Periodontal Disease and Its Association with Metabolic Syndrome—A Comprehensive Review

Periodontal disease is a complex and progressive chronic inflammatory condition that leads to the loss of alveolar bone and teeth. It has been associated with various systemic diseases, including diabetes mellitus and obesity, among others. Some of these conditions are part of the metabolic syndrome cluster, a group of interconnected systemic diseases that significantly raise the risk of cardiovascular diseases, diabetes mellitus, and stroke. The metabolic syndrome cluster encompasses central obesity, dyslipidemia, insulin resistance, and hypertension. In this review, our objective is to investigate the correlation between periodontal disease and the components and outcomes of the metabolic syndrome cluster. By doing so, we aim to gain insights into the fundamental mechanisms that link each systemic condition with the metabolic syndrome. This deeper understanding of the interplay between these conditions and periodontal disease can pave the way for more effective treatments that take into account the broader impact of managing periodontal disease on the comprehensive treatment of systemic diseases, and vice versa.


Introduction
Periodontitis is a chronic inflammatory disease characterized by dysbiosis and a shift in the subgingival plaque towards Gram-negative microbiota, leading to the destruction of the tooth-supporting structures in a host-mediated manner [1,2].According to the World Health Organization (WHO), periodontitis is a significant risk factor for tooth loss.It affects approximately 40% of individuals above 30 years old in the USA and around 60% of those above 65 years old [3].Furthermore, periodontitis has been associated with various medical conditions, including diabetes mellitus [4].Additionally, life-threatening medical conditions such as cardiovascular diseases and metabolic syndrome have been linked to periodontitis [5][6][7].
The metabolic syndrome, also known as "Syndrome X", is a cluster of conditions such as central obesity, dyslipidemia, insulin resistance, and hypertension [6,8] that relate to one another, and together, they are known to increase the risk of cardiovascular diseases and type 2 diabetes mellitus (T2DM) [6].Moreover, the syndrome was found to be associated with fatty liver [9] and obstructive sleep apnea [10].The definition of the metabolic syndrome itself varies across different guidelines and associations.The definitions most commonly used are those written by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) and the International Diabetes Federation (IDF).The NCEP ATP III in 2001 released guidelines for diagnosis of the metabolic syndrome [11], and they were updated in 2005 [12,13].It defined metabolic syndrome as occurring if three out of five of the following are present: abdominal obesity, measured by waist circumference ≥102 cm (40 in) in men and ≥88 cm (35 in) in females; serum triglycerides ≥150 mg/dL (1.7 mmol/L) or drug treatment for elevated triglycerides; serum high-density lipoprotein (HDL) cholesterol <40 mg/dL (1 mmol/L) in males and <50 mg/dL (1.3 mmol/L) in females or drug treatment for low HDL cholesterol; blood pressure ≥130/85 mmHg or drug treatment for elevated blood pressure; and fasting plasma glucose (FPG) ≥100 mg/dL (5.6 mmol/L) or drug treatment for elevated blood glucose.The last update of guidelines from the International Diabetes Federation (IDF) was in 2006.The current guidelines recommend the diagnosis of an individual with metabolic syndrome if three of the following are present: increased waist circumference, normalized to different ethnic-specific waist circumference cut-points; triglycerides ≥150 mg/dL (1.7 mmol/L) or treatment for elevated triglycerides; HDL cholesterol <40 mg/dL (1.03 mmol/L) in males or <50 mg/dL (1.29 mmol/L) in females or treatment for low HDL; systolic blood pressure ≥130, diastolic blood pressure ≥85, or treatment for hypertension; and FPG ≥ 100 mg/dL (5.6 mmol/L) or previously diagnosed type 2 diabetes.In the urban population in the USA, the IDF criteria found 15-20% more individuals with metabolic syndrome compared to the NCEP ATP III criteria.Overall, in determining the absence or presence of the metabolic syndrome, the two definitions overlapped in 93% of diagnoses [14].
In recent years, metabolic syndrome has been acknowledged as a major global epidemiological concern, with a reported prevalence of 17-32% in the general population [15].The primary connection between periodontitis and other systemic diseases associated with the metabolic syndrome cluster, like diabetes [16], cardiovascular diseases [17], and obesity [18], appears to be the inflammatory burden.This review aims to explore the associations between periodontal disease and other systemic medical conditions related to metabolic syndrome, understand how treating one affects the other, and learn about the pathological mechanisms linking them.
This review provides a comprehensive, original, and thorough perspective on the relationship between periodontitis and individual components of the metabolic syndrome as well as the metabolic syndrome as a whole.

Search Strategy
Data were searched online from two databases: MEDLINE and Embase.The data were searched four times on 31 December 2021; 10 August 2022; 1 March 2023; and 28 July 2023.

Inclusion Criteria
The search was based on the following inclusion criteria: (1) publication restricted to English, (2) studies conducted on humans, and (3) studies that were published between the years 2010-2022.Furthermore, publications with no age and sex limit were included in this review.Some relevant key publications related to the different aspects of this review were manually added even though they were published before 2010.

Exclusion Criteria
This review did not include publications that met the following criteria: (1) publications that were not focused on the association between periodontal disease and systemic diseases or (2) publications that did not meet these aims of the review, and (3) publications with fewer than 30 subjects.

Extraction of Publications from the Electronic Databases
Based on the inclusion and exclusion criteria, we used a structured search strategy defined by controlled vocabulary thesaurus terms, which are listed in Appendix A. Table 1 shows the publications extracted from the two databases based on the search strategy using these terms for each systemic disease and its association with periodontal disease.

Method for the Selection of Papers Extracted from the Databases
The method for selecting the papers extracted from the databases is shown in Scheme 1.In addition, individual schemes for each of the components of the metabolic syndrome cluster are shown in Appendix B (Scheme A1-metabolic syndrome, Scheme A2-obesity, Scheme A3-insulin resistance, Scheme A4-diabetes mellitus, Scheme A5-hyperlipidemia, and Scheme A6-hypertension).
diseases or (2) publications that did not meet these aims of the review, and (3) publications with fewer than 30 subjects.

Extraction of Publications from the Electronic Databases
Based on the inclusion and exclusion criteria, we used a structured search strategy defined by controlled vocabulary thesaurus terms, which are listed in Appendix A. Table 1 shows the publications extracted from the two databases based on the search strategy using these terms for each systemic disease and its association with periodontal disease.

Method for the Selection of Papers Extracted from the Databases
The method for selecting the papers extracted from the databases is shown in Scheme 1.In addition, individual schemes for each of the components of the metabolic syndrome cluster are shown in Appendix B (Scheme A1-metabolic syndrome, Scheme A2-obesity, Scheme A3-insulin resistance, Scheme A4-diabetes mellitus, Scheme A5-hyperlipidemia, and Scheme A6-hypertension).
Scheme 1.The selection method for publications included in this review.

Method for the Selection of Papers Extracted from the Databases
The method for selecting the papers extracted from the databases is shown in Scheme 1 and Appendix B. After the first filtering of duplicates, a second selection was made by reading the titles.After the title, the abstract was read and quality assessment of the whole article were performed.In the end, the final articles were selected for writing this review.This review was conducted using the following research engines: Embase and PubMed.This review was limited to articles published between 2010 and 2022 with manually searched-for key publications, publications in English, and studies conducted on humans.Scheme 1.The selection method for publications included in this review.

Method for the Selection of Papers Extracted from the Databases
The method for selecting the papers extracted from the databases is shown in Scheme 1 and Appendix B. After the first filtering of duplicates, a second selection was made by reading the titles.After the title, the abstract was read and quality assessment of the whole article were performed.In the end, the final articles were selected for writing this review.This review was conducted using the following research engines: Embase and PubMed.This review was limited to articles published between 2010 and 2022 with manually searched-for key publications, publications in English, and studies conducted on humans.To identify the paper, the keyword and free term included the following: "insulin resistance syndrome" OR "metabolic syndrome" OR "syndrome X" OR "insulin resistance syndrome" OR "Insulin Resistance" OR "Resistance, Insulin" OR "Insulin Sensitivity" OR "Sensitivity, Insulin" OR "resistance, insulin" OR "diabetes mellitus" OR "diabetes" OR "Hyperlipidemias" OR "Hyperlipemia" OR "Hyperlipemias" OR "Hyperlipidemia" OR "Lipidemia" OR "Lipidemias" OR "Lipemia" OR "Lipemias" OR "hyperlipaemia" OR "hyperlipemia" OR "hyperlipidaemia" OR "hyperlipidaemia type ii" OR "hyperlipidaemia type iii" OR "hyperlipidaemia type v" OR "hyperlipidaemias" OR "hyperlipidemic" OR "lipaemi" OR "lipemia" OR "lipidaemia" OR "obesity" OR "Abdominal obesity" OR "Blood Pressure, High" OR "Blood Pressures, High" OR "High Blood Pressure" OR "High Blood" OR "arterial hypertension" OR "cardiovascular hypertension" OR "HTN (hypertension)" OR "hypertensive disease" OR "systemic hypertension" AND periodontitis OR "periodontal disease".

The Epidemiological Association between Metabolic Syndrome and Periodontal Disease
Publications related to the association between metabolic syndrome and periodontal disease are summarized in Table 2.

Forsythia and actinomycetemcomitans
There was an association between periodontitis and metabolic syndrome, diabetes, and cardiovascular disease.Metabolic syndrome and diabetes may alter the oral microbiome.Metabolic syndrome includes conditions such as abdominal obesity, dyslipidemia, arterial hypertension, insulin resistance, and changes in lipid metabolism [19].
Hlushchenko et al. reported that the prevalence of periodontal disease was 1.2 times higher in people with metabolic syndrome compared to healthy individuals within the age range of 25-55 years old [20].When looking at the opposite direction, Gomes-Filho et al. found that people with moderate to severe periodontal disease were twice as likely as people without periodontal disease to have metabolic syndrome [21].Pham et al. investigated the association between metabolic syndrome and the severity of periodontal disease and found that 21% of the individuals with metabolic syndrome had severe periodontitis compared to only 6.8% of the healthy individuals.The BOP, GI, PI, PD, and CAL were significantly higher in individuals with metabolic syndrome compared to healthy ones [22].Furthermore, the study revealed that the severity of the periodontal disease correlated to the number of components of the metabolic syndrome.Individuals with zero to two components of the metabolic syndrome showed better periodontal parameters than those with three components, and those with four to five components presented the worst periodontal parameters among the study groups [22].Similar results were found in a recent meta-analysis and systematic review, as the association between periodontal disease and the metabolic syndrome was found to be in a dose-response gradient; with more components of the metabolic syndrome, the association with periodontal disease was stronger [23].Moreover, a recent clinical trial showed that periodontal treatment improved periodontal parameters in metabolic syndrome patients, but no improvement was found in metabolic parameters such as HbA1c, waist circumference, CRP levels, and more [24].

Underlying Mechanisms Linking Periodontal Disease to Metabolic Syndrome Inflammatory Mechanisms
One of the underlying mechanisms linking periodontal disease to metabolic syndrome might be due to oxidative stress [25].As both diseases have an inflammatory nature, pro-inflammatory cytokines originating from the gingiva infiltrate the bloodstream and increase oxidative stress.The higher oxidative stress may facilitate insulin resistance and atherosclerotic changes, and both may lead to the development of the metabolic syndrome.The connection is bidirectional, as inflammatory cytokines resulting from the metabolic syndrome components may increase the oxidative stress in the gingiva, thus Impairing the ability of the periodontium to respond to a bacterial challenge, which may result in an increased risk for periodontal disease [25].

Microbiological Mechanisms
Another plausible mechanism linking the two diseases might be microbial-related.It is known that obesity and type 2 diabetes can alter the oral microbiome, leading to microbial dysbiosis [26].Subjects with periodontal disease who were obese differed dramatically from subjects with periodontal disease who were not obese in their oral microbiome composition.The obese patients had lower diversity in their oral microbiome, which may have increased the risk of developing periodontal disease [6].

The Epidemiological Association between Obesity and Periodontal Disease
Publications related to the association between obesity and periodontal disease are summarized in Table 3.

Overweight and obesity
Obesity is a risk factor for clinical attachment loss, and it is more pronounced in women.

Saito et al. Review MI Obesity
Obesity was negatively correlated with periodontal parameters and risk for periodontal disease.

Overweight and obesity
Obesity was correlated with an increase in perio-pathogens.
MI-missing information.
Obesity is one of the most recognized medical conditions of the 21st century.In 2022, the WHO published a European regional report about obesity.According to this report, obesity causes about 1.2 million deaths annually in the European region.Moreover, the report stated that overweight and obesity, especially in adolescents and children, worsened after the COVID-19 pandemic [27].Obesity is one of the fundamental characteristics of metabolic syndrome.It is usually measured by waist circumference or body mass index (BMI) (kilogram/meter 2 ).An overweight adult will be considered as one with a circumference of >90 in women or >100 in men or with a BMI of 25.0-29.9kg/m 2 , and an obese adult will be considered as one with a circumference of >105 in women or >110 in men or with a BMI of ≥30.0 kg/m 2 [28].
The association between obesity and periodontal disease was shown to be stronger when the BMI was higher [29].Moreover, it was claimed that weight gain and obesity might be risk factors for developing periodontitis [30,31].A recent meta-analysis showed that individuals who become overweight have an increased risk of 1.13 times for periodontal disease compared to healthy individuals, and obese individuals have a risk of 1.33 times for periodontal disease compared to healthy individuals [32].A prospective study from South America revealed that women who were obese had a higher rate of CAL and an increased risk of 1.64 times for periodontal disease [33].Moreover, individuals with higher BMI, especially above 30 kg/m 2 , showed worse periodontal parameters (CAL, BOP, PI, and PD) and a higher risk of the development of periodontitis.This was true across several years, study designs, and different races and nationalities [34].BMI was also correlated with other components of the metabolic syndrome.As such, Fento glu and his group published that BMI was correlated with hyperlipidemic parameters and negatively correlated with PI, PD, BOP, and CAL [35].Several studies suggested an association between periodontal disease and obesity, while the most prominent association was between young-and middle-aged females with high BMI and weight circumference to periodontal disease [36,37].Another meta-analysis showed similar results, indicating that women with high BMI and high waist circumference had a higher association with periodontal disease, especially between the ages of 18 and 34.Moreover, the meta-analysis found that European individuals had a higher chance of developing periodontal disease [38].

Mechanisms Inflammation
The associated mechanism between the two might be due to the role of pro-inflammatory cytokines.Pro-inflammatory cytokine production of IL-1β, TNF-α, and IL-6 was elevated by adipocytes and macrophages in the fat tissues of obese people [39].These cytokines produce C-reactive protein, which in turn causes an acute inflammatory state [39].TNF-α gained particular attention since this cytokine is known to play a fundamental role in periodontal disease, as it activates osteoclasts that facilitate bone resorption and periodontitis [18].

Oxidative Stress
Another plausible mechanism proposed that could link the two diseases is the fact that obesity elevates the production of ROS.Elevated ROS will result in the chronic activation of inflammatory mediators in the gingiva, such as the cytokines stated above.Gingival chronic inflammation will lead to alveolar bone destruction, deeper pockets, and higher CAL [18].Interestingly, being obese does not interfere with the outcome of nonsurgical periodontal treatment [40][41][42].

Biochemical Pathways
Some studies found that obesity might interfere with the differentiation of osteoblasts.Adipocytes and osteoblasts share the same embryogenic origin: the pluripotent bone marrow stem cells (BMSC) [43].It was reported that the Wnt/β-catenin signaling pathway could drive BMSC toward osteoblasts, but this pathway is inhibited in obesity.Secreted frizzled-related protein 1, an inhibitor of Wnt/β-catenin signaling, has been reported to be increased in mild obesity but falls in morbid obesity, resulting in increased marrow adipose [44].

Microbiology
Another approach to the connection between the two diseases may be bacterial.Obesity is known to alter the composition of the oral microbiota.One study found higher numbers of the periodontal pathogen Tannerella forsythia (T.forsythia) in the subgingival biofilms of overweight and obese individuals than in those from individuals of normal weight [45].Moreover, it was found that obese people had elevated proportions of T. forsythia, Fusobacterium spp., and P. gingivalis in their saliva, regardless of whether they had a periodontal disease or a healthy periodontium [46,47].Another study showed that people with chronic periodontitis had higher levels of perio-pathogens such as A. actinomycetemcomitans, Prevotella intermedia (P.intermedia), T. forsythia, and Fusobacterium spp.[46].

The Epidemiological Association between Insulin Resistance and Periodontal Disease
Publications related to the association between insulin resistance and periodontal disease are summarized in Table 4.  Insulin resistance is a metabolic condition that is considered a prediabetic one.The condition is defined as a reduction in insulin, targeting the responsiveness of the tissues to physiological insulin levels and insulin resistance development, which leads to higher levels of glucose in the blood [48].Fasting plasma glucose (FPG) ≥100 mg/dL (5.6 mmol/L), diagnosis of diabetes mellitus, or drug treatment for elevated blood glucose comprise one of the defining criteria of the metabolic syndrome [11].Insulin resistance has been linked before to other components of metabolic syndrome, such as central obesity and dyslipidemia [49].Insulin resistance has been associated with periodontal disease.Individuals with a previous diagnosis of insulin resistance showed a significantly higher level of moderate to severe periodontal disease compared to healthy individuals [50].Conversely, in individuals with a previous diagnosis of insulin resistance, the severity of periodontal disease was higher.The study measured insulin resistance measured by the homeostasis model assessment of insulin resistance (HOMA-IR) and showed that for every 1 mm of periodontal probing depth, the HOMA-IR score was elevated by 1.04 [51].

Mechanisms Inflammation
An underlying mechanism associated with the connection between periodontal disease and insulin resistance might be an inflammatory one [51].Insulin resistance is considered a low-level chronic inflammatory condition.It is known that in insulin resistance, there is an increase in pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α [40,52].Another inflammatory mediator that might be associated with the disease is reactive oxygen species (ROS) [53].

Microbiology
Besides an inflammatory approach, a bacterial one might link periodontal disease and insulin resistance.An in vitro study found that Porphyromonas gingivalis (P.gingivalis) stimulates insulin secretion in pancreatic cell lines [54].
The connection between insulin resistance and periodontal disease is thought to be a bidirectional one.Periodontal disease is a chronic inflammatory disease, so proinflammatory cytokines secreted in the gingiva enter the circulation and may worsen the existing insulin resistance and even cause it to develop into diabetes mellitus [48].
It is important to note that there is a substantial lack of quality studies on the connection between insulin resistance and periodontal disease.This might be because diabetes mellitus, which is the result of insulin resistance and one of the most linked systemic conditions to periodontal disease, gained most of the attention.Another explanation might be that it is hard to detect subjects in the prediabetic stage, and most of the population receives treatment after being diagnosed with diabetes mellitus.

The Epidemiological Association between Diabetes Mellitus and Periodontal Disease
Publications related to the association between diabetes mellitus and periodontal disease are summarized in Table 5.The association between periodontitis and T1DM is less solid than between periodontitis and T2DM.

Novotna et al. Review
Epidemiological, in vivo, and in vitro publication

T1DM in adolescence and childhood
Younger individuals with T1DM tend to have higher amounts of dental plaque and an increased incidence of chronic gingivitis.
DM is a major predisposing factor for periodontal disease.Demmer et al. reported that people with DM are about three times more likely to have periodontal disease compared to people who do not have it [57].
Type 1 diabetes mellitus (T1DM) and periodontitis: While T2DM is the most common, nonetheless, a correlation has been ascertained between periodontitis and type 1 diabetes mellitus (T1DM), which is less frequently encountered.T1DM is often characterized in young, healthy people.Individuals with T1DM tend to have more dental plaque and a higher incidence of chronic gingivitis, which may develop into periodontitis at younger ages [58].Adolescents with T1DM were found to have a prevalence of periodontal disease that is about five times higher and a rapid, more pronounced periodontal breakdown [59].Children had a higher incidence of gingivitis when they had T1DM [60,61], and children with T1DM had four times the prevalence of periodontal disease compared to healthy individuals [61,62].Severe periodontal disease was more frequent in the poor metabolic control group than in the good metabolic control group and the controls (26.0% vs. 20.0%vs. 5.0%) [62].The CAL was higher in adult diabetic individuals than in healthy ones by almost twofold (4.3 mm vs. 2.3 mm, respectively) [63].Moreover, the CAL was greater in poor glycemic control individuals compared to those with good to fair glycemic control [61].A recent review could not determine with high certainty whether periodontal therapy helps the glycemic control in T1DM patients.A total of 9 out of 10 eligible studies showed no effect of periodontal therapy on the glycemic control, while 1 did show an improvement.The authors of the review highlighted the need for high-quality, long-term studies in this field [64].
Type 2 diabetes mellitus (T2DM) and periodontitis: The connection between T2DM and periodontal disease has been well established before.Several studies showed that individuals with T2DM have a higher risk of developing periodontal disease (two-to threefold) compared to healthy individuals [57,[65][66][67].Moreover, previous works showed that individuals with T2DM show a more significant periodontal loss, higher CAL, and deeper periodontal pockets [55,68,69].DM is known to affect the body in several ways.

Mechanisms Oxidative Stress
First, DM leads to a constant hyperglycemic state.Hyperglycemia is known to worsen oxidative stress through several metabolic pathways, such as the polyol pathway [70], the hexosamine pathway [71], and the activation of protein kinase C (PKC) [72].Second, pro-inflammatory cytokines, created mainly in adipose tissue, increase insulin resistance and are a significant cause of diabetes complications.
Moreover, the insulin resistance caused by DM is also known to elevate ROS levels, increase the number of pro-inflammatory cytokines, and reduce adiponectin.All of these changes increase the systemic inflammatory burden [48].

Inflammation
Another plausible mechanism linking the two diseases might be related to proinflammatory cytokines.Some pro-inflammatory cytokines have gained special attention, such as TNF-α, IL-1β, IL-6, and IL-18 [71].These cytokines are known to cause an elevated full-body inflammation state, which may result in bone loss and periodontal breakdown [48,71].One of the key factors in treating DM is glycemic control.Previous studies showed that individuals with higher glycated hemoglobin (also known as hemoglobin A1C (HbA1c)) had an increased risk of periodontal disease [73][74][75].The mechanism associated with the two diseases is probably a multifactorial one.The inflammation burden that both diseases cause has a bidirectional relationship that worsens each disease.
The inflammatory cytokines activate metalloproteinase (MMPs) [76].Activated MMPs with ROS will result in collagen degradation and periodontal attachment loss [55].Moreover, diabetes is also known to increase the RANKL/OPG ratio and promote osteoclastogenesis and activation, which in turn will lead to alveolar bone loss, deeper pockets, and periodontal disease [55].Interestingly, in other dental procedures such as extraction, similar results were found.Three months after the extraction, salivary inflammatory markers such as OPG, the OPG/RANKL ratio, and total antioxidant capacity increased in both controls and diabetic patients, while IL-18, MMP-9, and RANKL decreased in both study groups, HGF was elevated only for the control group, and TNF-α showed a marked reduction in the diabetic group.Different statistical models showed that HbA1C was correlated with these inflammatory cytokines, especially OPG and RANKL [77].
The bidirectional relationship became clear when studies found that nonsurgical periodontal treatment benefits DM patients.Periodontal treatment reduced 3-4 mmol/mol (0.3-0.4%) of glycated hemoglobin after 3-4 months, but the supporting evidence that surgical root planning (SRP) may help with the glycemic control in T2DM is of low quality [78,79].Conversely, a systematic review from 2022 showed that after 3-4 months, there was a reduction of 0.43% (4.7 mmol/mol); after 6 months, a reduction of 0.30% (3.3 mmol/mol); and after 12 months, a reduction of 0.50% (5.4 mmol/mol) of HbA1C in diabetic patients who were diagnosed with diabetes mellitus and who went through subgingival instrumentation.Due to the new findings, the authors changed their opinion about the primary outcome of periodontal therapy and glycemic control and have now increased their level of certainty about the association [80].It is also known that periodontal treatment might help with glycemic control in patients who are prediabetic or already diabetic [81].Conversely, increased levels of pro-inflammatory cytokines caused by insulin resistance may reach the gingiva via systemic circulation, worsening preexisting periodontal disease [82].Another study suggests that patients who are both diabetic and smokers who went through a complete periodontal treatment improved periodontal parameters as well as metabolic parameters such as HbA1C and fasting plasma glucose while improving inflammatory markers such as CRP.This study was conducted over a short time period (up to 6 months) [83].

Microbiology
Another factor that might link the diseases is a microbial one.It has been established by now that patients with DM have a reduction in the oral biological and phylogenetic diversity of the microbiome compared to normal subjects [84,85].Moreover, similar changes were found within the subgingival microbiome.Subjects with DM had lower species diversity but higher numbers of periodontal pathogens than healthy individuals [84,86,87].This means that while the periodontium may appear healthy, patients with DM have a higher predisposition to develop periodontal disease [86,87].Another study, which compared healthy controls both to periodontal disease patients and to diabetic patients with periodontal disease, showed that patients with periodontal disease had higher numbers of perio-pathogens (mostly pathogenic from the red group), but patients with diabetes and periodontal disease had higher numbers of periodontal pathogens which connected with other pathogens (orange group).Although no major diversity was found within the phyla of the pathogens, the authors suggested that the connection between the periodontal pathogens is the cause for the rapid progression of periodontal disease in diabetic patients [88].

The Epidemiological Association between Hyperlipidemia and Periodontal Disease
Publications related to the association between hyperlipidemia and periodontal disease are summarized in Table 6.

Metabolic syndrome components
An association was found between metabolic syndrome and periodontal disease.Women with periodontitis had higher triglycerides in their blood and lower HDL.Hyperlipidemia is defined as changes in the lipid accumulation in the blood, which mainly refers to elevated levels of triglycerides (TG), high levels of low-density lipoprotein (LDL) cholesterol, and low levels of high-density lipoprotein (HDL) cholesterol [25].Arreguin-Cano et al. found that subjects with periodontal disease had higher TG levels in their blood, lower HDL, and worse metabolic parameters [89].Conversely, patients with hyperlipidemia showed worse periodontal parameters including BOP, CAL, and PD [90].Another study showed that a previous diagnosis of hyperlipidemia negatively impacted individuals' periodontal parameters in term of BOP, CAL, PD, and periodontal index (PI).Also, the study showed that plasma HDL levels were negatively correlated with CAL, but total cholesterol, LDL, and plasma triglycerides were significantly associated with BOP, CAL, PD, and PI [35].

Mechanisms Microbiology
The mechanism linking hyperlipidemia and periodontal disease might be bacterial.Low HDL cholesterol was found to be associated with higher levels of serum antibodies against P. gingivalis, which is known to be a marked pathogen associated with periodontitis [91].Moreover, higher LDL cholesterol levels were associated with higher serum antibodies against Aggregatibacter actinomycetemcomitans (A.actinomycetemcomitans), and P. gingivalis [92].

Inflammation
Another plausible explanation for the link between the diseases is an inflammatory one.In an in vivo study, mice with metabolic syndrome induced by a high-fat diet showed markedly elevated osteoclastogenesis and alveolar bone loss [93].Furthermore, there was a marked elevation in the expression of inflammatory cytokines (IL-6, monocyte chemoattractant protein1, Receptor activator of nuclear factor kappa-B ligand (RANKL), and macrophage colony-stimulating factor), which led to further osteoclastogenesis and alveolar bone loss [93].The mechanism hypothesized was that systemic inflammation caused an increased biosynthesis of cholesterol, which is secondary to bacteremia, and systemic lipopolysaccharide (LPS) caused by periodontal disease.Moreover, periodontal therapy combined with antihyperlipidemic therapy showed promising results in lowering serum pro-inflammatory cytokines [94].

The Epidemiological Association between Hypertension and Periodontal Disease
Publications related to the association between hypertension and periodontal disease are summarized in Table 7.  Hypertension is the most common cardiovascular disease (CVD) and is defined by a systolic blood pressure higher than 140 mmHg or a diastolic blood pressure higher than 90 mmHg [95].The WHO reported in 2014 that hypertension is responsible for 51% of deaths from stroke and 45% of overall CVD mortality in all ages and ethnic groups [96].Hypertension has a long-term effect on the heart.As of 2015, the Global Burden of Disease Committee marked it as one of the causes of hypertensive heart failure and, ultimately, heart failure [97].Hypertension is considered fundamental in establishing metabolic syndrome.One study showed that the prevalence of hypertension was correlated to periodontal disease severity [98].Another cohort study showed that hypertension was positively associated with periodontal disease.Moreover, it showed that individuals in a hypertensive state were more susceptible to developing periodontal disease compared to prehypertension individuals and individuals with normal blood pressure [99].A recent meta-analysis found that individuals with periodontal disease have a higher prevalence of hypertension [100].Another cross-sectional study showed that the odds for arterial hypertension were higher in individuals with periodontal disease.Moreover, it showed that the odds became higher as the severity of the periodontal disease worsened [101].

Mechanisms Inflammation
The association between periodontal disease and hypertension is believed to be related to the inflammatory nature of the two diseases [5].Oral pathogens may invade the bloodstream through the periodontal pockets and release toxins, resulting in endothelial inflammation.Endothelial inflammation is known to be the first stage in many CVDs and atherosclerosis, specifically, which may later develop into hypertension [102].Bacteria infiltrating through the periodontal pockets and their endotoxins can draw inflammatory cells to the arterial endothelium and vascular smooth muscle, causing the initiation of the coagulation process [102].

Microbiology
Perio-pathogens are known to cause chronic endothelial inflammation, leading to vasospasm and potential thromboses [102].This process may be enhanced by the inflammatory cytokines coming from the periodontium with constant low-grade inflammation [102].The cytokines cause the endothelium to produce vasoconstrictors, promoting the aggregation and adhesion of leukocytes, possibly leading to thromboses [102].A recent study showed that hypertensive patients had higher levels of perio-pathogens (especially P. intermedia, P. gingivalis, and F. nucleatum) compared to normotensive patients [103].
Only a few studies have focused on periodontal treatment and its effects on blood pressure and hypertension [104][105][106].However, studies did show that following periodontal treatment, there was a reduction of 12.5 mmHg in systolic blood pressure and 10 mmHg in diastolic blood pressure [104].Moreover, six months after periodontal treatment, a reduction in CRP and IL-6 levels was observed, as well as a reduction in the left ventricular mass of 12.9 g [104].Another systematic review from the Cochrane database found that patients diagnosed with periodontal disease and CVDs (not including hypertension) experienced no beneficial effect on blood pressure after periodontal treatment [106].Moreover, the systematic review did not find added value of intensive periodontal treatment compared to supragingival scaling only [106].Lastly, the periodontal treatment showed promising results in patients diagnosed with periodontitis and hypertension.Periodontal treatment caused a reduction in the short term of 11.20 mmHg in systolic blood pressure and 8.40 mmHg in diastolic blood pressure in hypertensive patients with periodontal disease [106].It should be noted that the beneficial effect of periodontal therapy had only a short-term effect, while in the long term, no effect on blood pressure was found [106].These studies suggest an association between periodontal disease and hypertension, suggesting the consideration of periodontal treatment as part of hypertensive therapy in patients with periodontal disease [107].

Discussion
Periodontal disease affects most of the adult population worldwide [3,98].It is considered a multifactorial disease and is associated with other systemic diseases.Most of the strong association between periodontitis and other systemic diseases is connected to the cluster known as metabolic syndrome.This cluster includes obesity, hyperlipidemia, insulin resistance, and hypertension [6].It is important to mention that the etiology of both diseases is considered multifactorial, and several association mechanisms have been proposed between the two.The mechanism linking metabolic syndrome and periodontal disease is thought to be related to the fact that both diseases are caused by inflammatory reactions, inflammatory cytokines, and elevated systemic oxidative stress [25].As depicted in this review, in insulin resistance, there is an increase in pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α [40,52] and ROS [53].Furthermore, in T2DM there is an increase in TNF-α, IL-1β, IL-6, and IL-18 [71], which are known to elevate HbA1C, which increases the risk for periodontal disease [73][74][75].Moreover, the inflammatory state is known to activate MMP, which, together with ROS, will result in periodontal breakdown [76].Also, T2DM is known to alter the RANKL/OPG ratio, which may lead to the loss of alveolar bone [55].An in vivo study showed that a high-fat diet will result in osteoclastogenesis, elevated levels of RANKL, and alveolar bone loss [93].Moreover, in the study, pro-inflammatory cytokines such as IL6, MCSF, and MCP-1 will further lead to alveolar bone loss [93].In obese individuals, elevated levels of IL-1β, TNF-α, and IL-6 were found [39].These cytokines will produce C-reactive protein, which in turn will cause an acute inflammatory state [39].Moreover, in obese individuals, higher ROS will lead to a higher inflammatory state and periodontal breakdown [18].
Other suggestions for the associated mechanism between the two include a bacterial one.An in vitro study found that Porphyromonas gingivalis (P.gingivalis) stimulates insulin secretion in pancreatic cell lines [54].Moreover, a reduction in biological and phylogenetic diversity of the oral microbiome with higher perio-pathogens was found in T2DM patients [84][85][86][87].In individuals with low HDL cholesterol, there were higher levels of serum antibodies against P. gingivalis compared to healthy individuals [91].Moreover, higher LDL cholesterol levels were associated with higher serum antibodies against Aggregatibacter actinomycetemcomitans (A.actinomycetemcomitans) and P. gingivalis [92].Similarly, one study found higher numbers of Tannerella forsythia (T.forsythia) in the subgingival biofilms of overweight and obese individuals than in those from individuals of normal weight [45].Higher levels of perio-pathogens were found in obese people [46,47].Also, perio-pathogens are known to cause chronic endothelial inflammation, leading to vasospasm and potential thromboses [102].This process may be enhanced by the inflammatory cytokines coming from the periodontium, leading the endothelium to produce vasoconstrictors, promoting the aggregation and adhesion of leukocytes, and possibly leading to thromboses [102].Taken together, the suggested mechanism accounting for the association between periodontal disease and each of the components of the metabolic syndrome cluster was similar: an increased inflammatory burden through inflammatory cytokines (mostly IL-1β, IL-6, and TNF-α) which results in systemic elevated oxidative stress and the invasion of Gramnegative bacteria, which further increase the inflammatory burden and the activation of bone-resorbing agents.The bacterial and inflammatory burden from the periodontal tissue worsens the initial phase of the components of the metabolic syndrome cluster, exacerbating each component and the cluster itself [6,20,21,[24][25][26][27][28]46,51,[60][61][62][63].
This review aims to give a broader view of the association between periodontal disease and the components of metabolic syndrome.Here, we reviewed the association between periodontal disease and each of the metabolic syndrome cluster components and the metabolic syndrome itself.We suggest seeing the association in a broader view, as each component affects the others and increases the risk for periodontal disease.Based on this review, we also suggest that part of the treatment for the metabolic syndrome or any of its components should include a periodontal examination, as the relationship is bidirectional.Moreover, the periodontal treatment in patients with a previous diagnosis of any of the components of the metabolic syndrome should consider looking for other systemic diseases, especially other components of the metabolic syndrome, and therefore consider the treatment possibilities while considering the possible association with the metabolic syndrome.

Conclusions
Metabolic syndrome is positively associated with periodontal disease.The associated mechanisms between periodontal disease and metabolic syndrome components were increased pro-inflammatory mediators (including different cytokines, ROS, and elevated CRP) and constant penetration of periodontal pathogenic bacteria into the bloodstream.
Periodontal status should be checked as part of the metabolic syndrome treatment, as it significantly impacts the initiation and progression of the metabolic syndrome and its components.
Future research directions should address the gap in the literature and focus on conducting multicenter longitudinal studies in different ethnic populations to study the association of periodontal disease and its treatment with each of the metabolic syndrome components and the metabolic syndrome as a whole.assessment of the whole article was performed.In the end, the final articles were selected for writing this review.Scheme A4.The selection method for publications assessing the association between periodontal disease and Diabetes mellitus.Scheme A5.The selection method for publication assessing the association between periodontal disease and hyperlipidemia.Scheme A4.The selection method for publications assessing the association between periodontal disease and Diabetes mellitus.Scheme A4.The selection method for publications assessing the association between periodontal disease and Diabetes mellitus.Scheme A5.The selection method for publication assessing the association between periodontal disease and hyperlipidemia.Scheme A5.The selection method for publication assessing the association between periodontal disease and hyperlipidemia.Scheme A4.The selection method for publications assessing the association between periodontal disease and Diabetes mellitus.Scheme A5.The selection method for publication assessing the association between periodontal disease and hyperlipidemia.Scheme A6.The selection method for publication assessing the association between periodontal disease and hypertension.

Figure A2.
The mechanism of microbiology includes systemic inflammation caused by metabolic syndrome components which in turn may lead to gingival inflammation.The gingival inflammation causes the gingiva to become more permeable, which may later end in periodontal disease.In periodontal disease, there is an increase in perio-pathogens which may invade systemically through the bloodstream, which may initiate or worsen already established components of the metabolic syndrome.The components are known to increase the inflammatory state of the body by releasing pro-inflammatory mediators which in turn may cause gingival inflammation.

Table 1 .
Publications extracted from electronic databases using the search strategy and thesaurus terms.

Table 1 .
Publications extracted from electronic databases using the search strategy and thesaurus terms.

Table 2 .
Summary of included articles exploring the association between metabolic syndrome and periodontal disease.

Table 3 .
Summary of included articles exploring the association between obesity and periodontal disease.

Table 4 .
Summary of included articles exploring the association between insulin resistance and periodontal disease.

Table 5 .
Summary of included articles exploring the association between diabetes mellitus and periodontal disease.

Table 6 .
Summary of included articles exploring the association between hyperlipidemia and periodontal disease.

Table 7 .
Summary of included articles exploring the association between hypertension and periodontal disease.
MI-missing information.