Should We Be Concerned about the Association of Diabetes Mellitus and Periodontal Disease in the Risk of Infection by SARS-CoV-2? A Systematic Review and Hypothesis

Abstract

The objective of this article was to conduct a systematic review of the literature to contrast the existing evidence regarding the relationship between periodontal disease (PD) and diabetes mellitus (DM) with the possibly increased risk of SARS-CoV-2 infection, as well as to establish a hypothesis that explains the ways in which this interaction could take place. A literature search up from 1 January 2020 to 21 March 2021 was conducted in three electronic databases, namely, PubMed, Web of Science, and Scopus, in order to identify studies on periodontal disease alone or in conjunction with diabetes mellitus, reporting any relation with SARS-CoV-2 infection as a primary outcome. Only articles published in the English language were included. Due to the lack of studies, we decided to collect all the theoretical and clinical evidence suggesting a possible biological pathway evidencing the relationship among PD, DM, and SARS-CoV-2 infection. From a total of 29 articles, 12 were included for final review studies (five reviews, two hypotheses, one Special Issue, one perspective, one commentary, one case–control study, and one case report). In addition, this systematic review article hypothesizes the correlation between PD and type 2 diabetes mellitus (T2DM) by expression of angiotensin-converting enzyme 2 (ACE2) in periodontal tissue and the risk of SARS-CoV-2 infection. T2DM is a metabolic disorder characterized by high blood glucose levels resulting from altered insulin secretion or action. Likewise, periodontitis and T2DM are inflammatory disorders with a bidirectional association, and both diseases have a similar immunomodulatory cascade and cytokine profile. ACE2 is a crucial component of the renin–angiotensin system (RAS) and the key factor of entry in the cells by the new SARS-CoV-2. ACE2 is widely distributed in the lung and kidneys, and interestingly has a great distribution in the oral cavity, principally in the tongue and periodontal tissue. ACE2 in periodontal tissue plays a crucial role between health and disease. Moreover, the ACE2/Ang-(1-7)/MasR axis is downregulated in the dysbiotic and inflammatory periodontal environment. Nevertheless, the balance of ACE2 activity is modified in the context of concurrent diabetes, increasing the expression of ACE2 by the uncontrolled glycemia chronic in T2DM. Therefore, the uncontrolled hyperglycemia possibly increases the risk of developing periodontitis and triggering overexpression of ACE2 in periodontal tissue of T2DM patients, with these events potentially being essential to SARS-CoV-2 infection and the development of mild-to-severe form of COVID-19. In this sense, we would like to point out that the need for randomized controlled trials is imperative to support this association.

Does periodontitis influence the risk of COVID‐19? A scoping review

“…In addition, a strong correlation between the severity of COVID‐19 and type 2 diabetes in patients with periodontitis was recently reported, showing that the number of ACE2 receptors was prominently higher in those with periodontal disease and diabetes than in those with periodontal disease alone (Casillas Santana et al, 2021 ). In other words, diabetes and periodontal disease significantly contributed to the increase in the number of ACE2 receptors among individuals, thereby enhancing the susceptibility to SARS‐CoV‐2 infection and subsequently accelerating the disease prognosis.…”

Impact of COVID-19 on Periodontitis and Peri-Implantitis: A Narrative Review

“…Furthermore, according to Basso et al, periodontal bacteria increase the expression of ACE-2 [ 15 ]. Another clinical aspect was suggested by Casillas Santana et al, that uncontrolled hyperglycemia in diabetic patients could increase the expression of ACE-2, reducing the activity of MMP [ 36 ].…”

Beneficial Effects of Melatonin on Periodontitis Management: Far More Than Oral Cavity

“…The underlying mechanisms have been identified as well [ 174 ]. For instance, angiotensin-converting enzyme 2 (ACE2), one of the key receptors for the invasion of SARS-CoV-2, is highly expressed on the epithelial cells of oral mucosa [ 175 ], and could be upregulated in patients with periodontal disease and diabetes [ 176 ]. Moreover, periodontopathogens aspirated into the lungs could facilitate more SARS-CoV-2 invasion and replication [ 177 ].…”