Anti-inflammatory and pro-healing impacts of exendin-4 treatment in Zucker diabetic rats: Effects on skin wound fibroblasts.

Using male Zucker diabetic fatty (ZDF) rats implanted subcutaneously with polyethylene mesh pieces stimulating granulation tissue development, we investigated the effects of the in vivo and in vitro treatment with exendin-4, a glucagon-like peptide-1 agonist displaying a variety of antidiabetic actions, on the markers of metabolism, inflammation, and healing in addition to skin wound fibroblast/myofibroblast activities. Exendin-4 at increasing doses of 3-10 μg/kg or 0.9% saline was injected daily to ZDF rats pre-implanted with the mesh for 3 weeks. Then, fibroblasts/myofibroblasts isolated from the granulation tissue in both groups were further exposed in vitro to exendin-4 at concentrations of 0-100 nmol/l. After a 3-week administration period, cumulative food and water intake and body weight were reduced significantly. The serum and fibroblast culture medium C-reactive protein (CRP) concentrations and matrix metalloprotease-9/tissue matrix metalloproteinase inhibitor-1 (MMP-9/TIMP-1) ratio in the fibroblast culture medium were diminished significantly in the exendin-4 pretreated group, indicating the increased expression of anti-inflammatory and pro-healing biomarkers. In vivo exendin-4 treatment also increased the number of living fibroblasts/myofibroblasts in cell cultures. The subsequent in vitro exposure to exendin-4 significantly increased metabolic activity and total collagen content in fibroblast/myofibroblast colonies derived from exendin-4-pretreated rats but reduced the number of viable cells. A cytotoxic effect was noted at the highest exendin-4 concentrations used. To conclude, the treatment of diabetic rats with exendin-4 had beneficial effects on systemic and tissue metabolic, inflammatory, and healing markers and on fibroblast functions crucial for wound repair but showed some cytotoxicity on these cells.