-Poulsen T, et al. Multifactorial treatment increases endothelial progenitor cells in patients with type 2 diabetes. Diabetologia. 2010;53(10):2129-33.

75. Acosta JB, del Barco DG, Vera DC, Savigne W, Lopez-Saura P, Guillen Nieto G, et al. The pro-inflammatory environment in recalcitrant diabetic foot wounds. Int Wound J. 2008;5(4):530-9.

76. Jagannathan-Bogdan M, McDonnell ME, Shin H, Rehman Q, Hasturk H, Apovian CM, et al. Elevated proinflammatory cytokine production by a skewed T cell compartment requires monocytes and promotes inflammation in type 2 diabetes. J Immunol. 2011;186(2):1162-72.

77. Weigelt C, Rose B, Poschen U, Ziegler D, Friese G, Kempf K, et al. Immune mediators in patients with acute diabetic foot syndrome. Diabetes Care. 2009;32(8):1491-6.

78. Tuvdendorj D, Zhang XJ, Chinkes DL, Aarsland A, Kulp GA, Jeschke MG, et al. Intensive insulin treatment increases donor site wound protein synthesis in burn patients. Surgery. 2011;149(4):512-8.

79. Zhang XJ, Chinkes DL, Irtun O, Wolfe RR. Anabolic action of insulin on skin wound protein is augmented by exogenous amino acids. Am J Physiol Endocrinol Metab. 2002;282(6):E1308-15.

80. Adams CM. Role of the transcription factor ATF4 in the anabolic actions of insulin and the anti-anabolic actions of glucocorticoids. J Biol Chem. 2007;282(23):16744-53.

81. Gupta V. Pleiotropic effects of incretins. Indian J Endocrinol Metab. 2012;16 Suppl 1:S47-56.

82. Ta NN, Li Y, Schuyler CA, Lopes-Virella MF, Huang Y. DPP-4 (CD26) inhibitor alogliptin inhibits TLR4-mediated ERK activation and ERK-dependent MMP-1 expression by U937 histiocytes. Atherosclerosis. 2010;213(2):429-35.

83. Galkowska H, Wojewodzka U, Olszewski WL. Chemokines, cytokines, and growth factors in keratinocytes and dermal endothelial cells in the margin of chronic diabetic foot ulcers. Wound Repair Regen. 2006;14(5):558-65.

84. Blakytny R, Jude EB. Altered molecular mechanisms of diabetic foot ulcers. Int J Low Extrem Wounds. 2009;8(2):95-104.

85. Surh CD, Sprent J. TGF-beta puts the brakes on homeostatic proliferation. Nat Immunol. 2012;13(7):628-30.

86. Daley WP, Peters SB, Larsen M. Extracellular matrix dynamics in development and regenerative medicine. J Cell Sci. 2008;121(Pt 3):255-64.

87. Schultz G, Berlanga-Acosta J, Cowan L, Stechmiller J. Linking the Advanced Glycation Endproducts/Receptor for Advanced Glycation Endproducts Pathway in Diabetics with Inflammation and Topical Antiinflammatory Treatments of Chronic Wounds. In: Sen CK, editor. Advances in Wound Care. Volume 1. Ohio: The Ohio State University Medical Center; 2010. p. 248-52.

88. Skoutas D, Papanas N, Georgiadis GS, Zervas V, Manes C, Maltezos E, et al. Risk factors for ipsilateral reamputation in patients with diabetic foot lesions. Int J Low Extrem Wounds. 2009;8(2):69-74.

89. Loots MA, Lamme EN, Zeegelaar J, Mekkes JR, Bos JD, Middelkoop E. Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds. J Invest Dermatol.1998;111(5):850-7.

90. Black E, Vibe-Petersen J, Jorgensen LN, Madsen SM, Agren MS, Holstein PE, et al. Decrease of collagen deposition in wound repair in type 1 diabetes independent of glycemic control. Arch Surg. 2003;138(1):34-40.

91. Sliman SM, Eubank TD, Kotha SR, Kuppusamy ML, Sherwani SI, Butler ES, et al. Hyperglycemic oxoaldehyde, glyoxal, causes barrier dysfunction, cytoskeletal alterations, and inhibition of angiogenesis in vascular endothelial cells: aminoguanidine protection. Mol Cell Biochem. 2010;333(1-2):9-26.

92. Berlanga-Acosta J, Schultz GS, Lopez-Saura P. Biology of the Diabetic Wound. In: Overhaussen PE, editor. Foot Ulcers: Causes, Diagnosis and Treatments. Hauppauge: Nova Science Publishers, Inc.; 2009. p. 51-88.

93. Mulder GD, Lee DK, Jeppesen NS. Comprehensive review of the clinical application of autologous mesenchymal stem cells in the treatment of chronic wounds and diabetic bone healing. Int Wound J. 2012. Forthcoming.

94. Usui ML, Mansbridge JN, Carter WG, Fujita M, Olerud JE. Keratinocyte migration, proliferation, and differentiation in chronic ulcers from patients with diabetes and normal wounds. J Histochem Cytochem. 2008;56(7):687-96.

95. Wetzler C, Kampfer H, Stallmeyer B, Pfeilschifter J, Frank S. Large and sustained induction of chemokines during impaired wound healing in the genetically diabetic mouse: prolonged persistence of neutrophils and macrophages during the late phase of repair. J Invest Dermatol. 2000;115(2):245-53.

96. Nwomeh BC, Yager DR, Cohen IK. Physiology of the chronic wound. Clin Plast Surg. 1998;25(3):341-56.

97. Naguib G, Al-Mashat H, Desta T, Graves DT. Diabetes prolongs the inflammatory response to a bacterial stimulus through cytokine dysregulation. J Invest Dermatol. 2004;123(1):87-92.

98. Goldberg MT, Han YP, Yan C, Shaw MC, Garner WL. TNF-alpha suppresses alpha-smooth muscle actin expression in human dermal fibroblasts: an implication for abnormal wound healing. J Invest Dermatol. 2007;127(11):2645-55.

99. Mast BA, Schultz GS. Interactions of cytokines, growth factors, and proteases in acute and chronic wounds. Wound Repair Regen. 1996;4(4):411-20.

100. Weiss SJ. Tissue destruction by neutrophils. N Engl J Med. 1989;320(6):365-76.

101. Piwowar A, Knapik-Kordecka M, Warwas M. Concentration of leukocyte elastase in plasma and polymorphonuclear neutrophil extracts in type 2 diabetes. Clin Chem Lab Med. 2000;38(12):1257-61.

102. Stanley CM, Wang Y, Pal S, Klebe RJ, Harkless LB, Xu X, et al. Fibronectin fragmentation is a feature of periodontal disease sites and diabetic foot and leg wounds and modifies cell behavior. J Periodontol. 2008;79(5):861-75.

103. Duckworth WC, Fawcett J, Reddy S, Page JC. Insulin-degrading activity in wound fluid. J Clin Endocrinol Metab. 2004;89(2):847-51.

104. Mantzoros CS, Moschos S, Avramopoulos I, Kaklamani V, Liolios A, Doulgerakis DE, et al. Leptin concentrations in relation to body mass index and the tumor necrosis factor-alpha system in humans. J Clin Endocrinol Metab. 1997;82(10):3408-13.

105. Mi Q, Riviere B, Clermont G, Steed DL, Vodovotz Y. Agent-based model of inflammation and wound healing: insights into diabetic foot ulcer pathology and the role of transforming growth factor-beta1. Wound Repair Regen. 2007;15(5):671-82.

106. Zou MH, Shi C, Cohen RA. High glucose via peroxynitrite causes tyrosine nitration and inactivation of prostacyclin synthase that is associated with thromboxane/prostaglandin H(2) receptor-mediated apoptosis and adhesion molecule expression in cultured human aortic endothelial cells. Diabetes. 2002;51(1):198-203.

107. Petrova N, Edmonds M. Emerging drugs for diabetic foot ulcers. Expert Opin Emerg Drugs. 2006;11(4):709-24.

108. Desmouliere A, Chaponnier C, Gabbiani G. Tissue repair, contraction, and the myofibroblast. Wound Repair Regen. 2005;13(1):7-12.

109. Mori L, Bellini A, Stacey MA, Schmidt M, Mattoli S. Fibrocytes contribute to the myofibroblast population in wounded skin and originate from the bone marrow. Exp Cell Res. 2005;304(1):81-90.

110. Fadini GP, Avogaro A. It is all in the blood: the multifaceted contribution of circulating progenitor cells in diabetic complications. Exp Diabetes Res. 2012;2012:742976.

111. Bermudez DM, Xu J, Herdrich BJ, Radu A, Mitchell ME, Liechty KW. Inhibition of stromal cell-derived factor-1alpha further impairs diabetic wound healing. J Vasc Surg. 2011;53(3):774-84.

112. Pilling D, Buckley CD, Salmon M, Gomer RH. Inhibition of fibrocyte differentiation by serum amyloid P. J Immunol. 2003;171(10):5537-46.

113. Morasso MI, Tomic-Canic M. Epidermal stem cells: the cradle of epidermal determination, differentiation and wound healing. Biol Cell. 2005;97(3):173-83.

114. Deveci M, Gilmont RR, Dunham WR, Mudge BP, Smith DJ, Marcelo CL. Glutathione enhances fibroblast collagen contraction and protects keratinocytes from apoptosis in hyperglycaemic culture. Br J Dermatol. 2005;152(2):217-24.

115. Lan CC, Liu IH, Fang AH, Wen CH, Wu CS. Hyperglycaemic conditions decrease cultured keratinocyte mobility: implications for impaired wound healing in patients with diabetes. Br J Dermatol. 2008;159(5):1103-15.

116. Zhu P, Yang C, Chen LH, Ren M, Lao GJ, Yan L. Impairment of human keratinocyte mobility and proliferation by advanced glycation end products-modified BSA. Arch Dermatol Res. 2011;303(5):339-50.

117. El Ghalbzouri A, Hensbergen P, Gibbs S, Kempenaar J, van der Schors R, Ponec M. Fibroblasts facilitate re-epithelialization in wounded human skin equivalents. Lab Invest. 2004;84(1):102-12.

118. Liu Y, Petreaca M, Yao M, Martins-Green M. Cell and molecular mechanisms of keratinocyte function stimulated by insulin during wound healing. BMC Cell Biol. 2009;10:1.

119. Goren I, Muller E, Schiefelbein D, Gutwein P, Seitz O, Pfeilschifter J, et al. Akt1 controls insulin-driven VEGF biosynthesis from keratinocytes: implications for normal and diabetes-impaired skin repair in mice. J Invest Dermatol. 2009;129(3):752-64.

120. Terashi H, Izumi K, Deveci M, Rhodes LM, Marcelo CL. High glucose inhibits human epidermal keratinocyte proliferation for cellular studies on diabetes mellitus. Int Wound J. 2005;2(4):298-304.

121. Wertheimer E, Spravchikov N, Trebicz M, Gartsbein M, Accili D, Avinoah I, et al. The regulation of skin proliferation and differentiation in the IR null mouse: implications for skin complications of diabetes. Endocrinology. 2001;142(3):1234-41.

122. Banno T, Gazel A, Blumenberg M. Effects of tumor necrosis factor-alpha (TNF alpha) in epidermal keratinocytes revealed using global transcriptional profiling. J Biol Chem. 2004;279(31):32633-42.

123. Stojadinovic O, Brem H, Vouthounis C, Lee B, Fallon J, Stallcup M, et al. Molecular pathogenesis of chronic wounds: the role of beta-catenin and c-myc in the inhibition of epithelialization and wound healing. Am J Pathol. 2005;167(1):59-69.

124. Sivamani RK, Garcia MS, Isseroff RR. Wound re-epithelialization: modulating keratinocyte migration in wound healing. Front Biosci. 2007;12:2849-68.

125. Coulombe PA. Wound epithelialization: accelerating the pace of discovery. J Invest Dermatol. 2003;121(2):219-30.

126. Nanney LB, Paulsen S, Davidson MK, Cardwell NL, Whitsitt JS, Davidson JM. Boosting epidermal growth factor receptor expression by gene gun transfection stimulates epidermal growth in vivo. Wound Repair Regen. 2000; 8(2):117-27.

127. Li S, Wang Q, Wang Y, Chen X, Wang Z. PLC-gamma1 and Rac1 coregulate EGF-induced cytoskeleton remodeling and cell migration. Mol Endocrinol. 2009;23(6):901-13.

128. Kusewitt DF, Choi C, Newkirk KM, Leroy P, Li Y, Chavez MG, et al. Slug/Snai2 is a downstream mediator of epidermal growth factor receptor-stimulated reepithelialization. J Invest Dermatol. 2009;129(2):491-5.

129. Frank S, Hubner G, Breier G, Longaker MT, Greenhalgh DG, Werner S. Regulation of vascular endothelial growth factor expression in cultured keratinocytes. Implications for normal and impaired wound healing. J Biol Chem. 1995;270(21):12607-13.

130. Aoki S, Toda S, Ando T, Sugihara H. Bone marrow stromal cells, preadipocytes, and dermal fibroblasts promote epidermal regeneration in their distinctive fashions. Mol Biol Cell. 2004;15(10):4647-57.

131. Gopalakrishnan V, Vignesh RC, Arunakaran J, Aruldhas MM, Srinivasan N. Effects of glucose and its modulation by insulin and estradiol on BMSC differentiation into osteoblastic lineages. Biochem Cell Biol. 2006; 84(1):93-101.