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AP was induced by pulp exposure of the maxillary and mandibular right first and second molars to the oral environment. After AP induction, oral supplementation with 5\u00a0mg\u00a0kg<jats:sup>\u22121<\/jats:sup>melatonin (diluted in drinking water) for 60\u00a0days was initiated. At the end of the treatment, the following were analysed: (1) plasma concentrations of insulin and inflammatory cytokines (TNF\u2010\u03b1, IL\u20106, IL\u20101\u03b2 and IL\u201010) using ELISA kits; (2) glycaemia using enzymatic assay; (3) insulin resistance using homoeostasis model assessment of insulin resistance (HOMA\u2010IR) index; and (4) phosphorylation status of pp185 tyrosine, Akt serine, IKK\u03b1\/\u03b2, and JNK in SM and EDL using Western blot. Analysis of variance of two or three factors was performed, followed by the Bonferroni test.<jats:italic>P<\/jats:italic>values\u00a0&lt;\u00a00.05 were considered statistically significant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>AP promoted insulin resistance, significantly increased (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) plasma concentrations of pro\u2010inflammatory cytokines (TNF\u2010\u03b1, IL\u20106, and IL\u20101\u03b2), significantly decreased (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) the concentration of anti\u2010inflammatory cytokine IL\u201010, impaired insulin signalling in SM, and increased IKK\u03b1\/\u03b2 phosphorylation status in SM and EDL. Melatonin supplementation in rats with AP improved insulin sensitivity, significantly decreased (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) TNF\u2010\u03b1 and IL\u20101\u03b2, significantly increased (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) IL\u201010 plasma concentrations, and changed the insulin signalling in soleus muscle and IKK\u03b1\/\u03b2 phosphorylation status in SM and EDL muscles.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Melatonin is a potent adjuvant treatment for improving apical periodontitis\u2010associated changes in insulin sensitivity, insulin signalling and inflammatory pathways. In addition, the negative impact of AP on general health was also demonstrated.<\/jats:p><\/jats:sec>","DOI":"10.1111\/iej.13474","type":"journal-article","created":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T00:44:57Z","timestamp":1610325897000},"page":"926-940","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Effects of melatonin on insulin signaling and inflammatory pathways of rats with apical periodontitis"],"prefix":"10.1111","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9437-8690","authenticated-orcid":false,"given":"B. 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