## 4 Discussion  
Diabetes and periodontitis manifest a strong inflammatory phenotype with considerable involvement of the innate immune system, which plays a crucial role in these complex etiologies [19]. While it is generally accepted that the association between the two diseases is probabilistic (not all diabetics develop periodontitis and vice versa), the complex nature of the mechanism underlying the correlation, assuming independence, makes it difficult to estimate the exact effect size [19]. Despite the recognition of the relevance of inflammatory pathways in regulating this relationship, little is currently known about the molecular apparatus that controls these pathways. The exponential growth in our understanding of the biology of inflammosomes has led to the recognition of the NLRP3 as a common nexus among several diseases. One of the most emerging hypotheses concerning the origin of the relationship is that the pyrin domain-containing protein 3 (NLRP3) inflammasome signaling pathway mediates the correlation [17]. Given the potential in targeting the pyrin domain (PYD) in the NLRP3 for therapeutic benefit to several disorders belonging to the family of inflammatory diseases, e.g., atherosclerosis, obesity, or type two diabetes mellitus (T2 DM), detecting the mechanism by which the NLRP3 is triggered in periodontitis and diabetes is attracting an increasing amount of attention. [19]. Based on these findings, our  
Figure 2: Schematic illustration of the mechanisms of NLRP3 activation in periodontitis and diabetes. Created with BioRender.com, accessed on 12 July 2023.  
goal was to investigate novel data on the comprehension of the NLRP3 inflammasome as well as the mechanistic knowledge of the correlation between these disorders. Both human and animal models have been utilized in the research that has been conducted on the activation of the NLRP3 inflammasome in diabetic and periodontitis patients. To date, only three studies have determined the role of the NLRP3 in modulating the relationship between diabetes and periodontitis using immunohistochemical analysis. The first evidence implicating the NLRP3 in the regulation of the interrelationships between periodontitis and diabetes arose from the study of [PERSON] et al., which directly revealed the importance of the NLRP3 in the context of both diseases [27]. As a model, they employed human gingival epithelial cells (HGECs), which were generated from patients with periodontal disease who either had or did not have type two diabetes. The levels of expression of the NLRP3 inflammasome, ASC, caspase-1, and IL-1 in the samples of patients with periodontitis and/or diabetes were considerably elevated when compared with the levels of expression in healthy controls. The levels of the NLRP3 were found to be higher in diabetic individuals, and this elevation was found to have a positive correlation with the severity of the condition. Results from [PERSON] and colleagues [29] confirmed this hypothesis because subjects with periodontitis and diabetes showed higher expression of NLRP3, CASP1, and ASC at the mRNA and protein levels in the epithelium and connective tissue in comparison to non-diabetic controls, supporting evidence of increased activation of inflammasome protein complexes, as shown by the over production of IL-1B (\(p=0.0018\)) in the gingival circular fluid of the diabetic group affected. Moreover, IL-18 (\(p=0.0063\)) was highly expressed in patients with periodontitis or diabetes compared with healthy subjects. Microarray analyses in experimental diabetes have added new information. Consistent with their previous study, [PERSON] et al. [28] showed that the expression of the NLRP3 inflammasome was increased in gingival tissues, along with ASC, caspase-1, and pro IL-1B. These findings were observed in a mouse model of diabetes and co-occurring periodontal infections.