Effect of periodontal treatment on adipokines in patients with type 2 diabetes mellitus: A systematic review

Abstract

Background

Periodontal disease (PD) is associated with type 2 diabetes mellitus (T2DM), while periodontal treatment (PT) improves glycemic control in T2DM patients. Leptin and adiponectin belong to the adipokines family and have almost antagonistic functions in inflammatory processes and insulin sensitivity modulation. Hence, these hormones have been linked with both PD severity and glycemic control. This systematic review aims to assess the effect of PT on serum levels of leptin and adiponectin in patients with T2DM.

Methods

PubMed, Cochrane Library, and Google Scholar databases and ClinicalTrials.gov website were searched up to January 5th, 2025. Randomized and non‐randomized controlled clinical trials (RCTs and CCTs) including patients with T2DM and PD who underwent PT and evaluated serum levels of leptin and adiponectin were included. Assessments of risk of bias and of certainty of evidence were performed.

Results

Seven trials were eligible for qualitative synthesis. A statistically significant increase in serum adiponectin levels was observed across most studies, while no such consistency was observed for leptin. The overall level of certainty of evidence was judged low in the RCTs and very low in the CCTs. Meta‐analysis could not be performed due to significant methodological heterogeneity.

Conclusions

Preliminary findings suggest a potential increase in adiponectin levels in T2DM patients, with possible implications for glycemic control. However, these results should be interpreted with caution due to the small number of studies and important methodological limitations. Well‐designed studies with larger sample sizes and adequate adjustment for confounders are necessary to verify this observation.

Plain language summary

People with type 2 diabetes often also have periodontitis, an inflammatory gum disease, which may affect their overall health. The aim of this study was to investigate whether treating periodontitis could help improve certain substances in the blood—called adiponectin and leptin—that are linked to blood sugar control and inflammation. Several studies that tested this in people with both diabetes and periodontitis were included and most of them showed that, after periodontal treatment, levels of adiponectin (which helps reduce inflammation and improve insulin sensitivity) increased. However, results for leptin were less clear. This suggests that taking care of gum health might support better diabetes management. The overall strength of evidence was low due to methodological limitations and heterogeneity among studies. Current findings should be interpreted cautiously, as available data remain preliminary. Still, more high‐quality research is needed to fully understand how treating periodontitis may benefit people with diabetes.

1. INTRODUCTION

1.1. Background

Periodontal disease (PD) is a chronic inflammatory disease that leads to the progressive destruction of the tooth‐supporting apparatus. ¹ Although a dysbiotic bacterial biofilm is considered the key etiologic factor for gingivitis and periodontitis, various endogenous and exogenous factors, such as diabetes mellitus (DM), immunodeficiencies, smoking, etc., may also contribute to the extent, severity, and rate of disease progression. ² Interestingly, in the case of DM there is strong evidence supporting the presence of a bidirectional relationship with periodontitis. Therefore, not only DM aggravates PD, but at the same time periodontal inflammation exerts a systemic effect which negatively affects glycemic control. ³ DM is a group of chronic metabolic disorders characterized by abnormal glucose metabolism caused by defects in insulin production and/or action. ⁴ The mechanisms that govern the bidirectional relationship between PD and DM have not been fully elucidated; however, aspects of immune functioning, neutrophil activity, and cytokine biology are thought to be involved. ³ The release of adipo(cyto)kines is considered to play a role in this equation since they have been linked both with insulin resistance in DM and with PD severity. ⁵ Of all adipokines, adiponectin and leptin have been extensively studied because of their involvement in immune response, bone, and lipid metabolism, energy expenditure, and insulin sensitivity modulation. ⁶ Leptin and adiponectin are highly active hormones predominately secreted from adipose tissue and have antagonistic functions. ⁷ Specifically, upon binding to its receptors, adiponectin exerts anti‐inflammatory effects such as inhibition of pro‐inflammatory cytokines, induction of anti‐inflammatory cytokines, reduction of adhesion molecule expression and performs an antagonistic effect on toll‐like receptors and their ligands. ⁸ Adiponectin receptors have been found in periodontal tissues ⁹ and in a systematic review and meta‐analysis, Zhu et al. ¹⁰ revealed decreased serum levels of adiponectin in patients with periodontitis compared with healthy controls. These data indicate a potential beneficial effect of this hormone in dampening periodontal inflammation. In addition, adiponectin promotes insulin sensitivity, and its low circulating levels are associated with obesity, insulin resistance and type 2 diabetes mellitus (T2DM). ¹¹ On the other hand, leptin has a pro‐inflammatory function. It induces the production of the pro‐inflammatory cytokines tumor necrosis factor alpha (TNF‐α) and interleukin (IL) ‐6, which in turn stimulate hepatic C‐reactive protein (CRP) synthesis. This may enhance periodontal inflammation and increase insulin resistance. ⁹ , ¹² , ¹³ , ¹⁴ Interestingly, elevated levels of circulating leptin are associated with periodontitis, ¹⁰ while leptin secretion is stimulated in part by insulin. ¹⁵

The association of these adipokines with periodontitis has intrigued investigators to assess the effect of periodontal treatment (PT) on serum levels of leptin and adiponectin. In a systematic review and meta‐analysis Zhu et al. found no significant changes in leptin and adiponectin levels after PT in systemically healthy patients. ¹⁰ However, this may not necessarily be the case in patients with T2DM. PT has been shown to improve glycemic control of individuals with DM, ¹⁶ although the effect of treatment on insulin resistance remains inconclusive. ¹⁷ Due to the close interplay of adipokines especially with DM, there is a growing interest in this subpopulation.

PD is an inflammatory disease linked to T2DM in a bidirectional way. Thus, individuals with T2DM have an increased risk for PD and patients with PD demonstrate difficulty in achieving and maintaining glycemic control and an increased risk for diabetes complications. ¹⁸ , ¹⁹ , ²⁰ , ²¹ The mechanisms by which DM influences periodontitis have been largely explained, but the reverse mechanisms (effect of periodontal inflammation on glycemic control of DM patients) are less clear, although systemic inflammation ²² induced by PD is considered to play an important role. ²³ Adiponectin and leptin are both adipokines with opposing effects on inflammatory responses and insulin resistance. ²⁴ Leptin has a pro‐inflammatory action and is associated with insulin resistance, ²⁵ while adiponectin has an anti‐inflammatory function and enhances insulin sensitivity. Therefore, elevated serum levels of leptin are associated with more severe PD and increased insulin resistance while the opposite occurs for adiponectin. ¹⁰ , ²⁶ , ²⁷

1.2. Objectives

To date, several intervention studies have examined the effect of PT on serum levels of leptin and adiponectin in patients with T2DM and compared them to T2DM patients that did not receive PT or to systemically healthy individuals that received periodontal intervention. ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ The need for a review that systematically synthesizes the above knowledge is evident. Therefore, the objective of the current systematic review is to critically assess and comprehensively summarize the available evidence regarding the effect of PT on serum levels of leptin and adiponectin in patients with T2DM.

2. MATERIALS AND METHODS

2.1. Protocol and registration

The present systematic review was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions version 6.2.0, ³⁵ and the PRISMA statement (Preferred Reporting Items for Systematic Reviews and Meta‐Analysis) was followed for reporting. ³⁶ The study protocol was registered with PROSPERO (international prospective register of systematic reviews) under the registration number: CRD42024624060. ³⁷ The review was conducted as planned.

2.2. Study design

A systematic review was undertaken to answer the PICO question: “In patients with periodontitis and T2DM (P), does periodontal treatment (I), compared to no treatment (C), change serum levels of leptin and adiponectin (O)?”

2.3. Eligibility criteria

2.3.1. Inclusion criteria

The inclusion criteria were based on the Population–Intervention–Comparison–Outcomes (PICO) schema:

1. Population: Adult patients with PD and T2DM regardless of ethnic group or sex.

2. Intervention: PT without limitations on the type of treatment that is, nonsurgical, surgical, or use of topical/systematic antibiotics.

3. Comparison: (a) with a control group with PD and T2DM that did not receive PT, or received only oral hygiene instructions or supragingival scaling (debridement) or (b) with a systemically healthy group with PD that received the same PT.

4. Outcome: Serum levels of leptin and/or adiponectin regardless of the follow‐up period.

2.3.2. Exclusion criteria

Studies were excluded for the following reasons: inclusion of patients with prediabetes, type 1 DM, gestational diabetes, metabolic syndrome, and periimplantitis; non‐English language; and full texts not available.

2.4. Search strategy and information sources

The search was conducted up to January 5, 2025 by two independent examiners (D.B. and N.C.). Detailed individual search strategies for PubMed and Cochrane Library databases were developed and a partial gray literature search was performed using Google Scholar. The appropriate Medical Subject Headings (MeSH) and free text words are presented in Table S1 in the online Journal of Periodontology. The reference lists of the included studies and relevant reviews were thoroughly screened for additional relevant papers. ClinicalTrials.gov was also searched to identify any registered but unpublished trials. Studies were collected, and duplicate hits were removed using the reference manager software EndNote. Any duplicates not identified by the software were removed by hand screening. The search was rerun prior to manuscript preparation to ensure that all recently published studies were captured.

Study selection was completed in two steps. In step 1, two authors (D.B. and N.C.) independently screened the titles and abstracts identified by all electronic databases and selected the articles that met all eligibility criteria. In step 2, the same authors read the full text of the studies selected in step 1, to further assess their eligibility. Next, the reference lists of the studies included were critically assessed by the authors (D.B. and N.C) for any inadvertently omitted references. Any disagreements in the first or second step were resolved by the other two authors (P.A.K. and Y.A.B.).

2.5. Data collection

Data collection was conducted independently by all four authors (D.B., N.C., P.A.K., and Y.A.B.) and was screened to verify that retrieved data was complete with no missing parts. Once again, in case of disagreements between investigators. Consensus was reached after re‐examining the studies. The data extraction spreadsheets included the following items: general information (authors, publication year, and study setting), methods (study design, treatment‐ comparison groups), participants (sample size, sex, age, body mass index [BMI], smoking status), intervention (type of PT; follow‐up time), main outcomes (difference in treated vs. controls and statistical significance of reported difference, limitations), and main conclusion. When necessary, attempts were made to contact the authors of the selected studies to clarify any information.

2.6. Risk of bias assessment

To avoid selection bias, quality assessment of the included studies was carried out independently by two authors (D.B. and N.C.) using the revised Cochrane Risk of Bias (RoB 2.0) tool for RCTs. ³⁸ Any disagreements between reviewers were resolved through discussion, and when needed, consultation with a third author (P.A.K.), ensuring consistency, and minimizing selection bias. The overall judgment of the risk of bias (low, some concerns, high) for each study was dictated by the highest RoB level in any of the domains that were assessed. The Risk of Bias in Non‐randomized Studies of Interventions (ROBINS‐I V2) tool ³⁹ was used to assess the methodological quality of CCTs based on seven domains. Each domain was rated as either “low,” “moderate,” “serious,” or “critical.”

2.7. Data synthesis

Studies were grouped for synthesis according to the review objectives and intervention characteristics. Eligibility for inclusion was determined by tabulating study characteristics (e.g., population, intervention type, comparator, and outcomes) and comparing them against the predefined criteria described in the protocol. Results were summarized in structured tables and supplemented by a narrative synthesis of the findings. Where summary statistics were missing or unclear, study authors were contacted to obtain the required information. Potential explanations for observed heterogeneity were qualitatively considered. A formal assessment of reporting bias was not conducted, owing to the limited number of studies and the qualitative nature of parts of the review.

2.8. Assessment of the certainty of evidence

The certainty of each outcome's evidence generated by the systematic review was assessed by the GRADE system, ⁴⁰ and a summary of findings table was built through the GRADE pro GDT software of COCHRANE. ⁴¹ The certainty for each outcome was categorized as high, moderate, low, or very low, and reasons that led to the level of evidence downgrading were clearly stated (risk of bias, inconsistency, indirect evidence, imprecision, or publication bias). RCTs and CCTs were evaluated separately.

3. RESULTS

3.1. Study selection

A total of 78 references were retrieved and after the removal of duplicate articles and screening, seven trials were eligible for qualitative synthesis. The PRISMA 2020 flow diagram of study selection is shown in Figure 1. ⁴²

FIGURE 1.

PRISMA flow diagram for new systematic reviews which included searches of databases and registers. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta‐Analysis.

3.2. Study characteristics

All seven studies were published between 2009 and 2019 and were written in English. Three were RCTs ²⁸ , ³⁰ , ³¹ and four were CCTs. ²⁹ , ³² , ³³ , ³⁴ All trials included adults with T2DM and PD, with variations in study design who underwent PT. Periodontal intervention involved subgingival scaling and root planing (SRP) in all studies, additional use of topical antibiotics in two ²⁸ , ²⁹ and use of systemic antibiotics and periodontal surgery in one. ³⁰ Follow‐up durations ranged from 1 to 9 months. A summary of the descriptive characteristics of the included studies is presented in Table 1.

TABLE 1.

Descriptive characteristics of included studies.

Study (country)	Study design	Total sample size/dropouts	Age (TG/CG) mean years ± SD	BMI (TG/CG) mean kg/m2 ± SD	Smoking status	TG sample size and disease status	CG sample size and disease status	TG periodontal treatment	CG periodontal treatment	Periodontitis definition	Diabetes definition	Observation time (in months)
Matsumoto et al. 2009 (Japan)	RCT	27/6	61.5 ± 7.9/ 56.4 ± 7	18.9‐25.9/ 20.2‐26.4	Mixed	11 T2DM + PD	10 T2DM + PD	OHI + SRP + TA	OHI + Supragingivalscaling with ultrasonic device	≥10 teeth present, ≥10 sites with PPD ≥ 4 mm	T2DM * HbA1c ≥ 5.5	4 and 9
Sun et al. 2011 (China)	RCT	190/33	55.13 ± 11.16/ 54.23 ± 10.85	23.71 ± 2.84/ 23.89 ± 2.73	Free	82 T2DM + PD	75 T2DM + PD	OHI + SRP + SA+ Surgery	No treatment	≥20 teeth present, PPD≥5 mm, more than 30% teeth with CAL≥4 mm, or over 60% teeth with PPD > 4 mm and CAL > 3 mm	T2DM † HbA1c 7.5–9.5	3
Bharti et al. 2013 (Japan)	CCT	31/2	60.2 ± 11.0/ 66.3 ± 8.3	24.2 ± 4.2/ 24.7 ± 4.2	Free	21 T2DM + PD	8 T2DM + PD	OHI + SRP+ TA	No treatment	≥10 teeth present, ≥2 sites with PPD ≥ 4 mm	T2DM HbA1c 5.8–10.0	2 and 6
Wang et al. 2017 (China)	RCT	44/5	61.58 ± 4.69/ 61.90 ± 6.75	24.32 ± 2.70/ 23.72 ± 3.46	Mixed	19 T2DM + PD	20 T2DM + PD	OHI + SRP	No treatment	≥15 teeth present and ≥30% of teeth with PPD≥ 5 mm and CAL > 4 mm, or ≥60% of teeth with PPD > 4 mm and CAL≥3 mm	T2DM HbA1c 6.5–10.0	3
Kardesler et al. 2010 (Turkey)	CCT	40/0	55.31 ± 5.44/ 50.25 ± 6.30/ 51.31 ± 8.64	29.04 ± 5.84/ 29.01 ± 3.96/ 26.62 ± 3.07	Mixed	two arms:13 well‐controlled T2DM + PD/ 12 poorly controlled T2DM + PD	15 SH + PD	OHI + SRP	OHI + SRP	≥4 teeth in each jaw with PPD ≥5 mm and CAL≥4 mm, ≥2 single‐rooted teeth with a PPD of 6–9 mm and BOP	T2DM ‡ HbA1c ≥ 6.5	1 and 3
Ahuja et al. 2019 (India)	CCT	60/0	40.5 ± 5.3	25.67 ± 2.73/ 23.63 ± 4.16	Free	30 T2DM + PD	30 SH + PD	OHI + SRP	OHI + SRP	patients with GI > 1, > 30% of sites with PPD ≥5 mm, positive BOP, CAL ≥5 mm with radiographic evidence of bone loss	T2DM HbA1c 6.5–8.0	3 and 6
Ghalwash et al. 2019 (Egypt)	CCT	60/0	>30 (TG mean 46.7, CG mean 38.1)	Not reported	Free	30 T2DM + PD	30 SH + PD	OHI + SRP	OHI + SRP	PPD < 6 mm and CAL ≤5 mm with radiographic evidence of bone loss	T2DM ‡ HbA1c 6.5–8.0	3

Abbreviations: BMI, body mass index; BOP, bleeding on probing; CAL, clinical attachment loss; CCT, controlled clinical trial; CG, control group; GI, gingival index; OHI, oral hygiene instructions; PD, periodontal disease; PPD, probing pocket depth; RCT, randomized clinical trial; SA, systemic antibiotics; SD, standard deviation; SH, systemically healthy; SRP, scaling and root planing; T2DM, type 2 diabetes mellitus; TA, topical antibiotics; TG, test group.

^*Based on the diagnostic criteria recommended by Japan Diabetes Society 1999.

^† WHO 1999 criteria.

^‡ Diagnostic criteria of the American Diabetes Association.

3.3. Risk of bias within studies

The results from the assessment of the risk of bias regarding RCTs and CCTs are demonstrated in Figures 2 and 3 respectively. All RCTs ²⁸ , ²⁹ , ³⁰ , ³¹ were assessed as having “Some concerns” overall, primarily due to issues in the allocation concealment process and the handling of missing data. Two CCT studies ²⁹ , ³² were judged to have a “serious” overall risk of bias while the remaining two ³³ , ³⁴ as “low” risk.

FIGURE 2.

Results of the Cochrane risk of bias (RoB 2.0) tool for RCTs. RCT, randomized clinical trial.

FIGURE 3.

Results of the risk of bias in non‐randomized studies of interventions, version 2 (ROBINS‐I V2) assessment tool for CCTs. CCT, controlled clinical trials.

3.4. Synthesis of results and assessment of the certainty of evidence

Among the six studies ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³⁴ evaluating adiponectin serum levels, five ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² reported a statistically significant posttreatment increase in patients with T2DM, although the magnitude and timing of the change varied. The results of the individual studies are summarized in Table 2. All three RCTs ²⁸ , ³⁰ , ³¹ showed consistent increases at follow‐up periods ranging from 3 to 9 months. Matsumoto et al. ²⁸ found that adiponectin levels significantly increased at 2 months (p < 0.002) in the intervention group compared to the control group. Sun et al. ³⁰ reported a statistically significant increase at 3 months after treatment (p < 0.01). Wang et al. ³¹ observed a significant rise in adiponectin levels at 6 (p < 0.05) and 3 months (p < 0.01) for the intervention group compared to the control respectively.

TABLE 2.

Outcomes and limitations of the included studies.

Authors and years	Study design	Outcomes for adiponectin	Outcomes for leptin	Limitations
Matsumoto et al. 2009	RCT	significant ↑ p < 0.002	not assessed	control group not considered as untreated since all subjects received SRP, smoking as confounder
Sun et al. 2011	RCT	significant ↑ p < 0.01	not assessed	obese, elderly and with diabetic complications were excluded
Bharti et al. 2013	CCT	significant ↑ p < 0.05	no significant change	uneven groups in size, selection bias, lack of adequate data regarding monitoring lifestyle
Wang et al. 2017	RCT	significant ↑ p < 0.01	not assessed	smoking as confounder, sample was elderly
Kardesler et al. 2010	CCT	significant ↑ in poorly controlled and SH, ↓ in well controlled, p < 0.05	significant ↑ in well controlled, ↓ in SH, no significant change in poorly controlled, p < 0.05	smoking as confounder
Ahuja et al. 2019	CCT	not assessed	significant ↓ p < 0,00001	small sample size
Ghalwash et al. 2019	CCT	nonsignificant ↑	not assessed	younger patients

Abbreviations: CCT, controlled clinical trial; RCT, randomized clinical trial; SH, systemically healthy; SRP, scaling and root planing.

Among the CCTs, Bharti ²⁹ also reported a significant rise (p < 0.05). However, Kardesler et al. ³² reported a statistically significant decrease in adiponectin levels in the well‐controlled group, while a statistically significant increase was observed only in the poorly controlled and systemically healthy groups (p < 0.05). Ghalwash et al. ³⁴ (CCT) found an increase although not statistically significant in serum adiponectin levels post‑treatment, however the T2DM group showed a significantly higher mean percentage increase in serum adiponectin level compared to the control group. Overall, a trend toward increased adiponectin levels can be observed, but the results are not sufficiently uniform to confirm a clear pattern.

Only three CCT studies reported results regarding changes in serum leptin levels, ²⁹ , ³² , ³³ and their findings were highly heterogeneous. Bharti et al. ²⁹ found a nonsignificant decrease 6 months after PT in T2DM patients. Kardesler et al. ³² concluded that for the well‐controlled group there was a statistically significant (p < 0.05) increase. For the poorly controlled T2DM group, there is no statistically significant increase while in the systemically healthy group a statistically significant decrease was found, 3 months post treatment. Finally, Ahuja et al. ³³ found a significant decrease in leptin levels (p < 0,00001) in all groups at 6 months after treatment. Thus, the available findings do not indicate a uniform trend in post‐treatment leptin levels.

The results regarding the certainty of evidence are shown in Figure 4. Two outcomes were evaluated: (1) if serum adiponectin levels increased in patients with T2DM and PD after PT and (2) if serum leptin levels decreased in patients with T2DM and PD after PT. The certainty of evidence was low in RCTs and very low in CCTs. It can be assumed with certainty that in the first case further research is very likely to have an important impact (estimation change) on the estimate of effect confidence and in the second case any estimation of effect is very uncertain. Quantitative synthesis (meta‐analysis) could not be performed due to significant methodological heterogeneity across the included studies.

FIGURE 4.

GRADE assessment: (a) Smoking; (b) use of antimicrobial agent additionally to SRP; (c) small sample size; (d) heterogeneity of results; (e) lack of adequate data regarding monitoring lifestyle; (f) uneven groups; (g) difference in population age. Explanations. SRP, scaling and root planing.

4. DISCUSSION

4.1. Summary of evidence

This systematic review evaluated the effect of PT on serum levels of adiponectin and leptin in individuals with T2DM. We found, with low certainty, a consistent trend across the included studies, showing that PT leads to a significant increase in adiponectin serum levels in patients diagnosed with T2DM. The observed increase in adiponectin levels posttreatment supports the hypothesis that PT reduces systemic inflammation and improves metabolic parameters. For leptin, conclusions could not be drawn, since the results from the few included studies did not follow a specific pattern. This may be due to shorter follow‐up periods or variability in treatment protocols across studies. To the best of our knowledge, the present systematic review is the first to examine the effect of PT on adiponectin and leptin levels in individuals with T2DM.

Consistent with the above observations, the studies included in this systematic review showed that at baseline serum levels of leptin were higher and those of adiponectin were lower in patients with T2DM and PD compared to systemically healthy individuals with PD. Only the study by Kardesler et al. ³² showed the opposite results, which may be explained by the fact that in the systemically healthy group the number of smokers was significantly larger. Previous studies suggest that smoking may cause a decrease in adiponectin levels ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶ , ⁴⁷ while results regarding leptin may vary. ⁴⁸

Despite the overall low quality of evidence, results from this systematic review indicate a clear pattern of increase of serum levels of adiponectin after PT in T2DM patients. Interestingly, these results are in contrast with the findings of the systematic review and meta‐analysis by Zhu et al. ¹⁰ that did not report significant changes in adiponectin and leptin serum levels after PT in systemically healthy individuals. It is possible that the close interplay between adiponectin and T2DM may influence differently this subset of patients. Adiponectin expression is regulated in part by inflammatory cytokines such as IL‐6 ⁴⁹ and TNF‐α. ⁵⁰ The reduction of systemic inflammation after PT could therefore result in the observed increase of this hormone. In addition, adiponectin has anti‐inflammatory properties and enhances insulin sensitivity and therefore its elevation may be beneficial for both periodontal health and glycemic control. As expected, all studies included in this systematic review demonstrated an improvement in HbA1c levels after PT. ⁵¹ Whether the glycemic control was ameliorated due to the reduction in systemic inflammation and/or by the enhanced insulin sensitivity induced by the increase in adiponectin levels is unknown. Indeed, it should be noted that the systematic review and meta‐analysis by Greggianin et al. ¹⁷ concluded that assertions about a causal link between nonsurgical PT and insulin resistance are weak and conflicting.

In the study by Matsumoto et al., ²⁸ the intervention group received topical antibiotics in addition to PT. While a significant increase in adiponectin levels was found, there was no significant difference in HbA1c levels compared to the control group. However, it should be noted that, in this study, the control group also received supragingival scaling. In addition, in the study by Matsumoto et al., ¹⁸ the severity of PD differed between the intervention and control group at baseline, as baseline mean numbers of sites with PPD > 4 mm were significantly higher in the test group compared to the control group (p < 0.005).

With regard to serum levels of leptin in patients with T2DM the results after PT were inconsistent. Only the study by Ahuja et al. ³³ showed a statistically significant decrease in leptin levels of T2DM patients after PT which is in accordance with the hypothesis that PT reduces systemic inflammation and improves metabolic parameters of patients with T2DM. The studies by Bharti et al. ²⁹ and Kardesler et al. ³² showed no significant change in leptin levels after treatment, a result that may have been affected by the limitations of both studies.

4.2. Limitations and strengths

The strength of evidence derived from our systematic review is low, mainly due to the small number of studies, existing methodological inconsistencies and limitations. Therefore, most of the studies were CCTs and only three were RCTs. In addition, the small sample size within most of the intervention studies may have generated bias in statistical power. The definition of PD also differed among all studies. Since the severity of PD is correlated with the induced systemic inflammation, the definition of PD could have determined the impact that PT may have on glycemic control and possibly on adipokines levels. Also, the included studies did not have predetermined endpoints of successful PT. Hence, the various periodontal interventions that ranged from SRP to surgical interventions may have resulted in differences in the remaining periodontal and, therefore, systemic inflammation. Similarly, most studies included patients with different levels of glycemic control at baseline. Smoking was also a confounder in several studies that could have affected the levels of leptin and adiponectin. Finally, Sun et al. ³⁰ reported limitations such as single facility, not blinded trial, exclusion of obese, elderly, and subjects with diabetic implications. Bharti et al. ²⁹ reported small and unevenly sized groups, selection bias (as not randomized) and reported a lack of adequate data regarding lifestyle monitoring. Wang et al. ³¹ mostly included elderly patients while Ghalwash et al. ³⁴ included mostly younger ones.

On the other hand, our systematic review had several strengths. We tried to minimize the risk of publication bias by performing a search in two well‐known databases, and we also searched gray literature. We also cross‐checked references from existing literature to ensure the identification of all relevant published articles.

5. CONCLUSION

The majority of the included studies reported a statistically significant increase in serum adiponectin levels following PT, suggesting a potentially beneficial role of periodontal intervention in modulating systemic inflammation and improving metabolic outcomes in Τ2DM patients. However, the evidence regarding leptin levels was insufficient to establish a clear pattern of change posttreatment. Overall, the findings suggest that PT may positively influence adiponectin levels in Τ2DM patients, although further high‐quality RCTs are required to establish these outcomes and to better understand the role of leptin in this context. Overall, the evidence from this systematic review is limited and should be interpreted with caution. Methodological inconsistencies, including variable PD definitions, intervention types, and short follow‐up periods, reduced the strength of the findings. Further well‐designed trials are needed to confirm these observations.

AUTHOR CONTRIBUTIONS

Dimitra Baladina and Natalia Christaki conceptualized the topic, designed the research, conducted the article screening, and wrote the manuscript. Yiorgos A. Bobetsis and Panagiotis A. Koromantzos performed the article screening, revised the manuscript, and critically revised the data.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

FUNDING INFORMATION

This research received no external funding.

Supporting information

Supporting Information

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available upon reasonable request from the corresponding author.