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(American Journal of Pathology. 2006;168:765-777.)
© 2006 American Society for Investigative Pathology

Severely Impaired Insulin Signaling in Chronic Wounds of Diabetic ob/ob Mice

A Potential Role of Tumor Necrosis Factor-{alpha}

Itamar Goren, Elke Müller, Josef Pfeilschifter and Stefan Frank

From the pharmazentrum frankfurt/Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany

Wound-healing disorders are major complications of diabetes mellitus. Here, we investigated insulin-mediated signaling in nonwounded skin and in cutaneous tissue regeneration of healthy C57BL/6 and diabetes-impaired leptin-deficient obese/obese (ob/ob) mice. The insulin receptor (InsR) was abundantly expressed in wound margins and granulation tissue during acute healing in healthy mice. Remarkably, active signaling from the InsR, as assessed by phosphorylation of downstream targets such as protein tyrosine phosphatase-1B, glycogen synthase (GS), and GS kinase, was nearly absent in nonwounded and acutely healing skin from ob/ob mice. Systemic leptin administration to ob/ob mice reverted the diabetic phenotype and improved tissue regeneration as well as the impaired expression of InsR, insulin receptor substrate-1 and insulin receptor substrate-2, and downstream signaling (phosphorylation of GS kinase and GS) in late wounds and nonwounded skin of ob/ob mice. Importantly, tumor necrosis factor (TNF)-{alpha} was a mediator of insulin resistance in keratinocytes in vitro and in ob/ob wound tissue in vivo. Systemic administration of a monoclonal anti-TNF-{alpha} antibody (V1q) in wounded ob/ob mice attenuated wound inflammation, improved re-epithelialization, and restored InsR expression and signaling in wound tissue of ob/ob mice. These data suggest that InsR signaling in diabetes-impaired wounds is sensitive to inflam-matory conditions and that anti-inflammatory approaches, such as anti-TNF-{alpha} strategies, improve diabetic wound healing.




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D. Schiefelbein, I. Goren, B. Fisslthaler, H. Schmidt, G. Geisslinger, J. Pfeilschifter, and S. Frank
Biphasic Regulation of HMG-CoA Reductase Expression and Activity during Wound Healing and Its Functional Role in the Control of Keratinocyte Angiogenic and Proliferative Responses
J. Biol. Chem., May 30, 2008; 283(22): 15479 - 15490.
[Abstract] [Full Text] [PDF]


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Copyright © 2006 by the American Society for Investigative Pathology.