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However, the underlying pathological mechanisms linking glucose variations and macrophage dysregulation remains elusive. In current study, we established an animal model of transient intermittent hyperglycaemia (TIH) to simulate early fluctuations in blood glucose levels. Our findings revealed that both TIH and diabetic group exhibited more severe periodontal lesions and increased secretion of pro\u2010inflammatory cytokines compared to healthy controls. In immortalized bone marrow\u2013derived macrophages (iBMDMs), phagocytosis and chemotaxis were impaired with transient and lasting hyperglycaemia, accompanied by enhanced glycolysis. We also found that TIH activated pyruvate kinase M2 (PKM2) through the phosphorylation of extracellular regulated protein kinase (ERK) in vivo, particularly at dimeric levels. In macrophage cultured with TIH, PKM2 translocated into the nucleus and involved in the regulating inflammatory genes, including TNF\u2010\u03b1, IL\u20106 and IL\u20101\u03b2. PKM2 translocation and secretion of inflammatory cytokines were attenuated by PD98059, while PKM2 tetramer activator TEPP\u201046 prevented the formation of dimeric PKM2 in macrophages. Moreover, inhibition of glycolysis alleviated the TIH\u2010induced pro\u2010inflammatory cytokines. In conclusion, our manuscript provides a rationale for understanding how TIH modulates metabolic rewiring and dysfunction in macrophages via ERK\u2010dependent PKM2 nuclear translocation.<\/jats:p>","DOI":"10.1111\/cpr.13651","type":"journal-article","created":{"date-parts":[[2024,5,25]],"date-time":"2024-05-25T04:39:49Z","timestamp":1716611989000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Intermittent hyperglycaemia induces macrophage dysfunction by extracellular regulated protein kinase\u2010dependent PKM2 translocation in periodontitis"],"prefix":"10.1111","volume":"57","author":[{"given":"Yuezhang","family":"Sun","sequence":"first","affiliation":[{"name":"State Key Laboratory of Orval Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology Sichuan University  Chengdu 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