Periodontal disease is the result of a complex interplay of bacterial infection and host responses, and is often modified by various systemic diseases such as diabetes mellitus. Such diseases are capable of affecting the periodontium and/or the treatment of periodontal disease. However, recent research has changed our concept of how periodontal disease should be treated. Here we present several concerns directed towards the periodontal therapy of patients with diabetes mellitus based on our studies. When treating periodontitis patients who have diabetes mellitus it is important to consider the type of diabetes. Patients with non-insulin dependent diabetes mellitus can be further classified according to the degree of insulin resistance, since recent epidemiological studies have suggested that successful anti-microbial therapy might result in improved insulin resistance in highly insulin resistant patients. Because the major contributing factor for insulin resistance is currently considered to be the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), and because periodontal surgery may cause transient bacteremia which may up-regulate the serum TNF-alpha level, which in turn suppresses insulin action, patients should be strictly treated non-surgically and their serum TNF-alpha levels should be periodically monitored. On the other hand, diabetic patients positive for serum anti-glutamate decarboxylase auto-antibody should be examined for the source of this antibody, since 1) gingival and periodontal ligament fibroblasts were found to express glutamate decarboxylase, and 2) some otherwise healthy periodontitis patients develop anti-glutamate decarboxylase antibody. Thus, chronic periodontitis may influence the level of this antibody which is widely used as a predictive marker for slowly progressive insulin dependent diabetes mellitus. Not only is periodontal disease thereby affected by systemic diseases, but carefully managed periodontal therapy may also have a positive effect on the general health of patients with systemic diseases.