Cytokines are substances secreted by immune cells or other cells that are recognized as inflammatory mediators and are related to the inflammatory reaction. Studies strongly show that diabetes and hyperglycemia directly induce a high inflammatory status in the infected periodontium, and the expression of proinflammatory cytokines is more significant in gingival tissue and crevice fluid of patients with diabetes periodontitis than in individuals with system health (77).

The most abundant data available concerns increased IL-1β, TNF-α, and IL-6. There is sufficient evidence to show that compared to patients with simple periodontitis, patients with combined diabetes and periodontitis have increased proinflammatory cytokines IL-6 and IL-1β, and there is a quantitative relationship between glycemic control and these cytokines (56, 57). On the other hand, a decreased secretion of anti-inflammatory cytokines such as transforming growth factor-beta (TGF-β), interleukin-4 (IL-4), and interleukin-10 (IL-10) may also lead to the aggravation of periodontal inflammation in diabetes patients (78). In conclusion, the hyperglycemia caused by diabetes can directly or indirectly reduce the expression level of anti-inflammatory cytokines such as IL-4, IL-10, and TGF-β1 and increase the expression level of proinflammatory cytokines such as IL-1β, IL-6, IL-8, IL-17, and TNF-α, all of which together enhance the periodontal inflammatory performance (79, 80).

In addition to cytokines, other proinflammatory mediators, such as metalloproteinases and chemokines, are also found to be associated with diabetes (4, 7, 71, 72, 77, 78, 81–84). Kim et al. (85) confirmed that the expression of matrix metalloproteinase-14 (MMP-14) was higher in the periodontal tissues of diabetes patients with poor glucose control. On the other hand, a reduction in proresolution mediators such as resolvins, protectins, maresins, and lipoxins may also contribute to enhanced periodontal inflammation (76), which involves three separate biosynthetic and potent mediator families. During the inflammatory process, the proinflammatory factors emit signals which can facilitate the synthesis of proresolution mediators such as resolvins, leading to the activation of the innate immune system and eliminating pathogens stimuli (86–88). Ozturk et al. (89) also confirmed that there were higher levels of proinflammatory peptide substance-P in the gingival crevicular fluid and serum of diabetic patients with poor glycemic control, which may aggravate the progression of periodontitis and cause greater periodontal destruction.

There are multifarious types of adipokines, including adiponectin related to metabolic function, resistin and leptin related to endocrine function, complement factors related to immunity, angiotensinogen related to cardiovascular function, and so on (90). According to previous studies, some adipokines are involved in the occurrence and progression of periodontal disease and diabetes, but the existing evidence is insufficient. There are also many studies trying to research the expression of adipokines in the gingival crevicular fluid or serum and related mechanisms in periodontitis patients with or without diabetes, and the results are also unclear; further investigations are warranted.

Resistin is produced by various cells of the immune/inflammatory system (91, and seems to be the most widely researched adipokine linking periodontal disease and diabetes. As a proinflammatory factor, resistin promotes the release of interleukin-12 (IL-12) and TNF-α, induces the activation of NF-κB, and enhances the secretion of monocyte chemoattractant protein-1 (MCP-1) and IL-6 (92). Two studies showed comparable resistin levels in gingival crevicular fluid and serum between periodontitis with/without diabetics (93, 94). However, the other study showed significantly higher levels of resistin in serum and gingival crevicular fluid in periodontitis with T2DM than in the chronic periodontitis group (95). A recent study identified that the expression of resistin in chronic periodontitis was significantly higher compared to the periodontal health group, and the level of resistin was also higher in the periodontitis patients with T2DM. There was a strong positive correlation between resistin, glycosylated hemoglobin (HbA1c) level, and periodontal clinical parameters, with significant statistical differences (96). This is due to the chronic systemic inflammatory state caused by T2DM and the chronic local expression of proinflammatory resistin in the periodontal tissue (97). Similarly, high levels of resistin can affect the activity of osteoclasts, thereby affecting the absorption of alveolar bone. At the same time, T2DM changes the composition of periodontal bacterial pathogens in patients and activates the host immune response, resulting in the release of resistin by neutrophils (98). Therefore, resistin as a potential mediator between T2DM and chronic periodontitis deserves more attention.

Adiponectin is an anti-inflammatory, while leptin is a proinflammatory. T2DM can increase the levels of leptin and decrease the levels of adiponectin (99–101). Recent studies have found that compared to individuals with systemic health, the adiponectin level in periodontitis patients with diabetes is significantly lower and the leptin level is significantly higher (102, 103). Similarly, Kardeşler et al. (104) also showed that, compared to patients with periodontitis without T2DM, patients with T2DM and periodontitis had lower adiponectin levels and higher leptin levels. Adiponectin, leptin, visfatin, and chemerin play an important role in the occurrence, development, and diabetes-related complications of T2DM (105). The adiponectin receptor agonist AdipoRon (APR) can activate the endogenous adiponectin receptors to exert osteoanabolic effects and reduce osteoclast numbers and alveolar bone loss significantly. At the same time, APR can enhance stem cells’ osteogenic differentiation, reduce stromal cell-derived factor 1, which can promote stem cell migration, and ultimately promote the repair and regeneration of alveolar bone (106). Adiponectin and its agonists may be promising potential therapeutic targets for the clinical treatment of diabetes-related periodontitis, but the potential mechanism and clinical application need further research (107).

Other adipokines also play a role in the progress of diabetes-related periodontitis. A recent study found that progranulin in the saliva of diabetes patients with periodontitis was significantly reduced after nonsurgical periodontal treatment, considering that progranulin might be a target inflammatory marker for diabetes-related periodontitis (108). Another interventional comparative study showed that there were significant differences in the levels of omentin-1 in the saliva and serum of chronic periodontitis patients with or without T2DM (109). In addition, compared to periodontitis alone, periodontitis patients with T2DM have higher levels of plasminogen activator inhibitor-1 (PAI-1) in saliva and serum, suggesting a possible role of adipokines in the regulation of glycemic levels and periodontal inflammation (110).

AGEs are produced by the nonenzymatic oxidation of lipids, nucleic acids, and proteins caused by hyperglycemia in diabetes and accumulate in the periodontium, leading to sustained periodontal tissue destruction (111, 112). Periodontitis patients with diabetes have higher AGE accumulation levels compared to periodontitis patients without diabetes (112, 113). The accumulation of AGEs in the periodontal tissue of diabetes patients will increase the susceptibility to periodontitis and aggravate the existing periodontitis, but the exact mechanism is still unclear.

AGEs have been demonstrated to decrease osteoblast-related molecule mRNA expression, such as type 1 collagen, core-binding factor alpha 1 (Cbfa1), and osteocalcin, and increase inflammation-related molecules such as IL-1β and calcium-binding protein S100A8 (114). Another potential action of AGEs is to influence bone metabolism and inflammation through the regulation of sclerostin expression, which has an adverse effect on bone formation or bone metabolism in osteocyte cells and may aggravate periodontitis with diabetes (115). AGE2, a form of AGEs, can respectively upregulate the expression of Toll-like receptor 2 (TLR2) and RAGE in periodontal tissue and significantly stimulate the production of sclerotin and IL-6 in osteocytes. The presence of AGEs can also upregulate the levels of proinflammatory cytokines TNF-α and IL-6, which will further exacerbate inflammatory reactions (115).

In addition to its effects on the bone system, further studies showed that AGEs affected almost all types of cells in periodontal tissue directly or indirectly by binding to their receptors(RAGEs), including periodontal ligament stem cells (PDLSCs), gingival fibroblasts (GFs), gingival epithelial cells (GECs), and periodontal ligament cells (PDLCs) (80, 80). AGEs can inhibit the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) by activating the classic Wnt/β-catenin pathway, reducing osteogenic potential and the regeneration and repair of alveolar bone (116). The accumulation of AGEs in human gingival fibroblasts (HGFs) can increase the protein and mRNA expressions of intercellular adhesion molecule-1 (ICAM-1), RAGE, and ROS through the NF-κB signaling pathways and MAPK pathways and aggravate periodontitis (117). It is also shown that AGEs stimulated the expression of RAGE and TLR2 by activating NF-κB, JNK-MAPK, and p38 signaling pathways in human gingival epithelial cells (hGECs), which could lead to increased activation of calprotectin in human gingival fibroblasts, including S100A9 and S100A8 (111). In human periodontal ligament cells (hPDLCs), the AGE/RAGE system can activate nucleotide-binding oligomerization domain-like receptors expression, such as NLRP1-inflammasome and NLRP3-inflammasome, promoting the inflammatory response through the NF-κB signaling pathway (118).

High concentrations of AGEs will cause the deterioration of diabetes periodontitis, and the siRNAs of RAGE can significantly reverse this result (111, 114, 115, 117, 119). The current research points to the beneficial effects of the administration of AGE inhibitors or blockers on periodontal tissue. The use of AGE inhibitors may improve periodontal inflammation, alleviate the damage of pathogenic bacteria to periodontal tissue, and ultimately improve the outcome of periodontal treatment. The huge potential of this method is obvious through the local application in periodontal tissue of new drugs such as vitamin C, which is an antioxidant and immunomodulator, to reduce the detrimental effect of diabetes mellitus on the periodontal tissue (120). Meanwhile, the natural antioxidant magnolol can alleviate periodontal inflammation for diabetes patients with periodontal disease by reducing the accumulation of AGEs, maybe through the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway (121).

In conclusion, chronic hyperglycemia increases the incidence/severity of periodontal diseases by inducing an exaggerated and prolonged inflammatory response driven by the accumulation of AGEs, which are considered to be the main pathogenesis of diabetes-related complications by inducing immune disorders and cell damage (122–124). AGEs can expand the release of proinflammatory mediators, enhance the immune inflammatory response of periodontal tissue, amplify oxidative stress by stimulating the production of ROS, and increase the susceptibility to periodontitis in diabetes patients (80). The administration of AGE inhibitors or blockers can partially reverse this result.

MicroRNAs (miRNAs) are a group of noncoding small RNAs that function as master protein synthesis regulators that can act directly on target genes or indirectly on their transcription factors, which in turn silence the expression of the target gene (125). It has been reported that more than 60% of the translation of human coding genes is regulated by these highly conserved single-stranded miRNAs (126). It is reported that miRNA expression is tissue-specific, and the imbalance of miRNA expression is not only closely related to various diseases but also affects other normal protein expression (127). Therefore, they not only play an important role in the normal physiological process but also in the pathological development of various diseases. Much literature has shown that tissue-specific miRNAs can be used as diagnostic markers for metabolic diseases such as diabetes and inflammatory diseases such as periodontitis (128, 129), and most detectable miRNAs are concentrated in the exosomes (130). As promising disease markers, miRNAs are confirmed to coordinate immune inflammatory responses and have a strong upward potential in future research (131). Although very important, due to the relative novelty of the field of miRNAs, the role of miRNAs in the pathology and physiology of diseases needs to be further elucidated (132).

Some miRNAs may play an important role in the comorbid pathogenesis of diabetes mellitus and periodontitis. Recent studies demonstrated that, when compared to the control groups, there was significant overexpression of miR-223 in chronic periodontitis patients with or without T2DM (133, 134). MiR-223 can regulate innate immunity, leading to the recruitment and overactivation of neutrophils (135); therefore, miR-223 is related to the pathogenesis of chronic periodontitis and is highly likely to become a diagnostic marker for periodontal disease. MiR-223 is also helpful in the differential diagnosis of T2DM combined with periodontitis and periodontitis alone (133, 134, 136). In addition, miR-223 is correlated with proinflammatory cytokines TNF-α, anti-inflammatory cytokines TGF-β and IL-10, and periodontitis clinical parameters such as probing depth (PD) and clinical attachment loss (CAL) in varying degrees; it is also highly correlated with susceptibility to diabetes mellitus and glycemic control levels (134).

MiR-200b, which is induced by inflammatory cytokines, plays a key role in the early stages of inflammatory response, mainly participating in innate immunity and promoting the differentiation of various immune cells, such as neutrophils and macrophages (137). Moreover, the study found that in the chronic periodontitis group of T2DM, there was a significant difference in the serum level of miR-200b, which was significantly negatively correlated with IL-10 and positively correlated with TNF-α (133). Moreover, miR-203 may also play have a connecting effect on diabetes mellitus and periodontitis and have an additional characteristic as a specific marker for differential diagnosis of patients with or without diabetes, as well as distinguishing diabetes with periodontitis from diabetes without periodontitis (133, 138, 139). MiR-203 can also reduce inflammation in periodontal tissue by repressing TNF-α (139).

In addition to the above-mentioned, miR-146a, miR-146b, and miR-155 are also identified as promising biomarkers for diabetes mellitus and periodontal diseases (139–142). The gene targets of these miRNAs involve both innate and acquired immune responses, including natural killer cells and T lymphocytes (143), indicating its potential role in immune-related inflammation diseases such as periodontitis and metabolic diseases such as diabetes mellitus. MiR-155, miR-146a, and miR-146b can sense pathogen stimulation through pattern recognition receptors via the NF-κB signaling pathway (144). The combination of NF-κB-miRNA-146a and NF-κB-miR-155 regulatory loops can regulate the duration and intensity of inflammatory responses, so miR-146 and miR-155 can cross-talk and provide optimum NF-κB pathway activity and ultimately reduce inflammation (140, 145). This result was confirmed in other studies (139, 139, 141, 142). MiR-146a, miR-146b, miR-155, and miR-203 expression were higher in patients with periodontitis with or without diabetes; MiR-146a is the only reliable predictor of periodontitis in diabetes patients, and miRNA-155 is the most reliable predictor of periodontitis in nondiabetes patients (139). Since miR-155 is a main regulator of immunity/inflammatory response, the transcription level of miR-155 can discriminate between diabetes and nondiabetes conditions (146).

Another study showed that high glucose related to diabetes mellitus induced apoptosis of human periodontal ligament cells through a diminution of miR-221 and miR-222 expression and an increment of caspase-3, a validated target for these miRNAs, and had an effect similar to the inhibition of miR-221/miR-222 in control groups using antagomiRs (147). On the contrary, the expression levels of miR-214 in the periodontium of diabetes-associated periodontitis patients were increased (148). In addition, miR-126 can inhibit the inflammatory response of HGFs caused by hyperglycemia by directly targeting tumor factor receptor-associated factor 6 (TRAF6), so it may be a potential therapeutic target for periodontitis with diabetes (149).

Dysregulated expression of miRNA profiles mediates the inflammatory stress response by various inflammatory factors, so miRNAs play an important role in the occurrence and development of diabetes and periodontitis (150, 151). However, the explicit regulatory mechanism of miRNA in aggravating periodontitis in patients with diabetes mellitus is still unclear, and it is a direction for future research.

The interaction between periodontal microbiota and host immunity response is key to the pathogenesis and periodontium destruction of periodontitis. The size (big or small) of the immune response of host periodontal tissue in combating dysbiotic microbiota is very important because it determines the clinical manifestation of periodontitis and the response to periodontal treatment (12). Hyperactive immune responses can increase inflammation and degradation of periodontal tissue (152).

Periodontal pathogenic bacteria are recognized by pattern recognition receptors such as TLR2, TLR4, TLR7, TLR8, and TLR9 on the surface of periodontal cells, which can lead to the response of the proinflammatory cell, activation of neutrophils, and recruitment of macrophages/lymphocytes through p38 mitogen-activated protein kinase and NF-κB signaling pathways. Similarly, prostaglandin E2 (PGE2) released by macrophages and oxidative stress induced by neutrophils can cause more release of proinflammatory cytokines such as TNF‐α, IL‐1β, and IL‐6 and matrix metalloproteinases (MMPs) such as MMP-1, MMP-2, MMP-8, MMP-9, and MMP-13, which lead to local degradation of collagen fibers, loss of periodontal attachment, and resorption of alveolar bone, promote the progression of periodontitis, and enlarge inflammatory response and periodontal tissue (153–157).

The inflammatory response induced by the dysbiotic microbiota community includes interleukin-23 (IL-23) (158), which is produced by both macrophages and dendritic cells (DCs) in the connective tissue (159), which can increase the proportion of Th17 lymphocytes and change the ratio of T helper 17/regulatory T cells (Th17/Treg) to tilt the balance toward proinflammatory Th17 cells (160). IL-17, which is derived from Th17 cells, also plays an important role in periodontal destruction; it can cause collagen destruction mediated by neutrocytes, alveolar bone loss via RANK/RANKL pathways, and contribute to periodontitis (161–163).

Host genotype may be closely related to periodontal susceptibility (164). Moreover, both comorbidities such as diabetes and environmental factors such as smoking are also very important (165).

Diabetes mellitus can affect the innate and adaptive immune systems of the periodontium; both of them are thought to contribute to the progression of periodontitis.

Neutrophils are an important component of innate immunity, forming the first effective line of defense for the host against periodontal bacteria (166). Neutrophil homeostasis can maintain a balance between body protection and destruction, and any imbalance may cause periodontal tissue damage (167). In previous studies, it was found that the numbers of neutrophils were enhanced, but the functional activity of neutrophils (such as chemotaxis, phagocytosis, bactericidal function, and others) was impaired in periodontitis patients with T2DM (168), which would give rise to intracellular killing and respiratory burst (166) and increase the severity of periodontitis in diabetic patients. Dysfunctional neutrophils may cause periodontal tissue damage through the release of inflammatory mediators or tissue-degrading enzymes (169). In diabetic patients with poor glycemic control, neutrophils can also be activated in advance to increase the periodontal damage by increasing the activity of protein kinase C (PKC) (170). Poorly functioning neutrophils can enhance tissue damage, produce more superoxide and proinflammatory cytokines as well as chemokines, and increase the number of neutrophils in periodontal tissue (171, 172). In addition, in diabetes patients, neutrophils will overexpress a key enzyme, peptidylarginine deiminase 4 (PAD4), which is a nuclear citrullinating enzyme that is involved in the release of decondensed chromatin from neutrophils, inhibit the periodontal defense response and promote periodontal inflammation, and form the neutrophil extracellular traps (NETs), which, together with fibrin, are implicated in host defense against pathogens (173, 174). Furthermore, the levels of calprotectin (S100A8/A9), the major cytoplasmic protein in neutrophils, are significantly higher in periodontitis patients with T2DM than those in chronic periodontitis and healthy controls (175).

Macrophages are another cell type associated with immune response and are thought to contribute to periodontitis. Diabetes can increase the polarization of the M1 proinflammatory phenotype of macrophages, thus increasing the susceptibility and severity of periodontal disease, and the number of M2 anti-inflammatory phenotype macrophages is correspondingly reduced (6). Classic pathways activate M1 proinflammatory macrophages, which are involved in the production of inflammation, while M2 anti-inflammatory macrophages are involved in the downregulation of inflammation (176). The systemic metabolic changes caused by diabetes-induced hyperglycemia and insulin resistance can change the polarization and function of macrophages, enhance myelopoiesis, and lead to increased release of monocytes, which are the predecessors of macrophages (177). Li et al. (178) found that among subjects with diabetes periodontitis, macrophages stimulated by high glucose would lead to insufficient secretion of SIRT6 and induce disorder of SIRT6-miR-216/217 axis, accompanied by neutrophil apoptosis, impeded efferocytosis, and increased neutrophil extracellular traps, thus aggravating the inflammatory response of periodontitis. Neutrophils obliterate periodontal microorganisms by performing phagocytosis or releasing NETs, later starting apoptosis and immediate efferocytosis by triggering macrophages to prevent greater damage to periodontal tissue. However, chronic disunion in patients with diabetes usually leads to long-term inflammation and the persistence of neutrophils and macrophages, which will aggravate the periodontal inflammation (173–178).

Although neutrophils and macrophages play an important role in host immune response, it is reported that other myeloid cells, such as T cells, are also important in periodontitis with diabetes mellitus. The inflammatory environment by maintenance of innate immune cells, including neutrophils and macrophages, as well as related inflammatory mediators, can be affected by adaptive immunity (163). It is conducive to the differentiation of initial CD4+ T cells in Th17 inflammatory cells in diabetes patients, thus affecting the balance of the Th17/Treg axis and increasing the proportion of Th17 cells (160). Since IL-17 cannot only change the pathogenicity of periodontal microbiota but also lead to increased inflammation and more periodontal bone loss, the increase in the Th17/Treg ratio further aggravates the deterioration of diabetes periodontitis (71, 72).

Host response modulation therapy aims to restore the balance between proinflammatory factors and anti-inflammatory mediators, prevent the development of periodontitis, and repair periodontal tissue destruction (179, 180).

The main kind of substances used in host response modulation therapy include nonsteroidal anti-inflammatory drugs (NSAIDs) (181), anti-cytokine therapy (182), sub-antimicrobial doses of doxycycline (SDD) (183), and specialized proresolving mediators (SPM) such as resolvins (184), maresins (185), lipoxins (186), probiotics (159), and other substances such as resveratrol (187) melatonin (188), and curcumin (189). Omega-3 polyunsaturated fatty acids (ω-3 PUFA) can change the neutrophil function, reduce inflammatory reactions, and improve host antioxidant capacity (190). They are represented by docosahexaenoic acid (DHA), which is the origin of marines and protectins, and eicosapentaenoic acid (EPA), which is related to the resolvin E series (RvE) (191).

NSAIDs are not an efficient modulation therapy (192). Systematic analysis also failed to prove that SDD treatment can bring significant improvement to diabetes patients with periodontitis (193). The use of ω-3 PUFAs can prevent excessive inflammatory processes by producing specialized proresolving mediators with effects on glycemic control and lipid profile (194). Some independent studies also suggested using resveratrol, curcumin, or melatonin as potential inflammatory immunomodulators for patients with diabetes periodontitis (195–197). However, current data are insufficient to demonstrate its absolute benefits for treating disease (192).

The production of ROS and the resulting oxidative stress state play a crucial role in the pathogenesis of diabetes, which is closely related to impaired glucose utilization, insufficient insulin secretion, and insulin resistance and ultimately leads to chronic hyperglycemia (200). It has been proven that the concentration of products of oxidative stress related to lipid peroxidation products, such as malondialdehyde (MDA), protein oxidation products (nitrotyrosine and carbonyl levels), and DNA oxidation markers such as 8-hydroxy-2′-deoxyguanosine (8-OHdG), in diabetes mellitus are a significant improvement, along with reduced antioxidant enzymatic (such as CAT, SOD and GPx) and nonenzymatic antioxidants (such as vitamins C and E) activity (198, 200, 205, 206).

Overproduction of ROS can occur through mechanisms associated with several pathways, such as polyol pathways, hexosamine pathways, PKC pathways, and AGE/RAGE pathways. Overactivation of all of the above signaling pathways ultimately leads to increased intracellular oxidative stress (207–209). The excessive production of ROS induced by hyperglycemia is conducive to inducing the polarization of M1-type proinflammatory macrophages, and activated polarized M1 macrophages are recruited to the inflammatory site where neutrophil-mediated respiratory burst occurs, where more proinflammatory mediators are released, which will produce more ROS and exacerbate the severity of oxidative stress (210). The bigger the OS that can cause damage to cellular macromolecules becomes, the greater the intensity of inflammatory reactions and mitochondrial dysfunction, ultimately leading to less insulin secretion and more insulin resistance (207, 209).

Studies have shown that excessive ROS can be produced through both nonmitochondrial pathways and mitochondrial inner membrane. Mitochondrial dysfunction may lead to intracellular calcium homeostasis disorders and ultimately reduce insulin sensitivity reduction in T2DM patients (211). ROS leads to the inhibition of antioxidant enzymes and the reduction of nonenzymatic antioxidants in systemic tissues, leading to the enhancement of chronic OS and aggravating the systemic symptoms of diabetes (212). Therefore, the excessive production of ROS induced by hyperglycemia, in addition to diluting the body’s antioxidant response, can also trigger a vicious cycle including hyperglycemia, oxidative stress, metabolic damage, and reduced insulin secretion or insulin resistance.

Multitudinous experimental studies have shown there is a close relationship between periodontitis and OS (198, 213, 214). An increasing number of reports also have also shown that increased oxidative stress markers and total oxidation levels have been detected in the blood, saliva, and gingival crevicular fluid of patients with periodontitis, further confirming the link between periodontal tissue inflammation and OS (214, 215). Periodontitis can induce a sustained low-level inflammation of periodontal tissue, thereby increasing the overproduction of ROS and creating an environment with reduced antioxidant capacity. Nonsurgical periodontal treatment can reduce the level of OS markers in periodontal tissue (216).

Periodontal microbial pathogens activate the host immune response, leading to the recruitment of leukocytes, predominantly polymorphonuclear neutrophils and macrophages, from the bloodstream to the site of periodontal infection (217). The neutrophils bind to periodontal pathogenic bacteria by cell surface pattern recognition receptors such as TLR2 and TLR4, and subsequently, periodontal pathogens are eliminated through functional activity change of neutrophils such as phagocytosis and bactericidal and the formation of NETs. This process involves a powerful intracellular killing and respiratory burst of neutrophils, with excessive release of ROS, leading to subsequent microbial killing. ROS and its induced excessive activation of oxidative stress can have a destructive effect on host cells and are therefore considered a double-edged sword (217–220).

Consistent with the effect of OS on diabetes, OS in periodontal tissue can also promote the release of proinflammatory factors and activate the NF-κB signal pathway (221, 222). ROS exerts antimicrobial activities by exacerbating nucleic acid damage, protein misfolding, lipid peroxidation, and endoplasmic reticulum stress, or mitochondria stress, thereby accelerating autophagy and apoptosis of defective cells (223). Moreover, ROS can also play an indirect role in the destruction of alveolar bone caused by periodontitis and function as signaling molecules intercellularly or intracellularly in the osteoclastogenesis of periodontal ligament stem cells. Therefore, the excessive production of ROS can trigger the inflammatory mechanism and osteoclast formation, leading to periodontal inflammation and alveolar bone loss during the progression of periodontitis (224, 225).

In addition to the inflammatory reaction mediated by periodontal pathogens and the subsequent production of excessive ROS caused by neutrophils, several pieces of evidence show that hyperglycemia caused by diabetes can also lead to the accumulation of oxidative stress products in periodontal tissue. High glycemic levels induce ROS by overactivating polyol pathways, hexosamine pathways, PKC pathways, and AGE/RAGE pathways, increasing AGE formation, mitochondrial dysfunction, and a significant OS increment (226–228). The preexisting periodontal disease together with these pathologic mechanisms in diabetes, with increased OS and aggravated release of proinflammatory mediators, may be the reason why diabetes patients have more periodontal damage, and it also partly explains the current situation that diabetes patients are more susceptible to periodontitis.

As one of the main disease mechanisms, AGEs are a major link between diabetes and its complications. Research shows that in chronic periodontitis associated with diabetes, the accumulated AGEs in the periodontium increase (229). The synergistic effect of ROS and AGE/RAGE axes can lead to excessive periodontal damage related to diabetes (230). In addition, in the presence of AGEs, ROS can enhance cell autophagy by activating the ERK pathway and change the oxygen diffusion state by altering the permeability and structure of cell membrane, resulting in increased OS in periodontal tissue (231). Another study has proved that under the condition of diabetes, AGEs accumulated in periodontal tissue induce OS by inhibiting the Sirt1/Nrf2/HO-1 signal axis through RAGE and further promoting the production of IL-6 and IL-8 (232). AGEs in synergy with TNF-α can promote stronger OS in hPDLSCs in vitro and exhibit greater damage to periodontal tissue (233). AGEs can also reduce osteogenic differentiation of PDLSCs through OS (234). Another study shows that the excessive accumulation of ROS in periodontal tissue caused by diabetes will produce an extended oxidative environment, leading to the telomere damage of PDLSCs and ultimately damaging the mechanism of periodontal tissue repair and regeneration (235).

The products of OS and markers of the antioxidant system have been used to research the pathogenesis of diabetes and periodontitis and the interaction between them, but no consistent conclusion has been reached until now. Studies have shown an increase in total antioxidant capacity in periodontitis patients with T2DM (236). Along the same lines, the level of malondialdehyde in the periodontal tissue of T2DM patients was also significantly increased (237). On the contrary, another study concluded that the OS markers (8-OHdG) and periodontal clinical parameters of the patients affected by T2DM and periodontitis had a significant reduction (238). A case-control study showed that the activity of SOD decreased in patients with periodontal disease alone and increased in periodontitis patients with T2DM (239); however, the level of GPx was upregulated due to periodontitis and independent of the individual’s diabetes status (240), suggesting that diabetes increases gingival activity as an adaptive mechanism.

An effective approach to improving the defense against OS is to supplement antioxidants, including vitamins C and E and carotenoids (241), lycopene (242), α- and γ-tocopherol, β-cryptoxanthin, N-acetylcysteine (NAC) (243), polyphenolic compounds (244), such as flavonoids (245), zeaxanthin, and lutein. It has been reported that NAC alone has limited antioxidant effects, but when used together with glycine, GlyNAC can synergistically improve mitochondrial dysfunction and insulin secretion reduction, increase GPx synthesis, and reduce OS (241, 243).

Nrf2 is an inflammatory-related transcription factor that is crucial for balancing oxidative stress damage and the regulation of antioxidant responses. So the targeted treatment of the Nrf2/HO-1 axis can improve the periodontal injury caused by oxidative stress reaction and the subsequent amplified inflammatory response in diabetes patients with periodontitis (246, 247). Magnolol is derived from Magnolia officinalis and is beneficial for the improvement of diabetic complications. It has been shown to have antioxidant and anti-inflammatory properties and have a protective effect against periodontitis by activating the Nrf-2/HO-1 signaling axis (248, 249).

However, there is no sufficient evidence to prove that the use of antioxidants alone can produce perfect treatment results, but the use of antioxidants can improve the prognosis of diabetes periodontitis and help periodontal tissue elevate its response to periodontal basic treatment (250).