## 4 _P. gingivalis_ and Systemic Diseases
### Diabetes Mellitus  
Diabetes mellitus is a metabolic disorder characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The biological relationship between diabetes and periodontal disease is well documented, with periodontitis having been shown to influence the pathogenesis of several systemic conditions, including diabetes. Periodontitis and diabetes exhibit a bidirectional interactive relationship: diabetes promotes the onset and progression of periodontitis, while periodontitis, in turn, impairs glycemic control and contributes to the development of diabetic complications. Diabetic patients generally present with more severe clinical manifestations of periodontal inflammation than non-diabetic individuals, and the severity of periodontal destruction is related to the presence of systemic complications, the degree of glycemic control, and the type of diabetes [45]. Microbial activity in periodontal infections is one of the main sources of the bidirectional connection between periodontitis and diabetes, because the hyperinflammatory state associated with this disorder could impose a significant increase in reactive oxygen species (ROS) (Figure 3 from [46]). A complex interplay exists between oxidative stress and advanced glycation end-products (AGEs)--a heterogeneous group of compounds that accumulate under hyperglycemic and oxidative conditions. AGEs intensify oxidative stress and inflammation, further impairing periodontal and systemic health [47]. Infections induced by periodontal bacteria trigger the production of lipopolysaccharides, which in turn increase inflammatory cytokines and attract immune cells, thus exacerbating diabetes. In contrast, patients with diabetes create a hyperglycemic environment that favors the growth of pathogenic bacteria, contributing to microbial dysbiosis [48]. Glycemic control in diabetic patients may be impaired by an increase in inflammatory cytokines. This phenomenon can be attributed to endotoxins produced by Gram-negative bacteria. The destruction of periodontal tissue begins with the activation of inflammatory cytokines by bacteria in periodontal tissues, which are elevated in the gingival crevicular fluid. These cytokines, in turn, lead to the breakdown of connective tissue and alveolar bone [49]. Tumor necrosis factor-\(\alpha\) (TNF-\(\alpha\)), secreted into the gingival sulcus by red complex bacteria such as _P. gingivalis_, plays a central role in the inflammatory cascade. TNF-\(\alpha\) induces the following mechanisms:  
* Increases the production of matrix metalloproteinases (MMPs);
* Promotes the secretion of prostaglandin E2 (PGE2);
* Activates osteoclasts and promotes bone resorption by inhibiting osteoblast differentiation;
* Induces apoptosis, preventing tissue regeneration and exacerbating periodontal destruction. Elevated levels of TNF-\(\alpha\), caused by inflammation, are associated with increased levels of HbA1c, apoptosis in pancreatic cells, and reduced insulin secretion, ultimately leading to insulin resistance [50]. Figure 3: From [PERSON] et al., 2025 [46], under the terms and conditions of the Creative Commons Attribution (CC BY) license. The bidirectional relationship between periodontitis and diabetes mellitus. Periodontitis-induced inflammation elevates systemic markers like C-reactive protein, worsens glycemic control and insulin resistance, and contributes to diabetes progression. In turn, hyperglycemia in diabetes impairs immune function, reduces wound healing, and increases oxidative stress, exacerbating periodontal inflammation and tissue damage and thus creating a vicious cycle. P. gingivalis can express various virulence factors to evade innate and adaptive immunities, enabling it to survive and propagate in the host, destroy periodontal tissues, and contribute to systemic diseases. It can invade and survive in host tissues by disrupting the gingival epithelial barrier, internalizing into epithelial cells, and enhancing autophagy in these cells [51].