DPP‐4 inhibitor linagliptin ameliorates imiquimod‐induced psoriasis‐like skin alterations in type 2 diabetic mice by inhibiting the MAPK/NF‐κB inflammatory pathway

Abstract Studies have shown that the DPP‐4 inhibitor was effective in improving skin damage in patients with psoriasis, but the exact mechanism was not known. To investigate the therapeutic effects of linagliptin in mice with type 2 diabetes mellitus (T2DM) with psoriasis and its possible therapeutic mechanisms. A total of 32 db/db mice and 16 db/m mice were randomly divided into six groups: normal group, psoriasis group, diabetes group, diabetes combined with psoriasis group, linagliptin‐treated diabetes group, and linagliptin‐treated diabetes combined with psoriasis group. The levels of serum fasting blood glucose, total cholesterol (TC), triglyceride (TG), high‐density lipoprotein cholesterol, and low‐density lipoprotein cholesterol were measured; the levels of serum FINS were determined by enzyme‐linked immunoassay and the insulin resistance index was calculated. Basic parameters of diabetes, Psoriasis Area and Severity Index, histopathology of skin, the expression of interleukin (IL)‐17A, IL‐23, IL‐22, and tumor necrosis factor (TNF)‐α, and expression levels of measuring p‐ERK, p‐MAPK and p‐nuclear factor kappa B (NF‐κB) in skin tissues were measured. After treatment with linagliptin, insulin resistance, and TC and TG levels were reduced in mice with T2DM and psoriasis ( p < .05). Moreover, the degree of epidermal tissue thickening, number of keratinized layers, and inflammatory cell infiltration were also reduced ( p < .05), as well as the expression levels of inflammatory factors: TNF‐α, IL‐1β, IL‐17A, IL‐23, and p‐P38/P38, p‐ERK/ERK, p‐P65/P65 proteins ( p < .05). Linagliptin significantly reduced the extent of skin lesions and skin inflammation. The underlying mechanism of this compound may be related to the inhibition of MAPK/NF‐κB inflammatory pathways and the consequential improvement of insulin resistance. Significance Statement : In this study, we evaluated the therapeutic effect of the DPP‐4 inhibitor linagliptin using a murine model of type 2 diabetes combined with psoriasis, and its potential mechanisms of action were further explored. The results of this study will help to uncover the pathogenesis of type 2 diabetes and psoriasis and, more importantly, provide a theoretical basis for the search for safe and effective drugs in the treatment of this specific patient population.