Adipocytokine levels in Chronic Periodontitis and Type 2 Diabetes Mellitus after Nonsurgical Periodontal Therapy

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Adipocytokine levels in Chronic Periodontitis and Type 2 Diabetes Mellitus after Nonsurgical Periodontal Therapy

https://doi.org/10.21203/rs.3.rs-5149444/v1

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Objective: A thorough meta-analysis was used to assess the levels of 4 adipocytokines in the gingival crevicular fluid(GCF) of individuals with chronic periodontitis (CP) linked to Type 2 Diabetes Mellitus (T2DM) before and after non-surgical periodontal therapy (NSPT).

Sources: PubMed, Scopus, and EBSCOhost databases were exhaustively searched.

Study selection: The three databases and Gray literature were searched for studies that fit the inclusion and exclusion criteria. The Joanna Briggs Criteria were used to assess the study's level of quality. The meta-analysis was performed for the GCF levels of adipocytokines and clinical parameters clinical attachment level(CAL), gingival index(GI), periodontal Index(PI), periodontal probing depth(PPD) to further analyze the effect of the NSPT on the same. After thoroughly reviewing the full texts, abstracts, and removal of duplicates, seventeen papers were identified and included for systematic analysis. Upon further critical evaluation, only seven publications qualified for the meta-analysis. The levels in the test and control groups were analyzed using meta-analysis since the results were in mean + standard deviation.

Conclusion: The results indicate that nonsurgical periodontal therapy significantly reduces the levels of adipocytokines in GCF of patients with CP and T2DM. Further, there is a significant improvement in the clinical parameters of periodontal disease after NSPT.

Biological sciences/Chemical biology

Biological sciences/Molecular biology

Health sciences/Biomarkers

Resistin

leptin

chemerin

visfatin

chronic periodontitis

Type 2 Diabetes Mellitus

gingival crevicular fluid.

The reduction of adipocytokine levels and improvement of clinical parameters of chronic periodontitis after nonsurgical periodontal therapy could pave the way for a quantitative method to diagnose the progress of the disease after treatment. The improvement in glycemic levels after NSPT is a significant finding in this review.

The two of the most prevalent ailments in the world, diabetes mellitus (DM) and chronic periodontitis (CP), are bi-directionally correlated[1].The term DM refers to a group of metabolic disorders brought on by improper control of glucose metabolism[2]. It is connected to macrovascular disorders, delayed wound healing, periodontitis, and myopathies[3].

One of the numerous pathologic characteristics shared by DM and CP is determined to be especially important; it exhibits increased immune-inflammatory responses in terms of inflammatory mediators. [4].

It is reasonable to assume that DM enhances the host's susceptibility to periodontitis because it modifies the microbiota, disrupts neutrophil function, and hinders wound healing. On the other hand, the found reciprocal relationship suggests that periodontal therapy may reduce blood sugar.[5].

To determine the type of periodontal disease, physicians around the world are still depending on traditional diagnostic techniques in the current diagnostic era. However, these are unreliable and have a propensity for operator bias. Thus, there is a paradigm change in favor of molecular biomarkers as a means of precisely predicting the kind and course of disease. Disease-specific biomarkers are urgently needed to distinguish between the oral debilitating disease and the systemic disease when a systemic disorder like diabetes mellitus is involved. Therefore, we only included studies in our systematic review and meta-analysis where the test group included patients with Type 2 DM and CP. Specifically linked to DM and CP, a set of adipocytokines is being studied as one of these markers. Adipocytokines, as the name suggests, are cytokines of the adipose tissue. Dyslipidemia is one of the most common causes of DM[6,7]. It is only fair to say that periodontitis thrives in the presence of DM. The adipose tissue once considered a fat storage area, is now known to be an endocrine organ that generates many adipokines responsible for controlling lipid metabolism and inflammation[8].

The role of four adipocytokines are being investigated because of their connection to DM in CP patients has been examined in the current meta-analysis.

Resistin is a recently discovered adipocytokine that is responsible for insulin resistance. It was always thought that resistin could only be produced by adipocytes, but recent studies have shown that other immune system cells may also create large amounts of resistin. This suggests that resistin has a role in a variety of chronic inflammatory illnesses and acts as a pro-inflammatory cytokine. The influence of diabetes mellitus on a person's glycaemic condition is known to be highlighted by elevated levels of resistin.[1].

Chemerin is a new chemoattractant adipokine that was formerly known as tazarotene-induced gene 2 protein (TIG2) and is now widely recognized as retinoic acid receptor responder (RARRES2). It is secreted as an 18 kDa inactive prochemerin and activated by post-translational C-terminal cleavage. Via coagulation cascade processes, neutrophil-derived proteases (elastase and cathepsin G), and mast cell synthesis (triptase), the final six amino acids of prochemerin quickly transform into chemerin. The association between chemerin, diabetes, and obesity has been extensively studied as it is known to affect the metabolism of fats, carbohydrates, and inflammatory levels. Obesity and T2DM patients displayed higher fluctuating chemerin levels. More importantly, chemerin has been linked to enduring micro and macrovascular alterations. Although evidence suggests that chemerin has an impact on glucose homeostasis, its precise role remains uncertain. Research suggests that human chemerin may be used as a measure of inflammation in GCF of patients with CP and DM[9].

Lymphocyte 7q31 DNA has the obesity gene (ob), which codes for the cytokine-like hormone leptin. It is a non-glycosylated peptide of a 16 kDa protein that circulates in the bloodstream. It causes the proliferation and activation of circulating monocytes, which in turn causes the production of pro-inflammatory cytokines by the monocytes, such as interleukin (IL)-1, TNF-α, or IL-6. The insulin receptor substrate and phosphoinositide 3 kinase-PI3K pathway are activated in diabetes conditions by leptin and insulin. This system is in charge of metabolic regulation and malfunction, which results in inadequate glucose homeostasis. Furthermore, leptin synthesis can be increased by the pro-inflammatory cytokines generated during inflammation, such as periodontitis [10].

Visfatin is named after the word "VISceral FAT." It can be expressed in isolated subcutaneous adipose tissue as well, while being primarily generated in visceral adipose tissue. It is also present in lymphocytes, bone marrow, liver, and skeletal muscle. There have been reports of elevated visfatin plasma levels in a T2DM patients on hypoglycemic therapy. Recent studies have found that, in comparison to healthy people, those with periodontal disease had higher levels of visfatin. It has been linked to functions like boosting neutrophil apoptosis, and on its own, it can be amplified by the release of several pro-inflammatory cytokines like IL-6 and TNF-α[11].

Most investigators initially classified GCF as an inflammatory exudate. GCF from clinically normal tissue, on the other hand, appears to be a modified serum transudate that only becomes an inflammatory exudate when a disease is present. It is also evident from comparing healthy sites from periodontally healthy individuals to healthy sites from diseased individuals that the GCF composition differs in terms of microbial composition and the concentration and makeup of molecular indicators. Moreover, the GCF's composition changes with the progression of the disease, and certain mediators may be able to predict future patient- or site-specific disease outcomes. Taken together the findings suggest that the composition of GCF can potentially be used to detect subclinical alterations in tissue metabolism, inflammatory cell, recruitment, and connective tissue remodelling[12].

There is no research undertaken to date to establish the consequence of NSPT on levels of 4 adipocytokines in the GCF. Therefore, this study aims to decipher the influence of non-surgical periodontal therapy on these adipocytokines which play orchestrated roles in reducing the inflammatory process and aid in maintaining periodontal health. Further, an attempt was made to analyze the influence of NSPT on clinical parameters of periodontal disease.

Study design

This systematic review and meta-analysis were carried out to analyze the GCF levels of novel adipocytokine in Type 2 DM patients with CP after NSPT. It was developed according to the PRISMA guidelines[13]. After registering the protocol in PROSPERO (CRD42023450510) the study thoroughly evaluated full-text articles published from 1980 to 2023. The study was carried out between August 2023 and April 2024.

Research Question

Thus the question framed for the literature search was: Does Non-Surgical periodontal therapy lower the GCF levels of adipocytokine in Type2 DM patients with CP?

The PICO for the eligibility criteria was:

(P): Human non obese patients diagnosed with CP and controlled Type 2 DM.

(I): Estimation of GCF levels for resistin, visfatin, chemerin, and Leptin using a commercially available ELISA kit.

(C): Healthy individuals with no systemic disorders and presence of no carious teeth.

(O): Adipocytokine levels are raised in patients with chronic periodontitis and Type 2 DM and decrease after NSPT.

Inclusion criteria:

(a) Clinical human randomized clinical trials evaluating resistin, chemerin, leptin and visfatin levels in human GCF

(b) Clinical studies where the test subjects were diagnosed with CP and Type 2 DM.

(c) Studies that used a commercially available ELISA kit to analyze the levels of resistin, leptin, visfatin, and Chemerin.

The publications with their titles and abstracts discovered during the electronic and manual searches were reviewed by three investigators (A.K.D. and A.P. and M.M) The articles that did not meet the criteria for inclusion were filtered out. All of the remaining articles were retrieved and thoroughly screened by two of the above‐mentioned reviewers to achieve a consensus. A fourth researcher (A.G.) verified the studies included and checked the cross-references were also included. In case of any doubt, the same was clarified by the fifth reviewer (D.A.)

Exclusion criteria:

(a) Animal studies.

(b) Studies not using gingival crevicular fluid as the test sample

(d) Narrative reviews.

(e) Studies that did a qualitative analysis

(f) Studies where patients with Type 2 DM and associated CP were not recruited.

Information Sources and Search Strategy

A broad-based search was implemented with individual keywords: “Resistin”, “gingival crevicular fluid” “chronic periodontitis” and “Type 2 Diabetes Mellitus”. The precise and prescribed combination of accepted Medical Subject heading keywords with the Boolean operators ‘AND’ and ‘OR’ was carried out to obtain the search strategy finalized as ("retn protein human"[Supplementary Concept] OR "retn protein human"[All Fields] OR "resistin"[All Fields] OR "resistin"[Supplementary Concept] OR "resistin"[MeSH Terms]) AND ("chronic periodontitis"[MeSH Terms] OR ("chronic"[All Fields] AND "periodontitis"[All Fields]) OR "chronic periodontitis"[All Fields]) AND ("gingival crevicular fluid"[MeSH Terms] OR ("gingival"[All Fields] AND "crevicular"[All Fields] AND "fluid"[All Fields]) OR "gingival crevicular fluid"[All Fields]) AND ("diabetes mellitus, type 2"[MeSH Terms] OR "type 2 diabetes mellitus"[All Fields]).

The PubMed, Scopus, and EBSCO databases were searched until April 2024, and the results are summarized in [Table 1]. A.P., A.K.D., and M.M manually searched the qualifying studies' references for any additional studies, and they also conducted an OpenGrey search for the grey literature. Whenever additional information was needed regarding the study or any other details, they got in touch with the authors of the relevant papers. A.D., a senior researcher, answered any questions or concerns, and a fourth researcher, D.A., cleared up any doubts.

Study Selection and Data Collection Process

Using the finalized search strategy defined in PubMed, the three databases were thoroughly searched, taking into consideration the inclusion and exclusion criteria. Three reviewers (A.G., A.K.D., and M.M) looked over each study two or three times. They gathered the data and input it into an Excel sheet that was powered by Microsoft 365 Office. A third senior researcher (D.A.), with more than 19 years of expertise applied the inclusion and exclusion criteria. After the data were carefully compiled, a comprehensive table [Tables 2 and 3] was created for further analysis. Any disputes were resolved by consensus.

Risk of Bias assessment

The data was collected and screened by three examiners (A.K.D., A.P., and M.M) adhering to the stringent inclusion criteria. The potential for bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist (The Joanna Briggs Institute 2014). The possibility of bias in cross-sectional and observational studies was evaluated using eleven variables. Each topic was then discussed after the senior assessor (A.G.) separately applied the risk of bias for each study. D.A., the fourth examiner, came to a final consensus and resolved any differences [Table 4]. After assessing the risk of bias with the Joanna Briggs tool all of the studies lie under low risk of bias.

Summary Measures and Synthesis of Results

Continuous data from eligible studies were only included in the meta-analysis. The continuous primary outcomes; GCF levels and periodontal probing depth (PPD) individual as well as the combined effect were assessed using the standardized mean difference (SMD) with 95% CI which is equal mean difference divided by the pooled standard deviation. SMD greater than zero is considered as raised in the values whereas less than zero is considered a decline in the values. This effect size was considered small (0.2), medium (0.5), and large (0.8). Heterogeneity was examined by inspecting the forest plot and using the statistical test Q-test and I-square. The random-effect model using the DerSimonian and Lard approach was used to perform the meta-analysis pooled effect because of high heterogeneity. All analyses were conducted using the RevMan 5.3(Review Manager v.5.3; Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration 2014).

In this systematic review, a comprehensive search across three databases (PubMed, EBSCOhost, Scopus) yielded a total of 17 studies. Following the removal of duplicates, a pool of seven studies remained for further scrutiny. These studies were then meticulously evaluated against the predefined eligibility and inclusion criteria, with the process and outcomes detailed by the updated PRISMA guidelines, as illustrated in [Fig 1].

For efficient reference management and duplicate elimination, the EndNote Basic Software (Thomson Reuters, New York, NY) was utilized. Six meta-analyses were done to get a comprehensive understanding of the relationship between GCF adipocytokine levels and CP with T2DM.

In all the six meta-analyses a random effect model was applied due to the presence of high heterogeneity.

There was a nonsignificant (p=0.59) reduction in the adipocytokine level after NSPT(Fig2) with a Standard Mean Difference(SMD) of 0.25995% CI, -0.66-1.15) and an I² value of 90% indicating an increased heterogeneity in the studies.

The experimental group (Fig 3) showed a highly significant reduction in GCF levels of adipocytokines after NSPT (p<0.00001). The heterogeneity of studies was high indicated by the I²value of 97%.In addition to this, we analyzed the periodontal clinical parameters with respect to NSPT.

The Clinical Attachment Level (CAL), Plaque Index(PI), Gingival Index(GI), and Periodontal Probing Depth(PPD) levels were significantly reduced after NSPT as evident in figures 4-7.

The analysis of CAL (Fig 4) reveals SMD of 2.58 ( 95% CI:1.22-3.95) and I² of 93% indicating a high heterogeneity of the studies included.

The analysis of PI (Fig 5) reveals SMD of -5.42 ( 95% CI:-7.5to -3.33) and I² of 90% also indicating a high heterogeneity of the studies included.

The analysis of GI (Fig 6) reveals SMD of -3.51 ( 95% CI:-5.08 to-1.94) and I² of 93%.

The analysis of PPD(Fig 7) reveals SMD of -3.20 ( 95% CI:-4.66 to-1.74) and I² of 92%.

GCF sample Collection

Except for the Hiroshima et al. study, which employed the paper strip method, all included investigations used the microcapillary method to extract the GCF.

Confirmatory tests

A commercially available ELISA kit was used in the included studies and the procedure was carried out according to the manufacturer's instructions. The ELISA test indicated that there is a significant increase in leptin, chemerin, resistin, and visfatin in the GCF of patients diagnosed with chronic periodontitis and associated type 2 diabetes mellitus. These levels showed a significant decrease after NSPT.

Study characteristics of the seven studies included in the meta-analysis

Ahuja C [10] assessed the influence of non-surgical periodontal therapy on gingival crevicular fluid leptin levels in the study groups of systemically and periodontally healthy patients and CP patients with T2DM. GCF collection was done using the microcapillary pipette. Significant reductions in the clinical parameters were observed after NSPT in all study groups. According to the study, the healthy group had the greatest GCF leptin level, whereas patients having CP with T2DM had the lowest (P < 0.0001). Improved clinical parameters and glycemic status were noted after NSPT. Further, it was observed that there was a significant reduction in the periodontal parameters after NSPT. (p<0.0001)

Dogan SB[14], analyzed the GCF chemerin levels before and after the NSPT. This study evaluated whether GCF chemerin levels could be considered as a predictive biomarker for the healthy as well as patients having CP and T2DM. Patients with T2DM diagnosed at least a year ago were classified as diabetics. NSPT was used to treat patients with CP. GCF sample protocols were carried out both before and after the start of treatment. The ELISA test was used to quantify the amounts of IL-6 and chemerin. Significant differences (P < 0.008) were seen in the GCF chemerin between the healthy control group, and the DM-CP group.
After treatment, GCF chemerin and IL-6 levels declined in the CP groups (P<0.025). The statistically higher levels of clinical parameters were observed among the DM-CP group than in the control group. (p<0.05)

Joshi A [1], in their study, measured the GCF resistin levels in healthy individuals with gingivitis and well-controlled diabetics with CP to determine the impact of non-surgical periodontal therapy. Both groups of subjects received NSPT. Pre and post non-surgical periodontal therapy GCF samples were taken. For the healthy group, the mean GCF resistin score was 1.96 ± 0.67 at baseline and 1.36 ± 0.62 after therapy, respectively. The statistical significance of the mean difference was considerable (P value < 0.001). The mean GCF resistin score for group II (Diabetic patients with CP) was 2.50 ± 0.25 at baseline and 1.93 ± 0.22 after treatment. The reduction in the post-treatment resistin levels was found to be statistically significant (P value < 0.001).

A study by Mishra V [11]aimed to assess and compare the changes in visfatin levels in the Gingival Crevicular Fluid (GCF) following the administration of NSPT in participants with CP and those with or without managed T2DM. The results showed that Group DM-CP visfatin scores drastically decreased from their pre-treatment values, but the group with healthy subjects showed no change. At the follow-up visit, healthy group scores remained unchanged as previously noted.

Gomathi GD [9] analysed the effect of chemerin on the pathophysiology of diabetes mellitus and CP, as well as the effect of NSPT on the levels of chemerin in saliva and GCF in patients with periodontitis who had T2DM. This study excluded patients with diabetes mellitus, pregnant or lactating women, those on antibiotics or anti-inflammatory drugs six months before the study, those who smoke or chew tobacco, alcoholics, patients with poorly controlled diabetes (HbA1c values < 8%), and those on insulin therapy. The group with periodontitis and T2DM had higher mean GCF chemerin levels compared to the healthy group. Six weeks after root planing, subjects with periodontitis and T2DM had lower GCF chemerin scores.

Wu Y [8] investigated the relationship between visfatin levels in serum and GCF in CP patients with T2DM before and after NSPT. Patients were randomized into two groups: treatment and control. The GCF visfatin concentration was found to be reduced after NSPT. The findings indicated that NSPT can improve glycemic management and reduce visfatin levels in T2DM patients with CP. They suggested that visfatin could be an inflammatory marker for periodontal disorders.

Rode PA [15] investigated the single-nucleotide polymorphisms (SNPs) of the resistin gene (RETN) at −420 and +299 sites are associated with resistin levels in serum and gingival crevicular fluid (GCF) in periodontally healthy, chronic periodontitis (CP) patients with and without type 2 diabetes mellitus (T2DM). Serum and GCF samples were collected from periodontally healthy and CP with T2DM patients to analyze resistin levels using an enzyme-linked immunosorbent assay test, and clinical parameters were assessed after NSPT. On comparing the pre-and post-levels of resistin in three groups, in the periodontally healthy group, the GCF resistin levels before and after treatment revealed significant differences. It was concluded that in the presence of polymorphisms of RETN at most frequently found loci such as −420 and +299, resistin levels of GCF and serum are almost always seen to be elevated, which reduced after a comprehensive 3 months of nonsurgical periodontal therapy in CP with and without T2DM.

Inflammation destroys the periodontal ligament and alveolar bone, causing pockets, gingival recession, or both[16]. Large epidemiological studies show that diabetes is a significant risk factor for periodontal disorders [6]. The primary goal of periodontal therapy is to remove subgingival plaque and calculus. NSPT is considered the most effective periodontal therapy[17]. Several longitudinal studies have demonstrated the effectiveness of NSPT in managing non-surgical periodontal disease [9].

Adipose tissue, an active endocrine organ, stores fat and produces adipokines that regulate lipid metabolism and inflammation. Adipokines, which are generated from adipose tissue, have been linked to immune-mediated inflammatory responses [18]. Research indicates that complicated signaling mechanisms govern cytokines, which play a role in the pathophysiology of diabetes and periodontal disease.

Resistin not only leads to insulin resistance, but it also aids in the inflammatory process via pro-inflammatory chemicals. Resistin is a pro-inflammatory molecule that secretes TNF-α, IL-6, and IL-12, creating a positive feedback cycle that induces its own production. Resistin levels are elevated with periodontitis because resistin is expressed from polymorphonuclear leukocyte cells and macrophages, and periodontopathogens stimulate resistin release from neutrophils via lipopolysaccharide stimulation[1]. Fluctuating chemerin levels were found to be higher in obesity and T2DM sufferers. It was also suggested that insulin resistance may be a forecaster of chemerin levels, but not necessarily by body mass index (BMI) or fasting insulin. Perhaps more significantly, chemerin has been associated with persistent micro and macrovascular complications[19].

Visfatin levels in the plasma of T2DM patients on hypoglycemic medication have been found to be higher. A recent study by Pradeep et al. demonstrated that patients with periodontal disease have higher quantities of visfatin than healthy subjects. The pathophysiologic mechanisms of visfatin may provide insight into the increased periodontal damage observed in diabetics whose oral fluids have elevated levels of this substance [11].

Leptin production can be increased by pro-inflammatory cytokines that are generated in response to inflammatory illnesses like periodontitis. Poor glucose homeostasis results from dysfunction in this system. Because GCF plays a role in modulating the inflammatory response, studies have demonstrated a negative link between GCF leptin levels and CP, but a positive correlation between blood leptin levels and CP [10].

If identified, these adipocytokines may help in the comprehension of their functions and the early development of a treatment plan, which may lessen the intensity of inflammatory diseases and their associated damage to the periodontium.

Except for one study, the remaining studies showed a significant reduction in GCF levels of adipocytokine in GCF after NSPT and further all studies showed improvement in clinical parameters of periodontitis. More clinical trials need to be done to achieve a substantial result but the studies included after passing the stringent inclusion criteria have led us to conclude that NSPT reduces the levels of biomarkers being evaluated. Further, there was an improvement in the glycemic levels documented by a few studies thus emphasizing the bidirectional relationship between CP and T2DM.

Hence NSPT could not only improve the clinical parameters of periodontitis, it could lower the HbA1c levels which is a significant finding.

Registration: This systematic review and meta-analysis has been registered in PROSPERO (CRD42023450510)

Author Contributions:

The manuscript has been read and approved by the authors, the requirements for authorship criteria as stated above have been met and each author believes that this review is a culmination of honest and hard work.

Dr. Dax Abraham: Methodology, Data Curation, Formal Analysis, Investigation, Project Administration, Validation, Writing – Original Draft Preparation, Writing - Review & Editing.

Dr. Aakansha Puri: Conceptualization, Methodology, Data Curation, Formal Analysis, Investigation, Project Administration, Supervision, Validation, Visualization, Writing Original Draft Preparation, Writing - Review & Editing.

Dr. Alpa Gupta: Methodology, Data Curation, Formal Analysis, Investigation, Project Administration, Validation, Writing – Original Draft Preparation, Writing - Review & Editing

Dr. Arun Kumar Duraisamy: Methodology, Data Curation, Formal Analysis, Investigation, Project Administration, Validation, Writing – Original Draft Preparation, Writing - Review & Editing

Dr. Mrinalini Mrinalini: Methodology, Data Curation, Formal Analysis, Investigation, Project Administration, Validation, Writing – Original Draft Preparation, Writing - Review & Editing

Dr. Rajeev Kumar Malhotra: Formal Analysis, Investigation, Project Administration, Validation

Acknowledgments: The authors would like to thank Dr. Rajeev Kumar, Senior Scientist (All India Institute of Medical Sciences, New Delhi) for his detailed statistical analysis of the data provided.

Conflicts of Interest: There are no conflicts of interests

Funding: none

Competing interests: None

Ethical approval statement: Not Applicable

Informed Consent: Not Applicable since this is a systematic review and meta-analysis

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Tables 1 to 4 are available in the Supplementary Files section

No competing interests reported.

Table1searchstrategy.docx
Table 1: Search strategy
table2charecteristicsofthestudiescopy.docx
Table 2: Characteristics of the studies included
Table3Clinicalperiodontalparameterscopy.docx
Table 3: Clinical periodontal parameters
Table4RiskofBiasassessment.docx
Table 4: Risk of Bias Assessment
PRISMA2020checklist.docx

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Adipocytokine levels in Chronic Periodontitis and Type 2 Diabetes Mellitus after Nonsurgical Periodontal Therapy

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