Metformin reverses periodontal destruction caused by experimental periodontitis by inhibiting interleukin‐1β activity

Abstract Background Periodontitis is a destructive disease that affects periodontal tissue. While current research focuses on disease management, research on tissue repair remains limited. Metformin, a first‐line medication for diabetes treatment, has positive effects on bone health in nondiabetic patients. However, its potential for repairing periodontal tissue remains unclear. Therefore, this study aimed to evaluate the reparative effects of metformin on periodontitis‐damaged periodontal tissue in mice. Methods A mouse model of periodontal repair was used, in which silk ligatures were removed from the molars after inducing periodontitis, followed by metformin administration. Histomorphometric and histological analyses were conducted to assess comprehensive repair of the periodontium. Additional in vitro studies were conducted to determine the effect of metformin on the function of the individual cells that comprise the periodontium. Results Metformin treatment promoted the repair of periodontal ligament, alveolar bone, and cementum affected by periodontitis, as evaluated using microcomputed tomography based morphometric and histologic analyses. The therapeutic effect was linked to mitigating persistent inflammatory activity during periodontitis resolution, primarily attributed to the sustained presence of interleukin‐1 beta (IL‐1β), which may delay tissue repair. In vitro studies simulating this pathological condition showed that AMP‐activated protein kinase (AMPK) activation by metformin counteracted the effect of IL‐1β, inhibited osteoclast differentiation and restored the osteogenic differentiation capacity of periodontal ligament cells and cementoblasts. Conclusion These findings suggest that metformin holds promise for repairing periodontal tissue following periodontitis, potentially through modulating inflammatory responses and regulating cellular differentiation processes. Plain language summary Periodontitis is a serious gum disease that destroys the structures that support the teeth, such as ligaments and bone. While current treatments focus on preventing further damage, little progress has been made in achieving complete restoration of damaged tissue. In this study, we investigated whether metformin, a common diabetes drug, could help repair periodontal tissue. Using a mouse model of periodontitis, we removed ligatures placed around the teeth to allow healing, followed by metformin treatment. Our results showed that metformin promoted the repair of key tissues such as the periodontal ligament, alveolar bone, and cementum. An important observation in this study is the persistence of inflammatory activity during periodontitis resolution, where prolonged inflammation, driven by molecules such as interleukin‐1β (IL‐1β), appears to hinder tissue recovery. Metformin was found to counteract prolonged inflammation by reducing IL‐1β activity, allowing tissue to heal. It also restored the function of bone‐forming cells and limited the activity of bone‐resorbing cells. These results suggest that metformin may be a promising therapy for promoting periodontal tissue repair by both controlling inflammation and enhancing cellular activity critical for tissue restoration.