Topical insulin application accelerates diabetic wound healing by promoting anti-inflammatory macrophage polarization

Besides regulating glucose levels, insulin has been reported to participate actively in many other functions such as modulating inflammatory reaction. In this study we investigated how insulin application topically would effort the diabetic wound healing process. We found that the excessive expression of insulin degrading enzyme in diabetic skin led to the insufficient insulin level in diabetic skin during the wound healing, which ultimately reduced the recovery rate of diabetic wounds. We confirmed the topical insulin application could reverse the impaired inflammation reaction in diabetic wound environment and promote diabetic wounds healing. Our study revealed that insulin promoted neutrophils apoptosis and following triggered macrophages phenotype polarization. Both in vivo and in vitro studies verified that insulin reestablished the damaged neutrophils phagocytosis function and promoted the process of phagocytosis induced apoptosis of neutrophils. Furthermore, we found that the insulin treatment also promoted macrophages efferocytosis of the apoptosed neutrophils and thus induced macrophages polarized from M1 to M2. In conclusion, our studies proved that the exogenous application of insulin could improve the diabetic wound healing via the normalization of inflammatory response.