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Side effects of frequently used oral antidiabetics on wound healing in vitro

Abstract

Lifestyle diseases such as diabetes and arteriosclerosis are rising in the increasingly aging society, and the number of patients with daily intake of glucose-lowering medication has also increased. Interestingly, knowledge about oral antidiabetics with regard to wound healing is scarce. Therefore, the aim of this study was to identify possible (side) effects of the most frequently prescribed oral antidiabetics on skin cells and wound healing. Four oral antidiabetics of different substance classes (i.e., metformin, glibenclamide, sitagliptin, repaglinide) were investigated with regard to the promotion of cell metabolism and migration of human skin fibroblasts and keratinocytes by XTT and scratch assays. In addition, histological and immunohistochemical analyses were performed in a 3D wound model to address the impact of the antidiabetics on regeneration processes, such as cell migration, fibroblast activity, epidermal thickness, and cell apoptosis. In comparison to systemic application, metformin displayed the most adverse effects in vitro in nearly all analyses, interestingly at serum equivalent concentrations. In contrast, sitagliptin and glibenclamide had a slight but insignificant effect on fibroblasts compared with keratinocytes. Repaglinide tended to have a negative influence on keratinocyte metabolism. Interestingly, antidiabetics generally induced a significantly enhanced rate of apoptosis in fibroblasts, with the exception of repaglinide.

Antidiabetics influenced key players in wound healing, namely, keratinocytes and fibroblasts. Particularly, metformin impaired human skin cells. These findings should be kept in mind in further studies because of their putative relevance in patients suffering from chronic wounds that do not respond to various wound therapies.

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Contributions

EKS and ALS designed the study. NT, ALS, MB, and VK carried out the experiments; EKS analyzed the results, performed the statistical analysis, and generated the figures; HSB focused on the pharmacological background; ALS, MB, and EKS drafted the manuscript.

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Correspondence to Ewa Klara Stuermer.

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Stuermer, E.K., Besser, M., Terberger, N. et al. Side effects of frequently used oral antidiabetics on wound healing in vitro. Naunyn-Schmiedeberg's Arch Pharmacol 392, 371–380 (2019). https://doi.org/10.1007/s00210-018-01597-9

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  • DOI: https://doi.org/10.1007/s00210-018-01597-9

Keywords

  • Wound healing
  • Antidiabetics
  • Metformin
  • Sulfonylurea
  • Dipeptidylpeptidase inhibitors
  • 3D wound healing model