Journal Article

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

dos Santos, Marinilce F., Pessoa, Ana Flávia M., Carvalheira, José B. C., Saad, Mario J. A., Lima, Maria H. M., Velloso, Lício A., de Abreu, Lélia L., Caricilli, Andréa M., Tsukumo, Daniela M., Thirone, Ana C. P., Araújo, Eliana P., Pelegrinelli, Fabiana F., de Moraes, Maria A.

2012

Overview

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. 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. 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. 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. ClinicalTrials.gov NCT01295177.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Administration, Topical / Aged / AKT protein / Animals / Bone marrow / Bone Marrow - metabolism / Cell adhesion & migration / Cellular signal transduction / Chemokine CXCL12 - metabolism / Chromones - pharmacology / Clinical Trial Biology / Clinical trials / Cream / Diabetes Complications - drug therapy / Diabetes Complications - metabolism / Diabetes mellitus / Diabetes Mellitus, Experimental - metabolism / Diabetes therapy / Double-blind studies / Extracellular signal-regulated kinase / Extracellular Signal-Regulated MAP Kinases - metabolism / Female / Humans / Immunoblotting / Insulin / Insulin - administration & dosage / Insulin receptor substrate 1 / Kinases / Male / Medicine / Metabolic pathways / Middle Aged / Morpholines - pharmacology / Nitric oxide / Nitric Oxide Synthase Type III - metabolism / Patients / Phosphoinositide-3 Kinase Inhibitors / Proteins / Proto-Oncogene Proteins c-akt - metabolism / Rats / Rats, Wistar / Research design / Rodents / Shc protein / Signal transduction / Signal Transduction - drug effects / Signaling / Skin / Skin - drug effects / Skin - metabolism / Skin - pathology / Studies / Topical application / Ulcers / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - metabolism / Wound care / Wound healing / Wound Healing - drug effects