The chronic inflammatory condition of periodontitis is induced by pathogenic biofilm or dental plaque, which accumulates on the tooth surface. Over 500 bacterial species have been detected in dental plaque; however, the composition of the causative bacterial species is still debated [25–28]. The classic periodontal pathogens are Gram-negative bacteria such as Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola [29]. Recent studies have identified other bacteria that may be pathogenic [30]. Although bacteria are necessary for periodontal disease to take place, a susceptible host is also needed [27]. The predisposing factors that make an individual susceptible have not yet been defined though periodontal disease increases considerably in aged humans and animals including dogs and mice and by conditions that increase inflammation such as diabetes [31]. The inflammatory process occurring in periodontitis is characterized by the infiltration of leukocytes, which limit the level of bacterial invasion and at the same time may be harmful to the periodontal tissue [31]. The destruction of periodontal ligament and bone is thought to be the result of a disruption of the homeostatic balance between the host response and bacteria that result in inflammation in close proximity to bone [31–33]. The host immune response to bacteria or their products stimulates production of osteoclastogenic factors by immune cells and cells of osteoblastic lineage, which then induce bone loss. Periodontal disease in humans and in experimental animal models is linked to both the innate and adaptive immune response. Several studies have reported that individuals with periodontitis exhibit increased levels of interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in gingiva and crevicular fluid in the gingival sulcus [34]. Both genetic deletion and specific inhibition of these cytokines have been found to reduce periodontal disease progression [34–37]. Similarly, mediators of the adaptive immune response are elevated in individuals with periodontal disease and inhibition or genetic deletion of mediators such as receptor activator of nuclear factor kappa-B ligand (RANKL) and interferon-γ (IFN-γ) result in reduced periodontal disease progression [36, 38, 39]. Our laboratory has recently shown that the production of factors by osteoblasts and osteocytes also contributes to osteoclast formation and activity in periodontal disease (unpublished data). Evidence that the host response plays a critical role was also shown when treatment with a prostaglandin inhibitor reduced periodontitis-related bone loss [40] or inhibition of inflammatory cytokines such as IL-1 and TNFα [35, 37]. Thus, periodontitis is a complex disease, where multiple causal risk factors play simultaneous and interactive roles. Periodontal bone loss is affected by the bacterial biofilm which forms, ability of bacteria or their products to pass through the epithelial barrier into connective tissue, the status of the host response, and the presence of environmental stressors and/or systemic disease such as diabetes [41–43].

Diabetes and periodontitis are two chronic diseases that are biologically linked [44, 45]. Periodontitis is one of the first clinical manifestations of diabetes [19]. Diabetes is an important risk factor for periodontitis [4, 46]. The risk of periodontitis is increased approximately 2–4 times in diabetic versus nondiabetic subjects [4, 47]. In one study, periodontitis was found in 60 % of T1DM patients compared to 15 % without diabetes [48]. Patients with diabetes are at higher risk of severe periodontitis compared with nondiabetic subjects [49]. A study in African Americans found 70 % T2DM patients had moderate periodontitis and 29 % had severe disease, which is significantly higher than the prevalence of 11 % without diabetes [50]. The severity of periodontitis is directly proportional to the level of glucose control [48, 51].

Bone remodeling begins with the activity of osteoclasts, followed by new bone formation through the activity of osteoblasts. Under physiological conditions, the two activities are coupled, but the two processes are uncoupled in pathologic processes. Human studies generally indicate that diabetes mellitus increases osteoclastogenesis. Individuals with DM generally have increased systemic levels of bone resorption markers as indicated by higher circulating levels of tartrate-resistant acid phosphatase [70]. Animal studies show similar results [71]. T2DM rats have increased osteoclastic bone resorption in periodontal bone compared to normoglycemic controls [61]. Increased inflammation, ROS, and AGEs are thought to increase osteoclast activity.

Bone resorption is followed by a period of bone formation, a coupling process that limits the amount of net bone loss, which occurs during the resolution of inflammation in the periodontium [20]. We found that T2DM rats do not generate a burst of bone formation that normally occurs following induction of periodontal disease [61]. Inflammation plays an important role in this effect by limiting repair of resorbed bone. This occurs by reducing osteoblast numbers through decreased proliferation of precursors and greater apoptosis of mature osteoblasts [59, 63]. These studies suggest a molecular basis for the negative impact of T2DM on bone by the effect of diabetes-enhanced inflammation on suppressing the expression of factors such as fibroblast growth factor or bone morphogenetic proteins that are needed for new bone formation.

In summary, individuals with diabetes mellitus have increased risk and severity of periodontal disease [9, 19, 133]. Periodontitis is one of the first clinical manifestations of diabetes [19]. Diabetes aggravates periodontitis by an increase in the inflammatory response to bacterial infection and reducing the capacity to downregulate inflammation [9, 55]. There is a direct link between persistent hyperglycemia, an exaggerated inflammatory response to periodontal pathogens and periodontal bone loss [31, 66]. The impact of diabetes on the periodontium involves inflammation associated with both the innate and adaptive immune response [8, 31]. Diabetes-enhanced inflammation increases osteoclastogenesis and decreases reparative bone formation. A number of factors are increased by diabetes including RANKL, AGEs, ROS, and TNF that stimulate osteoclasts. Moreover, diabetes prolongs inflammation leading to longer periods on osteoclast activity as well as interfering with subsequent bone coupling. The negative effect of inflammation on bone coupling is likely to be an important factor in the disease process [59, 112] as inflammatory cytokines interferes with bone morphogenetic protein and Wnt signaling and also stimulates osteoblast apoptosis [104, 108, 134, 135]. The mechanisms by which diabetes affects periodontitis are summarized in Fig. 5.2.