Skip to main content

Effects of insulin on the skin: possible healing benefits for diabetic foot ulcers

Archives of Dermatological Research volume 308, pages 677–694 (2016)Cite this article

Abstract

Diabetic foot ulcers affect 15–20 % of all diabetic patients and remain an important challenge since the available therapies have limited efficacy and some of the novel therapeutic approaches, which include growth factors and stem cells, are highly expensive and their safety remains to be evaluated. Despite its low cost and safety, the interest for topical insulin as a healing agent has increased only in the last 20 years. The molecular mechanisms of insulin signaling and its metabolic effects have been well studied in its classical target tissues. However, little is known about the specific effects of insulin in healthy or even diabetic skin. In addition, the mechanisms involved in the effects of insulin on wound healing have been virtually unknown until about 10 years ago. This paper will review the most recent advances in the cellular and molecular mechanisms that underlie the beneficial effects of insulin on skin wound healing in diabetes. Emerging evidence that links dysfunction of key cellular organelles, namely the endoplasmic reticulum and the mitochondria, to changes in the autophagy response, as well as the impaired wound healing in diabetic patients will also be discussed along with the putative mechanisms whereby insulin could regulate/modulate these alterations.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Aghdam SY, Eming SA, Willenborg S, Neuhaus B, Niessen CM, Partridge L, Krieg T, Bruning JC (2012) Vascular endothelial insulin/IGF-1 signaling controls skin wound vascularization. Biochem Biophys Res Commun 421:197–202

    Article  CAS  PubMed  Google Scholar 

  2. Aicher A, Heeschen C, Mildner-Rihm C, Urbich C, Ihling C, Technau-Ihling K, Zeiher AM, Dimmeler S (2003) Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 9:1370–1376

    Article  CAS  PubMed  Google Scholar 

  3. Armstrong DG, Kanda VA, Lavery LA, Marston W, Mills JL, Boulton AJM (2013) Mind the gap: disparity between research funding and costs of care for diabetic foot ulcers. Diabetes Care 36:1815–1817

    Article  PubMed  PubMed Central  Google Scholar 

  4. Asmann YW, Stump CS, Short KR, Coenen-Schimke JM, Guo Z, Bigelow ML, Nair KS (2006) Skeletal muscle mitochondrial functions, mitochondrial DNA copy numbers, and gene transcript profiles in type 2 diabetic and nondiabetic subjects at equal levels of low or high insulin and euglycemia. Diabetes 55:3309–3319

    Article  CAS  PubMed  Google Scholar 

  5. Aspenström P (1999) Effectors for the Rho GTPases. Curr Opin Cell Biol 11:95–102

    Article  PubMed  Google Scholar 

  6. Athavale V, Nirhale D, Deshpande N, Agrawal K, Calcuttawala M, Goenka G (2014) Role of topical use of insulin in healing of chronic ulcer. Med J DY Patil Univ 7:579–583

    Article  Google Scholar 

  7. Azevedo F, Pessoa A, Moreira G, Santos MD, Liberti E, Araujo E, Carvalho C, Saad M, Lima MH (2015) Effect of topical insulin on second-degree burns in diabetic rats. Biol Res Nurs. 18:181–192

    Article  PubMed  CAS  Google Scholar 

  8. Bach D, Naon D, Pich S et al (2005) Expression of Mfn2, the Charcot-Marie-tooth neuropathy type 2A gene, in human skeletal muscle effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor α and interleukin-6. Diabetes 54:2685–2693

    Article  CAS  PubMed  Google Scholar 

  9. Bach D, Pich S, Soriano FX et al (2003) Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity. J Biol Chem 278:17190–17197

    Article  CAS  PubMed  Google Scholar 

  10. Back SH, Kaufman RJ (2012) Endoplasmic reticulum stress and type 2 diabetes. Ann Rev Biochem 81:767–793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Baltzis D, Eleftheriadou I, Veves A (2014) Pathogenesis and treatment of impaired wound healing in diabetes mellitus: new insights. Adv Ther 31:817–836

    Article  CAS  PubMed  Google Scholar 

  12. Benoliel AM, Kahn-Peries B, Imbert J, Verrando P (1997) Insulin stimulates haptotactic migration of human epidermal keratinocytes through activation of NF-kappa B transcription factor. J Cell Sci 110:2089–2097

    CAS  PubMed  Google Scholar 

  13. Bernales S, Schuck S, Walter P (2007) ER-phagy: selective autophagy of the endoplasmic reticulum. Autophagy 3:285–287

    Article  PubMed  Google Scholar 

  14. Bitar MS, Al-Mulla F (2012) ROS constitute a convergence nexus in the development of IGF1 resistance and impaired wound healing in a rat model of type 2 diabetes. Dis Model Mech 5:375–388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Boden G, Silviera M, Smith B, Cheung P, Homko C (2010) Acute tissue injury caused by subcutaneous fat biopsies produces endoplasmic reticulum stress. J Clin Endocrinol Metab 95:349–352

    Article  CAS  PubMed  Google Scholar 

  16. Buffington CK, El-Shiekh T, Kitabchi AE, Matteri R (1986) Phytohemagglutinin (PHA) activated human T-lymphocytes: concomitant appearance of insulin binding, degradation and insulin-mediated activation of pyruvate dehydrogenase (PDH). Biochem Biophys Res Commun 134:412–419

    Article  CAS  PubMed  Google Scholar 

  17. Bunn RC, Cockrell GE, Ou Y, Thrailkill KM, Lumpkin CK, Fowlkes JL (2010) Palmitate and insulin synergistically induce IL-6 expression in human monocytes. Cardiovasc Diabetol 9:73

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Chen X, Liu Y, Zhang X (2012) Topical insulin application improves healing by regulating the wound inflammatory response. Wound Repair Regen 20:425–434

    Article  PubMed  Google Scholar 

  19. Chen X, Zhang X, Liu Y (2012) Effect of topical insulin application on wound neutrophil function. Wounds 24:178–184

    PubMed  Google Scholar 

  20. Cheng Z, Guo S, Copps K, Dong X, Kollipara R, Rodgers JT, Depinho RA, Puigserver P, White MF (2009) Foxo1 integrates insulin signaling with mitochondrial function in the liver. Nat Med 15:1307–1311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chisalita SI, Arnqvist HJ (2004) Insulin-like growth factor I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells. Am J Physiol Endocrinol Metab 286:E896–E901

    Article  CAS  PubMed  Google Scholar 

  22. Choi S-E, Lee S-M, Lee Y-J, Li L-J, Lee S-J, Lee J-H, Kim Y, Jun H-S, Lee K-W, Kang Y (2009) Protective role of autophagy in palmitate-induced INS-1 beta-cell death. Endocrinology 150:126–134

    Article  CAS  PubMed  Google Scholar 

  23. Christianson MA, Schwartz MW, Suzuki N (2006) Determinants of insulin availability in parenteral nutrition solutions. JPEN J Parenter Enteral Nutr 30:6–9

    Article  CAS  PubMed  Google Scholar 

  24. Deshmane SL, Kremlev S, Amini S, Sawaya BE (2009) Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res 29:313–326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dhall S, Silva JP, Liu Y, Hrynyk M, Garcia M, Chan A, Lyubovitsky J, Neufeld RJ, Martins-Green M (2015) Release of insulin from PLGA-alginate dressing stimulates regenerative healing of burn wounds in rats. Clin Sci (Lond) 1979 129:1115–1129

    Article  CAS  Google Scholar 

  26. Dimitriadis G, Mitrou P, Lambadiari V, Maratou E, Raptis SA (2011) Insulin effects in muscle and adipose tissue. Diabetes Res Clin Pract 93(Suppl 1):S52–S59

    Article  CAS  PubMed  Google Scholar 

  27. DiPietro LA, Burdick M, Low QE, Kunkel SL, Strieter RM (1998) MIP-1alpha as a critical macrophage chemoattractant in murine wound repair. J Clin Invest 101:1693–1698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dipietro LA, Reintjes MG, Low QE, Levi B, Gamelli RL (2001) Modulation of macrophage recruitment into wounds by monocyte chemoattractant protein-1. Wound Repair Regen 9:28–33

    Article  CAS  PubMed  Google Scholar 

  29. Doble BW, Woodgett JR (2003) GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 116:1175–1186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Douaiher J, Succar J, Lancerotto L, Gurish MF, Orgill DP, Hamilton MJ, Krilis SA, Stevens RL (2014) Development of mast cells and importance of their tryptase and chymase serine proteases in inflammation and wound healing. Adv Immunol 122:211–252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dovi JV, He L-K, DiPietro LA (2003) Accelerated wound closure in neutrophil-depleted mice. J Leukoc Biol 73:448–455

    Article  CAS  PubMed  Google Scholar 

  32. Ebato C, Uchida T, Arakawa M et al (2008) Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet. Cell Metab 8:325–332

    Article  CAS  PubMed  Google Scholar 

  33. Eken M, Ates G, Sanlı A, Evren C, Bozkurt S (2007) The effect of topical insulin application on the healing of acute tympanic membrane perforations: a histopathologic study. Eur Arch Otorhinolaryngol 264:999–1002

    Article  PubMed  Google Scholar 

  34. Ercolani L, Lin HL, Ginsberg BH (1985) Insulin-induced desensitization at the receptor and postreceptor level in mitogen-activated human T-lymphocytes. Diabetes 34:931–937

    Article  CAS  PubMed  Google Scholar 

  35. Fadini GP, Sartore S, Albiero M et al (2006) Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy. Arterioscler Thromb Vasc Biol 26:2140–2146

    Article  CAS  PubMed  Google Scholar 

  36. Fang KS, Farboud B, Nuccitelli R, Isseroff RR (1998) Migration of human keratinocytes in electric fields requires growth factors and extracellular calcium. J Invest Dermatol 111:751–756

    Article  CAS  PubMed  Google Scholar 

  37. Fini ME (1999) Keratocyte and fibroblast phenotypes in the repairing cornea. Prog Retin Eye Res 18:529–551

    Article  CAS  PubMed  Google Scholar 

  38. Flier JS, Usher P, Moses AC (1986) Monoclonal antibody to the type I insulin-like growth factor (IGF-I) receptor blocks IGF-I receptor-mediated DNA synthesis: clarification of the mitogenic mechanisms of IGF-I and insulin in human skin fibroblasts. Proc Natl Acad Sci USA 83:664–668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Foster NB (1925) Some surgical aspects of diabetes. J Am Med Assoc 84:572–576

    Article  Google Scholar 

  40. Fujimoto K, Hanson PT, Tran H, Ford EL, Han Z, Johnson JD, Schmidt RE, Green KG, Wice BM, Polonsky KS (2009) Autophagy regulates pancreatic beta cell death in response to Pdx1 deficiency and nutrient deprivation. J Biol Chem 284:27664–27673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Fujitani Y, Kawamori R, Watada H (2009) The role of autophagy in pancreatic beta-cell and diabetes. Autophagy 5:280–282

    Article  CAS  PubMed  Google Scholar 

  42. Gallagher KA, Joshi A, Carson WF et al (2014) Epigenetic changes in bone marrow progenitor cells influence the inflammatory phenotype and alter wound healing in type 2 diabetes. Diabetes 64:1420–1430

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Gerber RM, Van Ort SR (1979) Topical application of insulin in decubitus ulcers. Nurs Res 28:16–19

    Article  CAS  PubMed  Google Scholar 

  44. Germinario RJ, McQuillan A, Oliveira M, Manuel S (1983) Enhanced insulin stimulation of sugar transport and DNA synthesis by glucocorticoids in cultured human skin fibroblasts. Arch Biochem Biophys 226:498–505

    Article  CAS  PubMed  Google Scholar 

  45. Gilchrist JA, Best CH, Banting FG (1923) Observations with insulin on department of soldiers’ civil re-establishment diabetics. Can Med Assoc J 13:565–572

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Gillitzer R, Goebeler M (2001) Chemokines in cutaneous wound healing. J Leukoc Biol 69:513–521

    CAS  PubMed  Google Scholar 

  47. Goodson WH, Hunt TK (1978) Wound healing in experimental diabetes mellitus: importance of early insulin therapy. Surg Forum 29:95–98

    CAS  PubMed  Google Scholar 

  48. Goren I, Müller E, Pfeilschifter J, Frank S (2006) Severely impaired insulin signaling in chronic wounds of diabetic ob/ob mice: a potential role of tumor necrosis factor-α. Am J Pathol 168:765–777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Greaves NS, Ashcroft KJ, Baguneid M, Bayat A (2013) Current understanding of molecular and cellular mechanisms in fibroplasia and angiogenesis during acute wound healing. J Dermatol Sci 72:206–217

    Article  CAS  PubMed  Google Scholar 

  50. Greenway SE, Filler LE, Greenway FL (1999) Topical insulin in wound healing: a randomised, double-blind, placebo-controlled trial. J Wound Care 8:526–528

    Article  CAS  PubMed  Google Scholar 

  51. Gündüz D, Thom J, Hussain I et al (2010) Insulin stabilizes microvascular endothelial barrier function via phosphatidylinositol 3-kinase/Akt-mediated Rac1 activation. Arterioscler Thromb Vasc Biol 30:1237–1245

    Article  PubMed  CAS  Google Scholar 

  52. Guo S (2014) Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models to disease mechanisms. J Endocrinol 220:T1–T23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gurd FB (1937) Postoperative use of insulin in the nondiabetic. Ann Surg 106:761–769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Han S, Liang C-P, DeVries-Seimon T, Ranalletta M, Welch CL, Collins-Fletcher K, Accili D, Tabas I, Tall AR (2006) Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions. Cell Metab 3:257–266

    Article  CAS  PubMed  Google Scholar 

  55. Helderman JH (1981) Role of insulin in the intermediary metabolism of the activated thymic-derived lymphocyte. J Clin Invest 67:1636–1642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hrynyk M, Martins-Green M, Barron AE, Neufeld RJ (2010) Sustained prolonged topical delivery of bioactive human insulin for potential treatment of cutaneous wounds. Int J Pharm 398:146–154

    Article  CAS  PubMed  Google Scholar 

  57. Hrynyk M, Martins-Green M, Barron AE, Neufeld RJ (2012) Alginate-PEG sponge architecture and role in the design of insulin release dressings. Biomacromolecules 13:1478–1485

    Article  CAS  PubMed  Google Scholar 

  58. Hrynyk M, Neufeld RJ (2014) Insulin and wound healing. Burns 40:1433–1446

    Article  PubMed  Google Scholar 

  59. Huang JS, Mukherjee JJ, Chung T, Crilly KS, Kiss Z (1999) Extracellular calcium stimulates DNA synthesis in synergism with zinc, insulin and insulin-like growth factor I in fibroblasts. Eur J Biochem FEBS 266:943–951

    Article  CAS  Google Scholar 

  60. Hu Z-C, Tang B, Guo D, Zhang J, Liang Y-Y, Ma D, Zhu J-Y (2014) Expression of insulin-like growth factor-1 receptor in keloid and hypertrophic scar. Clin Exp Dermatol 39:822–828

    Article  PubMed  PubMed Central  Google Scholar 

  61. IDF (2014) IDF diabetes atlas, 6th edn. International diabetes federation, Brussels

    Google Scholar 

  62. Janssen H, Janssen PHE, Broelsch CE (2004) UW is superior to Celsior and HTK in the protection of human liver endothelial cells against preservation injury. Liver Transpl 10:1514–1523

    Article  PubMed  Google Scholar 

  63. Joseph B (1930) Insulin in the treatment of non-diabetic bed sores. Ann Surg 92:318–319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Khanna S, Biswas S, Shang Y, Collard E, Azad A, Kauh C, Bhasker V, Gordillo GM, Sen CK, Roy S (2010) Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice. PLoS One 5:e9539

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Kim K-A, Shin Y-J, Akram M, Kim E-S, Choi K-W, Suh H, Lee C-H, Bae O-N (2014) High glucose condition induces autophagy in endothelial progenitor cells contributing to angiogenic impairment. Biol Pharm Bull 37:1248–1252

    Article  CAS  PubMed  Google Scholar 

  66. Kondo T, Vicent D, Suzuma K, Yanagisawa M, King GL, Holzenberger M, Kahn CR (2003) Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization. J Clin Invest 111:1835–1842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kubo M, Li T-S, Kamota T, Ohshima M, Qin S-L, Hamano K (2009) Increased expression of CXCR4 and integrin alphaM in hypoxia-preconditioned cells contributes to improved cell retention and angiogenic potency. J Cell Physiol 220:508–514

    Article  CAS  PubMed  Google Scholar 

  68. Kuboki K, Jiang ZY, Takahara N, Ha SW, Igarashi M, Yamauchi T, Feener EP, Herbert TP, Rhodes CJ, King GL (2000) Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo a specific vascular action of insulin. Circulation 101:676–681

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Laybutt DR, Preston AM, Akerfeldt MC, Kench JG, Busch AK, Biankin AV, Biden TJ (2007) Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia 50:752–763

    Article  CAS  PubMed  Google Scholar 

  71. Leal EC, Carvalho E, Tellechea A et al (2015) Substance P promotes wound healing in diabetes by modulating inflammation and macrophage phenotype. Am J Pathol 185:1638–1648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. LeRoith D, Taylor SI, Olefsky JM (2004) Diabetes mellitus: a fundamental and clinical text. Lippincott Williams & Wilkins, Philadelphia

    Google Scholar 

  73. Liang C-P, Han S, Okamoto H, Carnemolla R, Tabas I, Accili D, Tall AR (2004) Increased CD36 protein as a response to defective insulin signaling in macrophages. J Clin Invest 113:764–773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Li C, Yu T, Liu Y, Chen X, Zhang X (2015) Topical application of insulin accelerates vessel maturation of wounds by regulating angiopoietin-1 in diabetic mice. Int J Low Extrem Wounds 14:353–364

    Article  PubMed  Google Scholar 

  75. Lima MHM, Caricilli AM, de Abreu LL et al (2012) Topical insulin accelerates wound healing in diabetes by enhancing the AKT and ERK pathways: a double-blind placebo-controlled clinical trial. PLoS One 7:e36974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Liu H, Cao M, Wang Y, Li L, Zhu L, Xie G, Li Y (2015) Endoplasmic reticulum stress is involved in the connection between inflammation and autophagy in type 2 diabetes. Gen Comp Endocrinol 210:124–129

    Article  CAS  PubMed  Google Scholar 

  77. Liu H-Y, Han J, Cao SY, Hong T, Zhuo D, Shi J, Liu Z, Cao W (2009) Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: inhibition of FoxO1-dependent expression of key autophagy genes by insulin. J Biol Chem 284:31484–31492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Liu Y, Petreaca M, Martins-Green M (2009) Cell and molecular mechanisms of insulin-induced angiogenesis. J Cell Mol Med 13:4492–4504

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Liu Y, Zhang X, Zhang Z, Fang P-Y, Xu W-S (2004) Effects of topical application of insulin on the wound healing in scalded rats. Zhonghua Shao Shang Za Zhi 20:98–101

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Maciolek JA, Alex Pasternak J, Wilson HL (2014) Metabolism of activated T lymphocytes. Curr Opin Immunol 27:60–74

    Article  CAS  PubMed  Google Scholar 

  83. Madibally SV, Solomon V, Mitchell RN, Van De Water L, Yarmush ML, Toner M (2003) Influence of insulin therapy on burn wound healing in rats. J Surg Res 109:92–100

    Article  CAS  PubMed  Google Scholar 

  84. Marhoffer W, Stein M, Schleinkofer L, Federlin K (1993) Evidence of ex vivo and in vitro impaired neutrophil oxidative burst and phagocytic capacity in type 1 diabetes mellitus. Diabetes Res Clin Pract 19:183–188

    Article  CAS  PubMed  Google Scholar 

  85. Marrotte EJ, Chen D-D, Hakim JS, Chen AF (2010) Manganese superoxide dismutase expression in endothelial progenitor cells accelerates wound healing in diabetic mice. J Clin Invest 120:4207–4219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Masuda M, Murakami T, Egawa H, Murata K (1990) Decreased fluidity of polymorphonuclear leukocyte membrane in streptozocin-induced diabetic rats. Diabetes 39:466–470

    Article  CAS  PubMed  Google Scholar 

  87. Matsuzaki H, Daitoku H, Hatta M, Tanaka K, Fukamizu A (2003) Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation. Proc Natl Acad Sci USA 100:11285–11290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Mills RE, Taylor KR, Podshivalova K, McKay DB, Jameson JM (2008) Defects in skin γδ T cell function contribute to delayed wound repair in rapamycin-treated mice. J Immunol 181:3974–3983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Montgomery MK, Turner N (2014) Mitochondrial dysfunction and insulin resistance: an update. Endocr Connect 4:R1–R15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Moura LIF, Dias AMA, Carvalho E, de Sousa HC (2013) Recent advances on the development of wound dressings for diabetic foot ulcer treatment—a review. Acta Biomater 9:7093–7114

    Article  CAS  PubMed  Google Scholar 

  91. Moura J, da Silva L, Cruz MT, Carvalho E (2013) Molecular and cellular mechanisms of bone morphogenetic proteins and activins in the skin: potential benefits for wound healing. Arch Dermatol Res 305:557–569

    Article  CAS  PubMed  Google Scholar 

  92. Musselmann K, Alexandrou B, Kane B, Hassell JR (2005) Maintenance of the keratocyte phenotype during cell proliferation stimulated by insulin. J Biol Chem 280:32634–32639

    Article  CAS  PubMed  Google Scholar 

  93. Nihei S, Yamashita K, Tasaki H, Ozumi K, Nakashima Y (2005) Oxidized low-density lipoprotein-induced apoptosis is attenuated by insulin-activated phosphatidylinositol 3-kinase/Akt through p38 mitogen-activated protein kinase. Clin Exp Pharmacol Physiol 32:224–229

    Article  CAS  PubMed  Google Scholar 

  94. Ozawa K, Kondo T, Hori O, Kitao Y, Stern DM, Eisenmenger W, Ogawa S, Ohshima T (2001) Expression of the oxygen-regulated protein ORP150 accelerates wound healing by modulating intracellular VEGF transport. J Clin Invest 108:41–50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Özcan U, Cao Q, Yilmaz E, Lee A-H, Iwakoshi NN, Özdelen E, Tuncman G, Görgün C, Glimcher LH, Hotamisligil GS (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306:457–461

    Article  PubMed  CAS  Google Scholar 

  96. Özcan U, Yilmaz E, Özcan L, Furuhashi M, Vaillancourt E, Smith RO, Görgün CZ, Hotamisligil GS (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313:1137–1140

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Pastar I, Stojadinovic O, Yin NC, Ramirez H, Nusbaum AG, Sawaya A, Patel SB, Khalid L, Isseroff RR, Tomic-Canic M (2014) Epithelialization in wound healing: a comprehensive review. Adv Wound Care 3:445–464

    Article  Google Scholar 

  98. Paul TN (1966) Treatment by local application of insulin of an infected wound in a diabetic. Lancet 2:574–576

    Article  CAS  PubMed  Google Scholar 

  99. Pereira MJ, Palming J, Rizell M, Aureliano M, Carvalho E, Svensson MK, Eriksson JW (2012) mTOR inhibition with rapamycin causes impaired insulin signalling and glucose uptake in human subcutaneous and omental adipocytes. Mol Cell Endocrinol 355:96–105

    Article  CAS  PubMed  Google Scholar 

  100. Pierre EJ, Barrow RE, Hawkins HK, Nguyen TT, Sakurai Y, Desai M, Wolfe RR, Herndon DN (1998) Effects of insulin on wound healing. J Trauma 44:342–345

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Pradhan L, Nabzdyk C, Andersen ND, LoGerfo FW, Veves A (2009) Inflammation and neuropeptides: the connection in diabetic wound healing. Expert Rev Mol Med 11:e2

    Article  PubMed  PubMed Central  Google Scholar 

  103. Rath S, Kalogeris T, Mai N, Zibari G, Alexander JS, Lefer D, Turnage RH (2006) Insulin prevents oxidant-induced endothelial cell barrier dysfunction via nitric oxide-dependent pathway. Surgery 139:82–91

    Article  PubMed  Google Scholar 

  104. Rauchfuss S, Geiger J, Walter U, Renne T, Gambaryan S (2008) Insulin inhibition of platelet-endothelial interaction is mediated by insulin effects on endothelial cells without direct effects on platelets. J Thromb Haemost JTH 6:856–864

    Article  CAS  PubMed  Google Scholar 

  105. Reiber GE, Vileikyte L, Boyko EJ, del Aguila M, Smith DG, Lavery LA, Boulton AJ (1999) Causal pathways for incident lower-extremity ulcers in patients with diabetes from two settings. Diabetes Care 22:157–162

    Article  CAS  PubMed  Google Scholar 

  106. Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A (1992) The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70:401–410

    Article  CAS  PubMed  Google Scholar 

  107. Ristow HJ (1993) Effect of insulin-like growth factor-I/somatomedin C on thymidine incorporation in cultured psoriatic keratinocytes after growth arrest in growth factor-free medium. Growth Regul 3:129–137

    CAS  PubMed  Google Scholar 

  108. Rubovitch V, Shachar A, Werner H, Pick CG (2011) Does IGF-1 administration after a mild traumatic brain injury in mice activate the adaptive arm of ER stress? Neurochem Int 58:443–446

    Article  CAS  PubMed  Google Scholar 

  109. Sadagurski M, Nofech-Mozes S, Weingarten G, White MF, Kadowaki T, Wertheimer E (2007) Insulin receptor substrate 1 (IRS-1) plays a unique role in normal epidermal physiology. J Cell Physiol 213:519–527

    Article  CAS  PubMed  Google Scholar 

  110. Sadagurski M, Weingarten G, Rhodes CJ, White MF, Wertheimer E (2005) Insulin receptor substrate 2 plays diverse cell-specific roles in the regulation of glucose transport. J Biol Chem 280:14536–14544

    Article  CAS  PubMed  Google Scholar 

  111. Sadagurski M, Yakar S, Weingarten G, Holzenberger M, Rhodes CJ, Breitkreutz D, Leroith D, Wertheimer E (2006) Insulin-like growth factor 1 receptor signaling regulates skin development and inhibits skin keratinocyte differentiation. Mol Cell Biol 26:2675–2687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Sartori M, Ceolotto G, Papparella I, Baritono E, Ciccariello L, Calò L, Leoni M, Semplicini A (2004) Effects of angiotensin II and insulin on ERK1/2 activation in fibroblasts from hypertensive patients. Am J Hypertens 17:604–610

    Article  CAS  PubMed  Google Scholar 

  113. Satoh T (2014) Rho GTPases in insulin-stimulated glucose uptake. Small GTPases 5:e28102

    Article  PubMed  PubMed Central  Google Scholar 

  114. Schürmann C, Goren I, Linke A, Pfeilschifter J, Frank S (2014) Deregulated unfolded protein response in chronic wounds of diabetic ob/ob mice: a potential connection to inflammatory and angiogenic disorders in diabetes-impaired wound healing. Biochem Biophys Res Commun 446:195–200

    Article  PubMed  CAS  Google Scholar 

  115. Secrest AM, Becker DJ, Kelsey SF, Laporte RE, Orchard TJ (2010) Cause-specific mortality trends in a large population-based cohort with long-standing childhood-onset type 1 diabetes. Diabetes 59:3216–3222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Seo H-Y, Kim YD, Lee K-M et al (2008) Endoplasmic reticulum stress-induced activation of activating transcription factor 6 decreases insulin gene expression via up-regulation of orphan nuclear receptor small heterodimer partner. Endocrinology 149:3832–3841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Shah M, Foreman DM, Ferguson MW (1994) Neutralising antibody to TGF-beta 1,2 reduces cutaneous scarring in adult rodents. J Cell Sci 107:1137–1157

    CAS  PubMed  Google Scholar 

  118. Shanley LJ, McCaig CD, Forrester JV, Zhao M (2004) Insulin, not leptin, promotes in vitro cell migration to heal monolayer wounds in human corneal epithelium. Invest Ophthalmol Vis Sci 45:1088–1094

    Article  PubMed  PubMed Central  Google Scholar 

  119. Sharma MD, Garber AJ, Farmer JA (2008) Role of insulin signaling in maintaining energy homeostasis. Endocr Pract 14:373–380

    Article  PubMed  Google Scholar 

  120. Siddle K (2012) Molecular basis of signaling specificity of insulin and IGF receptors: neglected corners and recent advances. Front Endocrinol 3:34

    Article  Google Scholar 

  121. Simpson DM, Ross R (1972) The neutrophilic leukocyte in wound repair. J Clin Invest 51:2009–2023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Sindrilaru A, Peters T, Wieschalka S et al (2011) An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Invest 121:985–997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Siqueira MF, Li J, Chehab L et al (2010) 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 53:378–388

    Article  CAS  PubMed  Google Scholar 

  124. Smith U, Axelsen M, Carvalho E, Eliasson B, Jansson PA, Wesslau C (1999) Insulin signaling and action in fat cells: associations with insulin resistance and type 2 diabetes. Ann N Y Acad Sci 892:119–126

    Article  CAS  PubMed  Google Scholar 

  125. Spagnoli A, Spadoni GL, Sesti G, Del Principe D, Germani D, Boscherini B (1995) Effect of insulin on hydrogen peroxide production by human polymorphonuclear leukocytes. Studies with monoclonal anti-insulin receptor antibodies, and an agonist and an inhibitor of protein kinase C. Horm Res 43:286–293

    Article  CAS  PubMed  Google Scholar 

  126. Spravchikov N, Sizyakov G, Gartsbein M, Accili D, Tennenbaum T, Wertheimer E (2001) Glucose effects on skin keratinocytes implications for diabetes skin complications. Diabetes 50:1627–1635

    Article  CAS  PubMed  Google Scholar 

  127. Stentz FB, Kitabchi AE (2004) De novo emergence of growth factor receptors in activated human CD4+ and CD8+ T lymphocytes. Metabolism 53:117–122

    Article  CAS  PubMed  Google Scholar 

  128. Stentz FB, Kitabchi AE (2007) Transcriptome and proteome expressions involved in insulin resistance in muscle and activated T-lymphocytes of patients with type 2 diabetes. Genom Proteom Bioinform 5:216–235

    Article  CAS  Google Scholar 

  129. Stratton IM, Adler AI, Neil HAW, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR (2000) Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321:405–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Straus DS (1984) Growth-stimulatory actions of insulin in vitro and in vivo. Endocr Rev 5:356–369

    Article  CAS  PubMed  Google Scholar 

  131. Stump CS, Short KR, Bigelow ML, Schimke JM, Nair KS (2003) Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. Proc Natl Acad Sci USA 100:7996–8001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Sun C, Sun L, Ma H, Peng J, Zhen Y, Duan K, Liu G, Ding W, Zhao Y (2012) The phenotype and functional alterations of macrophages in mice with hyperglycemia for long term. J Cell Physiol 227:1670–1679

    Article  CAS  PubMed  Google Scholar 

  133. Sweeney G, Somwar R, Ramlal T, Volchuk A, Ueyama A, Klip A (1999) An inhibitor of p38 mitogen-activated protein kinase prevents insulin-stimulated glucose transport but not glucose transporter translocation in 3T3-L1 adipocytes and L6 myotubes. J Biol Chem 274:10071–10078

    Article  CAS  PubMed  Google Scholar 

  134. Takagi Y, Kashiwagi A, Tanaka Y, Maegawa H, Shigeta Y (1995) Insulin-specific activation of S6 kinase and its desensitization in cultured rat vascular smooth muscle cells. Atherosclerosis 113:19–27

    Article  CAS  PubMed  Google Scholar 

  135. Takahashi Y, Tobe K, Kadowaki H, Katsumata D, Fukushima Y, Yazaki Y, Akanuma Y, Kadowaki T (1997) Roles of insulin receptor substrate-1 and Shc on insulin-like growth factor I receptor signaling in early passages of cultured human fibroblasts. Endocrinology 138:741–750

    Article  CAS  PubMed  Google Scholar 

  136. Tamura N, Hazeki K, Okazaki N, Kametani Y, Murakami H, Takaba Y, Ishikawa Y, Nigorikawa K, Hazeki O (2009) Specific role of phosphoinositide 3-kinase p110alpha in the regulation of phagocytosis and pinocytosis in macrophages. Biochem J 423:99–108

    Article  CAS  PubMed  Google Scholar 

  137. Tchaikovski V, Olieslagers S, Böhmer F-D, Waltenberger J (2009) Diabetes mellitus activates signal transduction pathways resulting in vascular endothelial growth factor resistance of human monocytes. Circulation 120:150–159

    Article  CAS  PubMed  Google Scholar 

  138. Tecilazich F, Dinh T, Pradhan-Nabzdyk L et al (2013) Role of endothelial progenitor cells and inflammatory cytokines in healing of diabetic foot ulcers. PLoS One 8:e83314

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Tellechea A, Kafanas A, Leal EC et al (2013) Increased skin inflammation and blood vessel density in human and experimental diabetes. Int J Low Extrem Wounds 12:4–11

    Article  PubMed  PubMed Central  Google Scholar 

  140. Tellechea A, Leal E, Veves A, Carvalho E (2010) Inflammatory and angiogenic abnormalities in diabetic wound healing: role of neuropeptides and therapeutic perspectives. TOCVJ 3:43–55

    Article  CAS  Google Scholar 

  141. Tepper OM, Galiano RD, Capla JM, Kalka C, Gagne PJ, Jacobowitz GR, Levine JP, Gurtner GC (2002) Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 106(22):2781–2786

    Article  PubMed  Google Scholar 

  142. Tesfaye S, Boulton AJM, Dyck PJ et al (2010) Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 33:2285–2293

    Article  PubMed  PubMed Central  Google Scholar 

  143. Theilgaard-Mönch K, Knudsen S, Follin P, Borregaard N (2004) The transcriptional activation program of human neutrophils in skin lesions supports their important role in wound healing. J Immunol 172:7684–7693

    Article  PubMed  Google Scholar 

  144. Van Belle TL, Coppieters KT, Von Herrath MG (2011) Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev 91:79–118

    Article  PubMed  CAS  Google Scholar 

  145. Viardot A, Grey ST, Mackay F, Chisholm D (2007) Potential antiinflammatory role of insulin via the preferential polarization of effector T cells toward a T helper 2 phenotype. Endocrinology 148:346–353

    Article  CAS  PubMed  Google Scholar 

  146. Wang J-M, Isenberg JS, Billiar TR, Chen AF (2013) Thrombospondin-1/CD36 pathway contributes to bone marrow-derived angiogenic cell dysfunction in type 1 diabetes via Sonic hedgehog pathway suppression. Am J Physiol Endocrinol Metab 305:E1464–E1472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT-H, Brickey WJ, Ting JP-Y (2011) Fatty acid-induced NLRP3-PYCARD inflammasome activation interferes with insulin signaling. Nat Immunol 12:408–415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Weringer EJ, Kelso JM, Tamai IY, Arquilla ER (1982) Effects of insulin on wound healing in diabetic mice. Acta Endocrinol 99:101–108

    CAS  PubMed  Google Scholar 

  149. Wertheimer E, Spravchikov N, Trebicz M, Gartsbein M, Accili D, Avinoah I, Nofeh-Moses S, Sizyakov G, Tennenbaum T (2001) The regulation of skin proliferation and differentiation in the IR null mouse: implications for skin complications of diabetes. Endocrinology 142:1234–1241

    CAS  PubMed  Google Scholar 

  150. Wertheimer E, Taylor SI, Tennenbaum T (1998) Insulin receptor regulation of cell surface integrins: a possible mechanism contributing to the development of diabetic complications. Proc Assoc Am Phys 110:333–339

    CAS  PubMed  Google Scholar 

  151. Wertheimer E, Trebicz M, Eldar T, Gartsbein M, Nofeh-Moses S, Tennenbaum T (2000) Differential roles of insulin receptor and insulin-like growth factor-1 receptor in differentiation of murine skin keratinocytes. J Invest Dermatol 115:24–29

    Article  CAS  PubMed  Google Scholar 

  152. Wetzler C, Kämpfer H, Stallmeyer B, Pfeilschifter J, Frank S (2000) 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 115:245–253

    Article  CAS  PubMed  Google Scholar 

  153. White MF (2003) Insulin signaling in health and disease. Science 302:1710–1711

    Article  CAS  PubMed  Google Scholar 

  154. Wilgus TA, Roy S, McDaniel JC (2013) Neutrophils and wound repair: positive actions and negative reactions. Adv Wound Care 2:379–388

    Article  Google Scholar 

  155. Wilson J, Baines R, Babu E, Kelley C (2008) A role for topical insulin in the management problematic surgical wounds. Ann R Coll Surg Engl 90:160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Wurm S, Neumeier M, Weigert J, Wanninger J, Gerl M, Gindner A, Schäffler A, Aslanidis C, Schölmerich J, Buechler C (2008) Insulin induces monocytic CXCL8 secretion by the mitogenic signalling pathway. Cytokine 44:185–190

    Article  CAS  PubMed  Google Scholar 

  157. Xiao M, Li L, Hu Q, Ma L, Liu L, Chu W, Zhang H (2013) Rapamycin reduces burn wound progression by enhancing autophagy in deep second-degree burn in rats. Wound Repair Regen 21:852–859

    Article  PubMed  Google Scholar 

  158. Xin C, Yan-Fu W, Ping H, Jing G, Jing-Jing W, Chun-Li M, Wei L, Bei C (2009) Study of the insulin signaling pathways in the regulation of ACAT1 expression in cultured macrophages. Cell Biol Int 33:602–606

    Article  PubMed  CAS  Google Scholar 

  159. Yang L, Di G, Qi X, Qu M, Wang Y, Duan H, Danielson P, Xie L, Zhou Q (2014) Substance P promotes diabetic corneal epithelial wound healing through molecular mechanisms mediated via the neurokinin-1 receptor. Diabetes 63:4262–4274

    Article  CAS  PubMed  Google Scholar 

  160. Yang S, Xia C, Li S, Du L, Zhang L, Zhou R (2014) Defective mitophagy driven by dysregulation of rheb and KIF5B contributes to mitochondrial reactive oxygen species (ROS)-induced nod-like receptor 3 (NLRP3) dependent proinflammatory response and aggravates lipotoxicity. Redox Biol 3:63–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Yerby B, Deacon R, Beaulieu V, Liang J, Gao J, Laurent D (2008) Insulin-stimulated mitochondrial adenosine triphosphate synthesis is blunted in skeletal muscles of high-fat-fed rats. Metabolism 57:1584–1590

    Article  CAS  PubMed  Google Scholar 

  162. Yoo JK, Kwon H, Khil L-Y, Zhang L, Jun H-S, Yoon J-W (2005) IL-18 induces monocyte chemotactic protein-1 production in macrophages through the phosphatidylinositol 3-kinase/Akt and MEK/ERK1/2 pathways. J Immunol 175:8280–8286

    Article  CAS  PubMed  Google Scholar 

  163. Yorimitsu T, Nair U, Yang Z, Klionsky DJ (2006) Endoplasmic reticulum stress triggers autophagy. J Biol Chem 281(40):30299–30304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Zagon IS, Klocek MS, Sassani JW, McLaughlin PJ (2007) Use of topical insulin to normalize corneal epithelial healing in diabetes mellitus. Arch Ophthalmol 125:1082–1088

    Article  CAS  PubMed  Google Scholar 

  165. Zhang X, Chinkes DL, Sadagopa Ramanujam VM, Wolfe RR (2007) Local injection of insulin-zinc stimulates DNA synthesis in skin donor site wound. Wound Repair Regen 15:258–265

    Article  PubMed  Google Scholar 

  166. Zhang J, Liu F (2014) Tissue-specific insulin signaling in the regulation of metabolism and aging. IUBMB Life 66:485–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Zhang C, Ponugoti B, Tian C, Xu F, Tarapore R, Batres A, Alsadun S, Lim J, Dong G, Graves DT (2015) FOXO1 differentially regulates both normal and diabetic wound healing. J Cell Biol 209:289–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon MJ, Alkon DL (1999) Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem 274:34893–34902

    Article  CAS  PubMed  Google Scholar 

  169. Zhou L, Zhang J, Fang Q, Liu M, Liu X, Jia W, Dong LQ, Liu F (2009) Autophagy-mediated insulin receptor down-regulation contributes to endoplasmic reticulum stress-induced insulin resistance. Mol Pharmacol 76:596–603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Zykova SN, Jenssen TG, Berdal M, Olsen R, Myklebust R, Seljelid R (2000) Altered cytokine and nitric oxide secretion in vitro by macrophages from diabetic type II-like db/db mice. Diabetes 49:1451–1458

    Article  CAS  PubMed  Google Scholar 

Related articles recently published in Archives of Dermatological Research (selected by the journal’s editorial staff)

  1. Lopez-Lopez N, Gonzalez-Curiel I, Trevino-Santa Cruz MB, Rivas-Santiago B, Trujillo-Paez V, Enciso-Moreno JA, Serrano CJ (2014) Expression and vitamin D-mediated regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in healthy skin and in diabetic foot ulcers. Arch Dermatol Res 306:809–821

    Article  CAS  PubMed  Google Scholar 

  2. Nishikori Y, Shiota N, Okunishi H (2014) The role of mast cells in cutaneous wound healing in streptozotocin-induced diabetic mice. Arch Dermatol Res 306:823–835

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Authors thank Dr. M. Martins-Green, Dr. H. Jenssen and Dr. J. Moura Alves for a critical reading of the manuscript.

Author information

Authors and Affiliations

  1. Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal

    T. Emanuelli, A. Burgeiro & E. Carvalho

  2. Department of Food Technology and Science, Federal University of Santa Maria, Santa Maria, RS, 97105-900, Brazil

    T. Emanuelli

  3. The Portuguese Diabetes Association (APDP), 1250-203, Lisbon, Portugal

    E. Carvalho

  4. Arkansas Children’s Research Institute, Little Rock, AR, 72202, USA

    E. Carvalho

  5. Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, 72202, USA

    E. Carvalho

Authors
  1. T. Emanuelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Burgeiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. Carvalho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. Carvalho.

Ethics declarations

Conflict of interest

The authors state no conflict of interest.

Funding

This work was funded by FEDER (QREN), under projects CENTRO-07-ST24-FEDER-002002, CENTRO-07-ST24-FEDER-002006, CENTRO-07-ST24-FEDER-002008, Operational Programme Competitiveness Factors–COMPETE, by Foundation for Science and Technology EXCL/DTP-PIC/0069/2012 (EC), the EFSD European Research Programme in Microvascular Complications of Diabetes supported by Novartis (EC), and strategic project UID/NEU/04539/2013. T. Emanuelli is the recipient of CNPq-CSF Post doc Fellowship.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Emanuelli, T., Burgeiro, A. & Carvalho, E. Effects of insulin on the skin: possible healing benefits for diabetic foot ulcers. Arch Dermatol Res 308, 677–694 (2016). https://doi.org/10.1007/s00403-016-1686-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00403-016-1686-z

Keywords

  • Angiogenesis
  • Diabetes
  • Inflammatory response
  • Insulin
  • Skin cells
  • Wound healing