BACKGROUND: Periodontitis is a chronic inflammatory disease that leads to the destruction of periodontal tissues and diabetes is a metabolic disease characterized by hyperglycemia. Both of these diseases affect many people worldwide. Epidemiological data have revealed a close relationship between periodontitis and diabetes. In particular, the high-glucose microenvironment plays an important role in the relationship between these two chronic inflammatory diseases, which makes it difficult to mitigate the progression of periodontitis and restore periodontal tissue in diabetic patients. Anti-inflammatory and regenerative processes are of fundamental importance for periodontal treatment and are mediated by diverse cell populations, including macrophages, T cells, neutrophils, stem cells, and fibroblasts that reside within periodontal tissues. MAIN BODY: This review summarizes the interaction between diabetes mellitus and periodontitis, and illustrates that the high-glucose microenvironment aggravates periodontal homeostasis. Furthermore, the mechanism by which the high-glucose microenvironment regulates the involvement of various cells in the destruction of periodontal tissue, leading to the significant inhibition of tissue regeneration and recovery, is discussed. On this basis, the current therapeutic strategies that can be used to target cells are summarized to improve the regeneration and repair processes in the high-glucose microenvironment. CONCLUSION: In this review, we assess how metabolic dysregulation mediated by a high-glucose microenvironment exacerbates inflammatory damage and inhibits tissue repair. A deeper understanding of the effects of a high-glucose microenvironment on periodontal tissue cells is essential for developing new therapeutic strategies to restore the structure and function of periodontal tissue.