people without diabetes.
● HbA1c is significantly reduced at 3 to 4 months following periodontal therapy. However, there are insufficient data to demonstrate that this effect is maintained after 6 months.
● Some studies identified that periodontitis increases insulin resistance (HOMA-IR levels) in people with diabetes.
● People with diabetes and periodontitis are more likely to suffer from diabetes-related complications than people with diabetes only.
1.3 Cellular and molecular mechanisms
The principal mechanisms that link oral infection with systemic diseases are:
● metastatic spread of infection from the oral cavity as a consequence of transient bacteraemia
● metastatic spread of cellular injuries because of the circulation of oral bacterial toxins
● metastatic spread of inflammation triggered by oral bacteria121.
In obesity, the mechanism behind its impact on periodontitis is still controversial. However, inflammation and the role of cytokines are surely of great importance in explaining a possible mechanism. Obesity is associated with a state of chronic low-grade systemic inflammation. Evidence from animal and human studies demonstrates a clear association between weight regulation and inflammation, with abnormalities of innate and adaptive immune function, including elevated serum levels of inflammatory cytokines, such as IL-5, -10, -12, -13, interferon (IFN)γ and TNF-α and peripheral blood lymphocyte subpopulation levels122. For example, in obese mice under a high-fat diet, pro-inflammatory T-helper cells 1 (Th1) and pro-inflammatory M1 macrophages, are activated and produce IFNγ, TNF-α, and IL-12123,124, whereas the differentiation of naïve T cells into anti-inflammatory Th2 and the activity of regulatory T cells (Treg), are reduced125. Moreover, as explained earlier, periodontal pathogen populations may be altered in obese subjects possibly leading to a higher virulence of the periodontal pathogens in those patients (Fig 1-1).
Fig 1-1 Potential mechanism linking obesity to periodontitis. Obesity increases the levels of inflammatory cytokines, oxidative stress and levels of periodontal pathogens, and can lead to diabetes mellitus, increasing the prevalence and severity of periodontitis. Environmental and genetic factors modulate both diseases. (IL = interleukin; MCP-1 = monocyte chemoattractant protein-1; TNF-α = tumour necrosis factor alpha.)
Many studies have demonstrated that adipose tissue cells (adipocytes, pre-adipocytes and macrophages) secrete cytokines and over 50 other bioactive substances collectively known as adipokines, explaining the low-grade systemic inflammation observed in obesity126. However, there are conflicting results regarding which cytokines play the main role in an obesity-periodontitis association. For example, high levels of TNF-α in plasma127 and gingival crevicular fluid (GCF)128 were found in obese subjects. On the other hand, Saxlin et al129 observed that serum IL-6, but not TNF-α, may mediate the possible inflammatory effect of body weight on the periodontium.
Several clinical studies have identified that the relationship between periodontitis and common major systemic pathologies is most probably due to systemic inflammation and bacteraemia.
Indeed, Hasturk and Kantarci130 described two models for the development of systemic inflammation secondary to periodontitis. The first is the dissemination of periodontal pathogens to distant sites via the blood stream (bacteraemia), where they trigger local inflammation. Whilst bacteraemia is a generally accepted occurrence, there is conflicting data on how many bacteria can be found in the systemic circulation in periodontitis or subsequent to mechanical instrumentation.
In the second model, periodontal bacteraemia triggers an acute-phase response by the liver, involving the release of C-reactive protein and production of IL-6, and also activates peripheral blood leukocytes (neutrophils) to release oxygen radicals, thus creating a peripheral oxidative stress response130. This low-grade peripheral inflammation arising in periodontitis is thought to contribute, in the longer term, to vascular endothelial damage and pancreatic beta-cell damage59.
1.3.1 Cytokines and inflammatory mediators
In patients with periodontitis, chronic low-level systemic exposure to periodontal microorganisms exists, which leads to significant changes in plasma levels of cytokines and hormones. This systemic response is the link between chronic subclinical inflammation and insulin resistance, initiating the development of T2DM131. In terms of the inflammatory mediators, there is sufficient evidence that their systemic and local expression is increased in patients with diabetes and periodontitis compared to patients with periodontitis only. For instance, subjects with poorly controlled diabetes and dyslipidaemia have high levels of the eosinophil chemotactic protein eotaxin, macrophage inflammatory protein-1a, granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-α, IL-6, IL-10 and IL-12 in their GCF132,133. In addition, patients with T2DM have an increased level of lipid peroxidation in the GCF indicated by the detection of malondialdehyde134. These findings are supported by animal and cell cultures studies134. Furthermore, studies have shown that a hyperglycaemic state leads to increased expression of innate immunity receptors, such as toll-like receptors (TLR) 2 and 4. Regarding cell function, there is some evidence that diabetes and periodontitis lead to an altered monocyte, T cell and aberrant neutrophil function135,136. Thus, diabetes and hyperglycaemic conditions induce a hyper-inflammatory state systemically and in the infected periodontal tissues, leading to an increase of the disease risk and severity.
1.3.2 Bone homeostasis
Other important evidence is that both T1DM and T2DM modulate alveolar bone homeostasis, which could be an important pathway of periodontal pathogenesis in people with diabetes. In animal studies, rats with diabetes T1DM137 and T2DM138 with experimental ligature- and pathogen-induced periodontitis had a two- to four-fold increase in osteoclast numbers compared with control rats139. The RANK–RANKL interaction is one of the most potent inducers of osteoclast formation and activity, and osteoprotegerin (OPG) inhibits osteoclast formation binding to RANK like a decoy receptor and thus blocks the activity of RANKL. Animal studies demonstrate that the RANK-RANKL/OPG ratio is a critical factor in the enhanced osteoclastogenesis in periodontitis with diabetes (Figs 1-2 and (1-3)139,140.