Abstract
In recent years, new and effective therapeutic agents for blood glucose control have been added to standard diabetes therapies: dipeptidyl peptidase-4 (DPP-4) inhibitors, which prolong the bioavailability of the endogenously secreted incretin hormone glucagon-like peptide-1 (GLP-1). Full-thickness excisional wounding was performed in wild-type (C57BL/6J) and diabetic [C57BL/6J-obese/obese (ob/ob)] mice. DPP-4 activity was inhibited by oral administration of linagliptin during healing. Wound tissue was analyzed by using histological, molecular, and biochemical techniques. In healthy mice, DPP-4 was constitutively expressed in the keratinocytes of nonwounded skin. After skin injury, DPP-4 expression declined and was lowest during the most active phase of tissue reassembly. In contrast, in ob/ob mice, we observed increasing levels of DPP-4 at late time points, when delayed tissue repair still occurs. Oral administration of the DPP-4 inhibitor linagliptin strongly reduced DPP-4 activity, stabilized active GLP-1 in chronic wounds, and improved healing in ob/ob mice. At day 10 postwounding, linagliptin-treated ob/ob mice showed largely epithelialized wounds characterized by the absence of neutrophils. In addition, DPP-4 inhibition reduced the expression of the proinflammatory markers cyclooxygenase-2 and macrophage inflammatory protein-2, but enhanced the formation of myofibroblasts in healing wounds from ob/ob mice. Our data suggest a potentially beneficial role of DPP-4 inhibition in diabetes-affected wound healing.
Footnotes
Boehringer Ingelheim Pharma GmbH and Co. KG paid for all ob/ob animals used in this study and provided the linagliptin. Medical writing assistance was provided by Mark Poirier of Envision Scientific Solutions during the preparation of this paper and was supported by Boehringer Ingelheim.
Data from this study were presented, in part, previously: Linke A, Frank S, Mark M, and Klein T (2009) The DPP-4 inhibitor linagliptin (BI 1356) improves wound healing in ob/ob mice, at the American Diabetes Association's Scientific Session, 2009 June 5–9, New Orleans, LA, American Diabetes Association, Alexandria, VA. Schürmann C, Frank S, Greischel A, Mark M, and Klein T (2010) Linagliptin functionally counteracts a dysregulation in DPP-4 expression in diabetes-impaired wounds, at the American Diabetes Association's Scientific Session, 2010 June 25–29, Orlando, FL, American Diabetes Association, Alexandria, VA.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- ob/ob
- obese/obese
- α-SMA
- α-smooth muscle actin
- AUC
- area under the curve
- BP1
- binding protein 1
- Cox-2
- cyclooxygenase-2
- DMEM
- Dulbecco's modified Eagle's medium
- DPP-4
- dipeptidyl peptidase-4
- EGF
- epithelial growth factor
- eIF
- eukaryotic initiation factor
- p-eIF-2
- phospho-eIF-2
- ELISA
- enzyme-linked immunosorbent assay
- GIP
- glucose-dependent insulinotropic polypeptide
- GLP-1
- glucagon-like peptide-1
- Mϕ
- macrophages
- MAPK
- mitogen-activated protein kinase
- MIP-2
- macrophage inflammatory protein-2
- OGTT
- oral glucose tolerance test
- PMN
- polymorphonuclear neutrophils
- PonS
- Ponceau S
- TNF-α
- tumor necrosis factor α.
- Received December 15, 2011.
- Accepted April 3, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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