Periodontitis and Systemic Diseases. Группа авторов

as a result of hyperglycaemia, aging and inflammation183. There are also exogenous sources of AGEs ingested through heat-treated and otherwise processed food products and tobacco184.

Chronic hyperglycaemia drives the formation of AGEs that bind to its receptor, RAGEs, on the surface of endothelial, smooth muscle and immune cells such as T and B-cells, monocytes, macrophages and polymorphonuclear neutrophils (PMNs)185. In mononuclear phagocytes, AGEs–RAGE interaction activates these cells, increasing the release of platelet-derived growth factor, insulin-like growth factor-1, and pro-inflammatory cytokines, such as IL-1β and TNF-α, and also increasing cell migration (chemotaxis)186. Cipollone et al187 observed that in macrophages extracted from atherosclerotic plaques from 60 diabetes (T2DM) and non-diabetes patients undergoing carotid endarterectomy, RAGE overexpression was associated with an increase in inflammatory response and cyclooxygenase-2/prostaglandin E synthase-1 (COX-2/mPGES-1) expression, leading to plaque destabilisation through MMP expression. In addition, RAGE, COX-2/mPGES-1 and MMP expression were linearly correlated with plasma levels of HbA1c187.

Thus, AGEs result in inflammatory responses, either directly or via interaction with RAGEs, acting as stimuli for activating intracellular signalling pathways as well as modifying the function of intracellular proteins. Higher levels of circulating AGEs have been linked to chronic diseases in aging subjects (Fig 1-5). In fact, AGEs are the major molecules involved in the development and progression of different diabetes complications. For example, AGEs modify collagen and elastin in the vascular wall, reducing the turnover of these proteins, and consequently making them more susceptible to further glycation188. Moreover, the AGE-RAGE coup­ling triggers NADPH oxidase (nicotinamide adenine dinucleotide phosphate oxidase) activation and overproduction of superoxide, oxidative stress and, consequently, results in tissue destruction189.

      Fig 1-5 Physiological and pathological roles of AGE/RAGE interaction (AGE = advanced glycation end product; MMP = matrix metalloproteinase; NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells; RAGE = cell surface receptors for AGE; ROS = reactive oxygen species).

Animal studies have demonstrated that this coup­ling leads to a sustained inflammatory response, inducing progressive periodontal bone loss190. So far, there is no evidence to suggest that periodontal therapy can modulate circulating and local AGEs (other than HbA1c) concentration. This is due to the lack of studies, negative outcomes of the few studies available, and low numbers of patients included in these trials. For example, Lin et al191 did not observe any change in plasma soluble RAGE (sRAGE) concentration 3 and 6 months after non-surgical periodontal therapy, with or without minocycline, in poorly controlled T2DM (HbA1c of ≥ 8.5% for more than 5 years). sRAGE results from the cleavage from the immune cell surfaces by AGEs, which also upregulates its expression. Experimental studies suggested that sRAGE can act as a decoy receptor for AGEs and thus protect the cells against AGE actions on its membrane receptor192. It is important to highlight that this study only included 28 patients divided into two groups, and only sRAGE, not membrane receptor RAGE, was analysed.

Ligand–RAGE interactions modulate vascular, neural, renal and cardiac functions, which are prominently affected in diabetes and aging. RAGEs are expressed in a wide variety of tissues, and are upregulated in several diseases, including Alzheimer disease and amyotrophic lateral sclerosis193. The most important pathological consequence of this interaction is cellular activation, leading to a broad spectrum of signalling mechanisms, including the induction of oxidative stress194, transcriptional activation of genes encoding pro-inflammatory mediators, such as TNF-α, IL-1β, IL-1, 6 and 8, IFNγ, and cell adhesion molecules193. Importantly, the wide distribution of RAGEs leads to prolonged cellular activation with a positive feedback activation, which, as consequence, further increases receptor expression.

In the periodontium and GCF, AGEs were found to be increased in periodontitis alone194a, and in combination with both T1DM and T2DM, with ­evidence of higher accumulation in the epithelium from subjects with T1DM than with T2DM195.Furthermore, a positive correlation was found ­between gingival expression of AGEs and diabetes duration195. AGEs may be associated with a state of enhanced oxidative stress locally in the periodontal tissues, thus the possibility of reducing glycation and tissue AGEs or blocking the binding of AGEs to RAGEs would be a promising target for delaying or preventing the bone loss in diabetes patients. In fact, Lalla et al196 demonstrated that blockade of RAGE results in suppression of both alveolar bone loss and markers of immune cell activation and tissue-­destruction in diabetic mice infected with Porphyromonas gingivalis. These data support the concept that activation of RAGE accounts for ­exaggerated inflammation and tissue destruction in the periodontium of those with diabetes.

      1.3.7 Microbiome alterations

Regarding the composition of the periodontal flora in patients with diabetes, some studies present evidence indicating a difference in the microbial composition in patients with DM, especially in those with poorly controlled diabetes. It was reported that in these patients, a higher bacterial count and more pathogenic bacteria are found. However, the available evidence of a causal relationship between poorly controlled diabetes and periodontal microbial dysbiosis is limited to date134^,135^,197. For example, two cross-sectional studies observed that in poorly controlled diabetes subjects, the red complex bacteria levels were significantly more abundant and that there was an association between levels of A. actinomycetemcomitans, P. gingivalis, Treponema denticola, T. forsythia and Actinomyces naeslundii and poorly controlled diabetes198^,199. In an in vitro study, Chang et al200 observed that high glucose levels increased the expression of intercellular adhesion molecule 1 (ICAM-1/CD54) by gingival fibroblasts and consequently P. gingivalis invasion into these cells. On the other hand, Taylor et al135 concluded that the presence of diabetes (T1DM and T2DM) has no effect on the composition of the periodontal microbiota. However, recent studies based on polymerase chain reaction (PCR) technology demonstrate a shift in microbial composition towards a more pathogenic one (orange and red complex) in patients with diabetes, especially in poorly controlled diabetes patients198^,201^,202. A 2018 meta-analysis,