Barrier abnormalities in type 1 diabetes mellitus: the roles of inflammation and ceramide metabolism.

Xerosis is a common sign of both type 1 and type 2 diabetes mellitus (DM); and DM patients and DM mouse models show a compromised epidermal permeability barrier. Barrier defects then allow the entry of foreign substances into the skin, triggering inflammation, infection and worsening skin symptoms. Characterizing how barrier abnormalities develop in DM could suggest treatments for xerosis and other skin disease traits. Since the proper ratio, as well as proper bulk amounts, of heterogeneous ceramide species are keys to forming a competent barrier, we investigated how ceramide metabolism is affected in type 1 DM (DM1) using a mouse model (induced by streptozotocin). Chronic inflammation, evident in DM mouse skin, leads to: 1) decreased de novo ceramide production through serine racemase activation-mediated attenuation of serine palmitoyl transferase activity by D-serine; 2) changes in ceramide synthase activities and expression that modify the ratio of ceramide molecular species; and 3) increased ceramide-1-phosphate, a pro-inflammatory lipid mediator, stimulates inflammatory cytokine expression (TNFα, IFNγ). Together, chronic inflammation affects ceramide metabolism, which attenuates epidermal permeability barrier formation; and ceramide-1-phosphate could amplify this inflammation. Alleviation of chronic inflammation is a credible approach for normalizing barrier function and ameliorating diverse skin abnormalities in DM.