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Topical Insulin Accelerates Wound Healing in Diabetes by Enhancing the AKT and ERK Pathways: A Double-Blind Placebo-Controlled Clinical Trial

BACKGROUND: Wound healing is impaired in diabetes mellitus, but the mechanisms involved in this process are virtually unknown. Proteins belonging to the insulin signaling pathway respond to insulin in the skin of rats. OBJECTIVE: The purpose of this study was to investigate the regulation of the ins...

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Autores principales: Lima, Maria H. M., Caricilli, Andréa M., de Abreu, Lélia L., Araújo, Eliana P., Pelegrinelli, Fabiana F., Thirone, Ana C. P., Tsukumo, Daniela M., Pessoa, Ana Flávia M., dos Santos, Marinilce F., de Moraes, Maria A., Carvalheira, José B. C., Velloso, Lício A., Saad, Mario J. A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3360697/
https://www.ncbi.nlm.nih.gov/pubmed/22662132
http://dx.doi.org/10.1371/journal.pone.0036974
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author Lima, Maria H. M.
Caricilli, Andréa M.
de Abreu, Lélia L.
Araújo, Eliana P.
Pelegrinelli, Fabiana F.
Thirone, Ana C. P.
Tsukumo, Daniela M.
Pessoa, Ana Flávia M.
dos Santos, Marinilce F.
de Moraes, Maria A.
Carvalheira, José B. C.
Velloso, Lício A.
Saad, Mario J. A.
author_facet Lima, Maria H. M.
Caricilli, Andréa M.
de Abreu, Lélia L.
Araújo, Eliana P.
Pelegrinelli, Fabiana F.
Thirone, Ana C. P.
Tsukumo, Daniela M.
Pessoa, Ana Flávia M.
dos Santos, Marinilce F.
de Moraes, Maria A.
Carvalheira, José B. C.
Velloso, Lício A.
Saad, Mario J. A.
author_sort Lima, Maria H. M.
collection PubMed
description BACKGROUND: Wound healing is impaired in diabetes mellitus, but the mechanisms involved in this process are virtually unknown. Proteins belonging to the insulin signaling pathway respond to insulin in the skin of rats. OBJECTIVE: The purpose of this study was to investigate the regulation of the insulin signaling pathway in wound healing and skin repair of normal and diabetic rats, and, in parallel, the effect of a topical insulin cream on wound healing and on the activation of this pathway. RESEARCH DESIGN AND METHODS: We investigated insulin signaling by immunoblotting during wound healing of control and diabetic animals with or without topical insulin. Diabetic patients with ulcers were randomized to receive topical insulin or placebo in a prospective, double-blind and placebo-controlled, randomized clinical trial (NCT 01295177) of wound healing. RESULTS AND CONCLUSIONS: Expression of IR, IRS-1, IRS-2, SHC, ERK, and AKT are increased in the tissue of healing wounds compared to intact skin, suggesting that the insulin signaling pathway may have an important role in this process. These pathways were attenuated in the wounded skin of diabetic rats, in parallel with an increase in the time of complete wound healing. Upon topical application of insulin cream, the wound healing time of diabetic animals was normalized, followed by a reversal of defective insulin signal transduction. In addition, the treatment also increased expression of other proteins, such as eNOS (also in bone marrow), VEGF, and SDF-1α in wounded skin. In diabetic patients, topical insulin cream markedly improved wound healing, representing an attractive and cost-free method for treating this devastating complication of diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01295177
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spelling pubmed-33606972012-06-01 Topical Insulin Accelerates Wound Healing in Diabetes by Enhancing the AKT and ERK Pathways: A Double-Blind Placebo-Controlled Clinical Trial Lima, Maria H. M. Caricilli, Andréa M. de Abreu, Lélia L. Araújo, Eliana P. Pelegrinelli, Fabiana F. Thirone, Ana C. P. Tsukumo, Daniela M. Pessoa, Ana Flávia M. dos Santos, Marinilce F. de Moraes, Maria A. Carvalheira, José B. C. Velloso, Lício A. Saad, Mario J. A. PLoS One Research Article BACKGROUND: Wound healing is impaired in diabetes mellitus, but the mechanisms involved in this process are virtually unknown. Proteins belonging to the insulin signaling pathway respond to insulin in the skin of rats. OBJECTIVE: The purpose of this study was to investigate the regulation of the insulin signaling pathway in wound healing and skin repair of normal and diabetic rats, and, in parallel, the effect of a topical insulin cream on wound healing and on the activation of this pathway. RESEARCH DESIGN AND METHODS: We investigated insulin signaling by immunoblotting during wound healing of control and diabetic animals with or without topical insulin. Diabetic patients with ulcers were randomized to receive topical insulin or placebo in a prospective, double-blind and placebo-controlled, randomized clinical trial (NCT 01295177) of wound healing. RESULTS AND CONCLUSIONS: Expression of IR, IRS-1, IRS-2, SHC, ERK, and AKT are increased in the tissue of healing wounds compared to intact skin, suggesting that the insulin signaling pathway may have an important role in this process. These pathways were attenuated in the wounded skin of diabetic rats, in parallel with an increase in the time of complete wound healing. Upon topical application of insulin cream, the wound healing time of diabetic animals was normalized, followed by a reversal of defective insulin signal transduction. In addition, the treatment also increased expression of other proteins, such as eNOS (also in bone marrow), VEGF, and SDF-1α in wounded skin. In diabetic patients, topical insulin cream markedly improved wound healing, representing an attractive and cost-free method for treating this devastating complication of diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01295177 Public Library of Science 2012-05-25 /pmc/articles/PMC3360697/ /pubmed/22662132 http://dx.doi.org/10.1371/journal.pone.0036974 Text en Lima et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Lima, Maria H. M.
Caricilli, Andréa M.
de Abreu, Lélia L.
Araújo, Eliana P.
Pelegrinelli, Fabiana F.
Thirone, Ana C. P.
Tsukumo, Daniela M.
Pessoa, Ana Flávia M.
dos Santos, Marinilce F.
de Moraes, Maria A.
Carvalheira, José B. C.
Velloso, Lício A.
Saad, Mario J. A.
Topical Insulin Accelerates Wound Healing in Diabetes by Enhancing the AKT and ERK Pathways: A Double-Blind Placebo-Controlled Clinical Trial
title Topical Insulin Accelerates Wound Healing in Diabetes by Enhancing the AKT and ERK Pathways: A Double-Blind Placebo-Controlled Clinical Trial
title_full Topical Insulin Accelerates Wound Healing in Diabetes by Enhancing the AKT and ERK Pathways: A Double-Blind Placebo-Controlled Clinical Trial
title_fullStr Topical Insulin Accelerates Wound Healing in Diabetes by Enhancing the AKT and ERK Pathways: A Double-Blind Placebo-Controlled Clinical Trial
title_full_unstemmed Topical Insulin Accelerates Wound Healing in Diabetes by Enhancing the AKT and ERK Pathways: A Double-Blind Placebo-Controlled Clinical Trial
title_short Topical Insulin Accelerates Wound Healing in Diabetes by Enhancing the AKT and ERK Pathways: A Double-Blind Placebo-Controlled Clinical Trial
title_sort topical insulin accelerates wound healing in diabetes by enhancing the akt and erk pathways: a double-blind placebo-controlled clinical trial
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3360697/
https://www.ncbi.nlm.nih.gov/pubmed/22662132
http://dx.doi.org/10.1371/journal.pone.0036974
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