Sodium Butyrate Enhances Bone Healing In Diabetes Via Glycolysis

Metabolic disorders linked to type 2 diabetes mellitus (T2DM) and bone injuries threaten public health. Osteoporosis patients often have poor prognoses in orthodontic treatment. Recent research has focused on improving systemic osteoporosis for localized treatments like orthodontics. While sodium butyrate (NaB) may enhance metabolic homeostasis, its therapeutic effects on T2DM-related bone injuries and regulatory mechanisms are still unclear. Eight-week-old leptin receptor knockout mice and heterozygous control mice were divided into three groups: disease group, control group, and treatment group. From week 10, the treatment group received NaB. At week 20, the mice were sacrificed, and methods including micro-CT, HE staining, immunohistochemistry, and immunofluorescence evaluated osteogenic capacity and biomarker expression. Bone marrow mesenchymal stem cells were categorized into a high glucose group, a control group, and a treatment group. The osteogenic potential, marker expression, and energy metabolism were analyzed using alkaline phosphatase staining, alizarin red staining, Western blot, and quantitative real-time PCR. Administration of sodium butyrate significantly alleviates bone injuries and restores impaired osteogenic function associated with type 2 diabetes mellitus (T2DM) by improving dysregulated glucose metabolism. It enhances glycolysis and oxidative phosphorylation, particularly through the overexpression of PKM2, which results in lactic acid accumulation. This accumulation induces histone lactylation, subsequently promoting osteogenic responses. Our findings suggest that NaB may be a potential therapeutic agent for T2DM-related bone injuries by enhancing the PKM2-regulated glycolytic pathway and promoting histone lactylation through lactic acid mechanisms.