Topical insulin accelerates wound healing in diabetes by enhancing the AKT and ERK pathways: a double-blind placebo-controlled clinical trial

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...

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Published in:PloS one 2012-05, Vol.7 (5), p.e36974-e36974
Main Authors: 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
Format: Article
Language:English
Subjects:
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
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0036974