Diabetes mellitus may adversely affect the regenerative capacities of tissues, including skin healing and bone health (osteoporosis). Dipeptidyl peptidase-4 (DPP4) inhibitors (DPP4i) are antidiabetic drugs that increase the half-life of incretins, improving glucose levels. Several proteins that regulate important physiological processes are also substrates of DPP4. Therefore, DPP4i may have multiple effects. The aim of this work was to study if DPP4i sitagliptin affects regenerative capacities in a diabetic animal model. Thus, its effects on skin wound healing were evaluated. Likewise, if it produces changes in serum composition that might affect the viability and differentiation of endothelial cells and mesenchymal stem cells (MSC).

Diabetic rats were dorsally wounded and treated with sitagliptin. At day six, CD34⁺ cells and endothelial progenitor cells (EPC) were quantified in blood by flow cytometry. At day 14, blood serum and wound samples were obtained for histological analyses. In vitro studies of viability, apoptosis and angiogenesis in human umbilical-cord vein endothelial cells (HUVEC) and MSC capabilities of differentiation into adipocytes or osteoblasts were tested using rat sera.

Sitagliptin treatments accelerated wound closure, decreased wound inflammation, and increased circulating EPC. Serum from sitagliptin-treated rats increased angiogenesis in HUVEC, while in MSC, it negatively affected osteogenic differentiation, promoting adipogenesis.

Sitagliptin treatment may have positive effects on ulcer healing in diabetics. However, the possible changes produced in serum composition may negatively affect bone formation. Therefore, sitagliptin may affect regenerative capacity and induce different responses in progenitor cells, depending on their niche.