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 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.


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.


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.


BACKGROUND
ClinicalTrials.gov NCT01295177.
Department of Nursing, FCM, University of Campinas, Campinas, São Paulo, Brazil.
Maria H M
MH
Lima
Andréa M
AM
Caricilli
Lélia L
LL
de Abreu
Eliana P
EP
Araújo
Fabiana F
FF
Pelegrinelli
Ana C P
AC
Thirone
Daniela M
DM
Tsukumo
Ana Flávia M
AF
Pessoa
Marinilce F
MF
dos Santos
Maria A
MA
de Moraes
José B C
JB
Carvalheira
Lício A
LA
Velloso
Mario J A
MJ
Saad
D000287:Administration, Topical; D000368:Aged; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D048909:Diabetes Complications / Q000188:drug therapy* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D007328:Insulin / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*
D054377:Chemokine CXCL12; D002867:Chromones; D007328:Insulin; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases