Introduction-Insulin exerts metabolic and growth-stimulating actions both through its own receptors and the receptors of its homologous factors (IGFs), although with different degrees of affinity. The A receptor of insulin acts more intensely on the cell membrane, with a metabolic response, whereas the B receptor is quickly internalized, stimulates cell growth, can be directed to the treatment of wounds difficult to heal. Objective-we proposes to evaluate the potential of insulin as an inducing agent in the regeneration of wounds that are difficult to heal as a therapeutic option. Methodology-Simultaneous intra and perilesional injections of 0.01ml of the solution containing 5UI of NPH single-component insulin diluted in 1 ml of lidocaine into various planes and wound sites. Clinical, glycemic and photographic evaluations of the patients were performed. Results-The cicatricial response occured in all patients and observed since the first applications. Withouth glycemic changes. Comments - The responses obtained can be attributed to both the stimulation of insulin receptors and that of their counterparts. Conclusions-The method was effective and without adverse effects. Different intervals between applications did not change the results. The availability of insulin and safety for its use indicate the method as a therapeutic option in difficult to heal wounds.
Neide Kalil Gaspar,
Antonio Pedro de Andrade Gaspar,
Difficult to Heal Wounds Intralesional Insulin Therapy Trial, Journal of Surgery.
Vol. 8, No. 6,
2020, pp. 184-189.
Czeck MP, Oppenheimer CL, Massagué J. Interrelationhip among receptor structures for insulin and peptide growth factors. Fed Proc. 1983; 42: 2598-602.
Ish-Shalon D, Christoffersen CT, Vorwek P, Sacerdoti-Sierra N, Naor D, De Metys P. Mitogenic properties of insulin and insulin analogues mediated by the insulin receptor. Diabetologia. 1997; 40: S25-S31.
Pandini G, Frasca F, Mineo R, Sciacca L, Vigneri R, Belfiore A. Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. J. Biol. Chem. 2002; 277: 39684-39695.
Slaaby R, Schäffer L, Lautrup-Larsen I, Andersen AS, Shaw AC, Mathiasen IS et al. Hybrid receptors formed by insulin receptor (IR) and insulin-like growth factor I receptor (IGF-IR) have low insulin and high IGF-1 affinity irrespective of the IR splice variant. J Biol Chem. 2006 Sep 8; 281 (36): 25869-74.
Mosthaf L, Grako K, Dull TJ, Coussens L, Ullrich A, and McClain DA. Functionally distinct insulin receptors generated by tissue-specific alternative splicing. EMBO. 1990; 9: 2409-2413.
Brzozowski AM, Dodson EJ, Dodson GG, Murshudov GN, Verma C, Turkenburg JP et al. Structural origins of the functional divergence of human insulin-like growth factor-I and insulin. Biochemistry. 2002 Jul 30; 41 (30): 9389-97.
Leitner JW, Kline T, Carel K, Goalstone M, Draznin B. Hyperinsulinemia potentiates activation of p21RAS by growth factors. Endocrinology. 1997; 138: 2211-4.
Pandini1 G, Vigneri R, Costantino A, Frasca F, Ippolito A, Fujita-Yamaguchi Y et al. Insulin and insulin-like growth factor-I (IGF-I) receptor overexpression in breast cancers leads to insulin/IGF-I hybrid receptor overexpression: evidence for a second mechanism of IGF-I signaling. Clin. Cancer Res. 1999; 5: 1935-1944.
Briekley GV, Macaulay SL, Forbes BE, Wallace JC, Cosgrove LJ, Macaulay VM. Silencing of the insulin receptor isoform A favors formation of type 1 insulin-like growth factor receptor (IGF-IR) homodimers and enhances ligand-induced IGF-IR activation and viability of human colon carcinoma cells. Endocrinology. 2010; 15: 1418-27.
Gauguin L, Klaproth B, Sajid W, Andersen AS, McNeil KA, Forbes BE et al. Structural basis for the lower affinity of the insulin-like growth factors for the insulin receptor. J Biol Chem. 2008 Feb 1; 283 (5): 2604-13.
Goalstone M, Carel K, Leitner JW, Draznin B. Insulin stimulates the phosphorylation and activity of farnesyltransferase via the Ras-mitogen-activated protein kinase pathway. Endocrinology. 1997; 138: 5119-24.
Goalstone ML, Wall K, Leitner JW, Kurowski T, Ruderman N, Pan SJ et al. Increased amounts of farnesylated p21Ras in tissues of hyperinsulinaemic animals. Diabetologia. 1999; 42: 310-6.
Draznin B, Miles P, Kruszninska Y, Olefsky J, Friedman J, Golovchenko I et al. Effects of insulin on prenylation as a mechanism of potentially detrimental influence of hyperinsulinemia. Endocrinology. 2000; 141: 1310-6.
Draznin B. Mechanism of the mitogenic influence of hyperinsulinemia. Diabetol Metabol Syndr. 2011; 3-10.
Mazur, Masur K, Vetter C, Hinz A, Tomas H, Niggemann B et al. Dibetogenic glucose and insulin concentrations modulate transcriptome and protein levels involved in tumour cell migration, adhesion and proliferation. Br J Cancer. 2011; 104: 345-52.
Vella V, Pandini G, Sciacca L, Mineo R, Vigneri R, Pezzino V et al. A novel autocrine loop involving IGF-II and the insulin receptor isoform-A stimulates growth of thyroid cancer. J Clin Endocrinol Metab. 2002; 87: 245-54.
Saydah, Saydah SH, Platz EA, Rifai N, Popllak MN, Brancati FL. Association of markers of insulin and glucose control with subsequent colorectal cancer risk. Am J Epidemiol. 2003; 157: 1092-100.
Nead KT, Sharp SJ, Thompson DJ, Painter JN, Savage DB, Semple RK et al. Evidence of a Causal Association Between Insulinemia and Endometrial Cancer: A Mendelian Randomization Analysis. J Natl Cancer Inst. 2015; 107 (9) pii: djv178.
Gaspar NK, Gaspar APA, Bruno AFM, Travassos Neto P. Tratamento das lipoatrofias localizadas com insulina monocomponente. An B Dermatol. 1984; 59: 135-136.
Gaspar NK. Tese: Concurso Prof Titular: A importância da insulina nos processos regenerativos cutâneos e subcutâneos. Universidade Federal Fluminense 1995. RJ Brasil.
Azevedo F, Pessoa A, Moreira G, Santos MD, Liberti E, Araujo E et al. Insulin on second-degree burns in diabetic rats. Biol Res Nurs. 2016; 18: 181-9.
Lv GF, Chen B, Zhang WF, Wang YC, Cai WX, Tang CW et al. The protective effect of intensive insulin treatment on the myocardium in severely scalded rats. Zhonghua Shao Shang Za Zhi. 2007; 23: 168-71.
Wang YC, Jia CY, Zhang WF, Lv GF, Dong ML, Tang CW et al. Protective effect of insulin on oxygen-radical induced hepatic injury in severely scalded rats. Zhonghua Shao Shang Za Zhi. 2007; 23: 428-31.
Jeschke MG, Kraft R, Song J, Gauglitz GG, Cox RA, Brooks NC et al. Insulin protects against hepatic damage postburn. Mol Med. 2011; 17: 516-22.
Zhang WF, Zhu XX, Hu DH, Xu CF, Wang YC, LY GF. Intensive insulin treatment attenuates burn-initiated acute lung injury in rats: role of the protective endothelium. J Burn Care Res. 2011; 32: e51-8.
Zhang J, Xue X, Xie P, Chang F. Effects of nerve growth factor mixed insulin on angiogenesis of burn wounds and expressions of bcl-2 and Bax in diabetic rats. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2011; 25: 354-60.
Fram RY, Cree MG, Wolfe RR, Barr D, Herndon DN. Impaired tolerance in pediatric burn patients at discharge from the acute hospital stay. J Burn Care Res. 2010; 31 (5): 72833.
Fram RY, Cree MG, Wolfe RR, Mlcak RP, Qian T, Chinkes DL et al. Intensive insulin therapy improves insulin sensitiivity and mitochondrial function in severely burned children. Crit Care Med. 2010; 38: 1496-83.
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: 512-8.
Corrêa MA, Okamoto CK, Gonçalves-de-Andrade RM, van den Berg CW, Tambourgi DV. Sphingomyelinase D from Loxosceles laeta Venom Induces the Expression of MMP7 in Human Keratinocytes: Contribution to Dermonecrosis. PLoS One. 2016; 11: e0153090.
Yan D1, Liu S, Zhao X, Bian H, Yao X, Xing J et al. Recombinant human granulocyte macrophage colony stimulating factor in deep second-degree burn wound healing kell. Medicine (Baltimore). 2017 Jun; 96: e6881.
Jasper J1, Roithmann S2, Camilotti RS3, Salum FG4, Cherubini K5, Zancanaro de Figueiredo MA5. Effect of G-CSF on oral mucositis and traumatic ulcers produced in the tongue of rats undergoing radiotherapy: clinical and histologic evaluation. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016; 122: 587-596.
Ma C, Hernandez MA, Kirkpatrick VE, Liang LJ, Nouvong AL, Gordon II. Topical platelet-derived growth factor vs placebo therapy of diabetic foot ulcers offloaded with windowed casts: a randomized, controlled trial. Wounds. 2015; 27: 83-91.
Smith OJ, Kanapathy M, Khajuria A, Prokopenko M, Hachach-Haram N, Mann H et al. Systematic review of the efficacy of fat grafting and platelet-rich plasma for wound healing. Int Wound J. 2018; 1-8. doi: 10.1111/iwj.12892.
Abo-Elkheir W, Hamza F, Elmofty AM, Emam A, Abdl-Moktader M, Elsherefy S et al. Role of cord blood and bone marrow mesenchymal stem cells in recent deep burn: a case-control prospective study. Am J Stem Cells. 2017; 6: 23-35.
Zou JP, Huang S, Peng Y, Liu HW, Cheng B, Fu XB et al. Mesenchymal stem cells/multipotent mesenchymal stromal cells (MSCs): potential role in healing cutaneous chronic wounds. Int J Low Extrem Wounds. 2012; 11: 244-53.
Hyldig K, Riis S, Pennisi CP, Zachar V, Fink T. Implications of Extracellular Matrix Production by Adipose Tissue-Derived Stem Cells for Development of Wound Healing Therapies. Int J Mol Sci. 2017; 31; 18: pii: E1167.
Martinez-Zapata MJ, Martí-Carvajal AJ, Solà I, Expósito JA, Bolíbar I, Rodríguez L et al. Autologous platelet-rich plasma for treating chronic wounds. Cochrane Database Syst Rev. 2016; 25: CD006899.