Background: The purpose of this study is to investigate whether local inflammatory events, such as periodontal disease, are able to increase tumor necrosis factor-alpha (TNF-alpha) plasmatic concentration and decrease insulin sensitivity and insulin signaling in non-diabetic rats.Methods: Forty-eight male Wistar rats (2 months old) were divided into two groups, with either ligature-induced periodontal disease (LPD) or control conditions (CN). Experiments were performed in both groups 28 days after ligature placement. Plasmatic concentration of glycemia and TNF-alpha (n = 10) were analyzed by the glucose oxidase and enzyme-linked immunosorbent assay method, respectively. Insulin sensitivity (n = 7) was measured using the insulin tolerance test. Insulin signal transduction (n = 7) was measured by pp185 tyrosine phosphorylation status in insulin-sensitive tissues using the Western blotting method.Results: The LPD group showed decreased insulin sensitivity (P <0.05), although no glycemic alterations were noted (P >0.05). TNF-alpha plasmatic concentration was higher in LPD rats compared to CN rats. In addition, a decrease in the pp185 tyrosine phosphorylation status was observed after insulin stimulus in both white adipose and skeletal muscle tissues of the LPD group compared with the CN group.Conclusions: LPD is able to cause alterations to both insulin signaling and insulin sensitivity, probably because of the elevation of TNF-alpha plasmatic concentration. Thus, the present results emphasize the importance of the prevention of local inflammatory diseases, such as periodontitis, to prevent diabetes mellitus. J Periodontot 2012;83:864-870.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)