Abstract
Background
Previous research has demonstrated that poor controlled diabetic showed higher prevalence of AP compared to well-controlled patients and endodontic treatment may improve metabolic control of patients with diabetes. The purpose of this trial was to clinically assess the effects of endodontic treatment on glycemic control in patients with type 2 diabetes mellitus (T2DM) and apical periodontitis (AP).
Study design
For present trial, AP + T2DM with patients insulin injection (Group1, G1,n = 65), AP + T2DM patients with hypoglycaemic agents (Group2, G2, n = 82), and AP patients without DM (Group3, G3, n = 86) were enrolled. After demographic characteristics and clinical examination were achieved, root canal treatment (RCT) was performed for each patient. Subjects were followed up at 2-week, 3- and 6-month. At each visit, blood samples were taken and clinical laboratory studies were performed. At 6-month follow-up, Periapical Index (PAI) score was used to assess the periapical status.
Results
A total of 237 subjects who met the including criteria were allocated in three groups and 223 subjects (94.1%) completed the treatments and the follow-up assessments. After treatment, taking PAI into consideration, both groups showed significant improvement of AP in each group (P < 0.05). Patients in G3 had a continued significant lower concentration of fasting plasma glucose (FPG) levels at follow-up (P < 0.05). A continued reduction of hemoglobin glycation (HbA1c) was observed in most of time points (P < 0.05). Throughout the trial, there are also significant changes in inflammatory factors in short-term.
Conclusion
Endodontic therapy improved AP healing, glycemic control and systemic inflammation in patients with T2DM and/or AP in each group. However, a continued reduction in inflammatory factors and decreasing of HbA1c in short-term could not be observed in this trial.
Keywords: Apical periodontitis, Type 2 diabetes, Endodontic treatment, Glycemic control, HbA1c
Abbreviations: type 2 diabetes mellitus, T2DM; apical periodontitis, AP; periapical Index, PAI; root canal treatment, RCT; fasting plasma glucose, FPG; hemoglobin glycation, HbA1c; C-reative protein, CRP
1. Introduction
Diabetes mellitus (DM) is characterized with characteristic features of an abnormal elevation in blood glucose levels, by which the metabolism of carbohydrates, lipids and proteins is affected [1]. The incidence of DM is up to 9.3%–10.5% in the adults aged between 20 and 79 years and deaths due to diabetes increased by 3% in the same period [2]. Based on the complex pathophysiology, the disease is classified into two types. T2DM leads to specific complications due to a progressive loss of adequate insulin that secreted by exocrine pancreatic β-cell [3,4]. It is well established that chronic low-grade and asymptomatic inflammation are closely involved in the pathogenesis of T2DM [5]. The most important reference for predicting the risk of development of DM is the level of HbA1c [6].
AP is a acute or chronic inflammatory process around a tooth root caused by microbial infection of the pulp space [7]. AP was traditionally considered to be a localized oral infection. The principal objects are elimination of bacteria and exclusion of further infection from the root canal [8]. In recent years, it has been reported that AP is not merely a local phenomenon. The local infectious elements may spread to other tissue and bring about severe inflammatory condition [9]. Accumulating evidence has indicated that AP disturbs the rhythm of immune system of patients with diabetes through multiple pathways [10,11]. Research has shown that an important pathway of the host inflammatory response is the activation of immune response by IL-6 and TNF-α [12,13]. A previous study found elevated C-reative protein (CRP) levels and novel biomarkers of the chronic inflammatory response to periapical pathogens in diabetic subjects [14].
In a cross-sectional study, Sánchez et al. [15] highlighted that HbA1c levels of DM patients are associated with periapical status. López-López et al. [16] showed a highly significant association between the prevalence of T2DM and endodontic treatment. There was already emerging scientific support for the association between DM and AP both in animals and humans [17]. Several studies have suggested that DM and AP share common mechanisms of pathogenesis relating to some altered immune-inflammatory responses at local and systemic levels. The mechanisms underlying the interaction between DM and AP were also addressed in several recent experimental studies [18]. Segura-Eegea et al. [19] investigated the cellular and molecular mechanisms that could explain the high levels of AP in T2DM subjects compared to non-diabetic individuals. Wang et al. [20] provided available scientific evidence indicating that DM aggravates AP and periodontitis, resulting in accelerated periodontal bone resorption. They also found that disordered glucose metabolism of reactive oxygen species overproductions would result in compromised bone healing and periodontal bone regeneration.
According to our literature research, various studies have been published on the effect of endodontic treatment on DM control [21,22]. Although several interventional studies have suggested that treatment may improve metabolic control of patients with diabetes, not all scientists have reached consensus and clinical evidence remains inadequate and inconclusive. With this background, our clinical trial was designed to evaluate the effect of a sound clinical management of AP on the metabolic control of T2DM subjects.
2. Methodology
2.1. Ethical statement
The research was conducted in full accordance with the World Medical Association Declaration of Helsinki. The protocol was evaluated and approved by the ethics committee of the Affiliated Huai'an Hospital of Xuzhou Medical University (HEYLL201912). It was designed in accordance with the 2010 CONSORT guidelines, and was registered at Chinese Clinical Trial Registry. A written informed consent was provided to each subject prior to the treatment.
2.2. Trial design
T2DM subjects with at least one AP tooth were consecutively recruited referred to Department of Endodontics, Affiliated Huai'an Hospital of Xuzhou Medical University. The diagnosis of T2DM was made by a physician according to the criteria recommended by the American Diabetes Association (ADA) [3]. They were all under diet regimen and/or use of oral hypoglycemic agents for at least 2 years.
AP subjects without any systemic disease were balanced for demographic characteristics with the aforementioned T2DM subjects. Clinical examination showed a crown corrosion, percussion test and sensitivity thermal test negative. AP was diagnosed on the basis of examination of digital Cone Beam Computed Tomography (CBCT, 80 kV acceleration voltage, 8 mA beam current and voxel size of 0.2 mm Belmont Equipment, New Jersey, USA) and clinical examination by two trained radiographic technician and two independent reviewers. The number and location of teeth, excluding third molars, present identifiable periapical lesion without root fillings, were recorded at first screening. Patients were allocated in three groups as depicted in Fig. 1.
Fig. 1.
Flow diagram of this clinical trial.
The exclusion criteria for all patients were: (1) consumption of immunosuppressives, antibiotics or anti-inflammatory drugs at least 3-months preceding the study; (2) status of pregnancy or lactation; (3) other systemic conditions that could affect the progression of AP; (4) history of systemic antibiotic administration, drinking or smoking; (5) without compliance to cooperate with the research protocol. All procedures were performed by one of the endodontists who was blinded to the groups to which the patients and their teeth belonged.
2.3. Sample size analysis
Sample size analysis using G Power version3.1.9.2 was determined with Walters's method by considering three groups of subjects, an effect size of 0.28 and a standard deviation of 1.5 as previously shown. With an assumption of normal sample distribution, we set a power of 0.8 and an error of α = 0.05. Keeping in mind the compensation of drop-out during the trial period, we set an increase of 20%. In each group, around 68 subjects were finally assigned, so that a power of 0.8 was obtained.
2.4. Clinical procedures
Approximately 2 h in length for all the sessions to allow for adequate treatment time. All treatments were performed by at least 2-year endodontic residents who were previously calibrated in a clinical training session. At the first appointment, the teeth were isolated with a rubber dam and anaesthetized with 2% lidocaine as needed for patient comfort. Endodontic straight-line access was obtained with low speed Gates-Glidden drills. Canal instrumentation was performed with ProTaper motorized nickel–titanium system for root canal expansion. After the use of each instrument, the root canals were gently irrigated with 25 ml fresh 2.5%NaOCl after each instrumentation cycle to achieve disinfection. Canals were then dried with sterile paper points, and filled all canal with calcium hydroxide paste for at least 2 weeks. At the second appointment, when the correct fill-in was identified, the root canal was irrigated again. After each canal was dried, they were filled using a warm vertical compaction technique (Elements Free, Kerr, Munich, Germany). Filling quality was checked by radiographs. The coronal surfaces were sealed with glass ionomer (Ketac-cem, 3 M ESPE) and a definitive restoration of metal or porcelain crown.
2.5. Endodontic and laboratory analyses
All radiographs were evaluated by two experienced board-certified endodontists immediately after RCT and at the 6-month follow-up, who were masked to the group allocation. After the independent scoring session, the two examiners met as a group to reach consensus when there were unanimous agreements. Another trained examiner would be invited if they could not reach an ultimate consensus. PAI was used to assessed the periapical status (Table 1) and an index greater than two was determined as the presence of periapical pathology [24]. Clinical findings and radiographic outcomes were recorded for each subject.
Table 1.
The mean PAI for each group at first screening and the 6-month follow-up.
| Index | Periapical status |
|---|---|
| 1 | Normal periapical structure |
| 2 | Small changes in bone structure |
| 3 | Changes in bone structure with some mineral loss |
| 4 | Periodontitis with well-defined radiolucent area |
| 5 | Severe periodontitis with exacerbating features |
Fasting venous blood samples were drawn from all the subjects at 6:00–8:00 a.m. after 8–12 h of fasting, prior to endodontic treatment at each follow-up. Serum samples were transported at −20 °C and kept at −80 °C in a freezer until analysis. Fasting glucose was analyzed by enzymatic methods using a One Touch Ultra 2 (Life Scan, Wayne, PA, USA). Blood sample was withdrawn from all the subjects to measure HbA1C values using a Boehringer Mannheim/Hitachi 911 automated discrete chemistry analyzer (Mannheim, Germany). Subjects who had HbA1c values > 8% were considered poorly controlled, whereas HbA1c levels ≤8% as better-controlled.
Patients in G1 and G2 were instructed to continue with their medical treatment of DM (oral hypoglycaemic agents or insulin injection), diet and life-style without modification during the study period. All subjects in the trial were reinforced with oral hygiene instructions. Subjects were followed up at 2-week, 3- and 6-months.
2.6. Statistical analysis
In this study, data were statistically analyzed using SPSS v20.0 software (IBM Corp, Armonk, NY, USA) and visualized using GraphPad Prism 7 (GraphPad Software Inc., La Jolla, CA, USA). The demographic and health status information at baseline were summarized using Means (SDs) for continuous variables and Frequencies (percentages) for categorical variables. Data were first examined for normality by the Kolmogorov-Smirnov test and, the data that achieved normality were analyzed using parametric methods while the others used non-parametric methods.
In our trial, the changes in PAI were analyzed using Wilcoxon signed-rank test. At the same time, the proportion of subjects in each group that could be considered improvement or heal of AP were assessed with chi-square test because the data did not have normal distributions. As to results of glycaemic control characteristics, Matched Pairs Tests were applied to test FPG and HbA1c levels to determine significant difference between follow-up and baseline. The changes in inflammatory factors are analyzed using ANOVA test for changes in CRPs level and paired t-tests for Serum IL-6 and TNF-α levels.
All reported p-values were from two-side tests and compared with a significance level of 0.05 (α = 0.05).
3. Results
A total of 275 subjects were screened for this trial from June 2020 to October 2021.237 subjects who met the including criteria were allocated in three groups. A total of 223 subjects (94.1%, female/male ratio 4.8, aged 67.3 ± 11.9 years) completed the treatments and the follow-up assessments (Fig. 1). The demographic and health status information at baseline are outlined in Table 2. Age, gender, nationality, BMI, diabetes duration, glycated hemoglobin and Serum insulin level did not differ significantly between subjects (P > 0.05).
Table 2.
The demographic and health status information at baseline.
| Characteristic | G1 | G2 | G3 | t/χ2 | P |
|---|---|---|---|---|---|
| Age, mean (SD), y | 56.6 (8.9) | 55.7 (11.9) | 57.6 (12.2) | t = 0.57 | P = 0.57 |
| Men, No. (%) | 41 (63.1) | 56 (68.3) | 60 (78.9) | χ2 = 4.51 | P = 0.11 |
| Han nationality,No. (%) | 63 (96.9) | 79 (96.3) | 73 (96.1) | χ2 = 0.08 | P = 0.96 |
| Body weight, (SD), kg | 64.7 (12.6) | 67.3 (10.5) | 63.4 (9.3) | t = 2.68 | P = 0.07 |
| BMI, mean (SD)a Normal,No. (%) Overweight,No. (%) Obese,No. (%) |
25.2 (2.9) 28 (43.1) 24 (37.0) 13 (20.0) |
24.2 (4.3) 33 (40.2) 29 (35.4) 20 (24.4) |
25.0 (3.8) 31 (40.8) 33 (43.4) 12 (15.8) |
t = 1.25 χ2 = 2.25 |
P = 0.30 P = 0.69 |
| Diabetes duration, (SD), y | 7.6 (4.0) | 6.8 (2.8) | 7.1 (3.1) | t = 1.20 | P = 0.30 |
Normal (BMI<24.9), Overweight (BMI25–29.9), Obese (BMI>30).
BMI, body mass index (calculated as weight in kilograms divided by height in meters squared).
The mean PAI for each group was shown at first screening and the 6-month follow-up was presented in Fig. 2. The difference among groups at base-line was not statistically significant (P > 0.05). All groups exhibited a statistically significant decrease in 6-month evaluation (P < 0.05). The proportion changes in healed periapical lesion in each group had significantly increased at 6-month follow-up (P < 0.05). Meanwhile the healed proportion in DM groups (G1,G2) was higher than the score in another group (G3), but a statistically significant difference was only found between G1 and G3 (P > 0.05) (Fig. 3).
Fig. 2.
Changes of PAI in each group between baseline and the 6-month follow-up.
Fig. 3.
The proportion of healed periapical lesion in each group.
Fig. 4 shows the results of glycaemic control characteristics. Compared with baseline, patients at follow-up had a continued significant lower concentration of FPG levels, except for G1 and G2 at 2-week follow-up. A continued reduction of HbA1c was observed but significance was not reached with respect to outcome at 2-week and 3-month in all groups (P > 0.05), while the levels had significantly reduced in G3 at 3-month and each group at 6-month follow-up (P < 0.05).
Fig. 4.
The Results of glycaemic control characteristics.
The changes in inflammatory factors are presented in Table 3. For the levels of CRP, a significantly decrease was detected at 2-week follow-up compared with that of baseline (P < 0.05), but it did not differ significantly at 3-month and 6-month (P > 0.05). Throughout the trial, at each time points, Serum IL-6 and TNF-α level continued to significantly decrease in each group (P < 0.05).
Table 3.
The changes in inflammatory factors.
| base-line | 2 week | 3 month | 6 month | Δ1(Z/t) | Δ2(Z/t) | Δ3(Z/t) | |
|---|---|---|---|---|---|---|---|
| CRP, mean (SD), mg/dlb | |||||||
| G1 | 2.3 (2.6) | 1.5 (1.9) | 2.1 (2.0) | 2.2 (1.9) | −4.8a | −1.08 | −0.54 |
| G2 | 1.8 (2.1) | 1.2 (1.4) | 1.9 (1.5) | 2.1 (1.0) | −4.73a | −1.77a | −0.94 |
| G3 | 1.4 (2.3) | 0.9 (1.8) | 1.5 (1.4) | 1.6 (0.8) | −3.27a | −1.20 | −2.31a |
| IL-6, mean (SD), pg/mlb | |||||||
| G1 | 101.0 (39.8) | 79.3 (35.1) | 71.3 (31.7) | 80.8 (37.6) | 15.6a | 18.4a | 14.1a |
| G2 | 97.6 (31.9) | 79.3 (26.9) | 72.2 (24.5) | 80.8 (30.2) | 11.9a | 14.7a | 9.7a |
| G3 | 81.6 (28.9) | 72.4 (26.8) | 65.5 (24.4) | 75.6 (31.2) | 6.5a | 10.9a | 3.4a |
| TNF-α, mean (SD), pg/mlb | |||||||
| G1 | 1163 (153) | 924 (97) | 800 (139) | 717 (128) | 15.4a | 26.6a | 32.1a |
| G2 | 1126 (185) | 876 (156) | 755 (150) | 679 (134) | 14.2a | 32.9a | 36.9a |
| G3 | 1199 (159) | 950 (104) | 792 (148) | 712 (134) | 16.6a | 36.0a | 43.1a |
Δ1: changes from baseline to 2-week; Δ2: changes from baseline to 3-month; Δ3: changes from baseline to 6-month.
Changes have significant difference.
Statistical significant difference at baseline between groups (P < 0.05).
4. Discussion
This is a double-blinded clinical trial aiming at the effect of endodontic treatment on metabolic and inflammatory control in T2DM patients. A control group of DM subjects not under endodontic treatment was not included because it is unethical to withhold any therapy for AP patients. In general, results of this trial showed that there are significant improvements in AP healing in the three groups. The levels of FPG and HbA1c were reduced after endodontic treatments. Moreover, the results of this study indicated that there was a reduction in CRP, cytokines IL-6 and TNF-α levels. In agreement with our result, Bakhsh et al. [8]demonstrated that successful endodontic treatment and periapical surgery resulted in a long-term reduction of inflammatory marker levels.
Previous research has demonstrated that poor controlled diabetic showed higher prevalence of AP compared to well-controlled patients [23]. The significantly different proportions of healed periapical lesion in the long-term were detected in this trial. This finding confirms previously published reports that diabetic and non-diabetic subjects do not differ in AP healing [24]. Segura-Egea et al. [25] Recently reported a worse success rate of RCT, with higher percentage of postoperative radiolucent periapical lesions, associated with several systemic conditions, such as DM. Though there is no significant difference between G2 and G3, endodontic treatments may be considered in patients with DM for benefits to tooth retention, based on the inter-group changes in PAI from baseline to follow-up.
As the most common type of diabetes, T2DM is characterized by tissue resistance to insulin action, which is associated with hyperglycaemia and hyperinsulinaemia development, causing glucose metabolism failure in the bloodstream [26,27]. Therefore, T2DM patients are more susceptible to infection processes because of reduced oxygen diffusion through the capillary wall [28]. Several cross-sectional studies in diabetic subjects have confirmed that the increase in proinflammatory cytokines in blood such as CRP, cytokines IL-6 and TNF-α could be suppressed by an extract of apical pathogens [29,30]. In this regard, evidence has suggested that both AP and DM share common mechanisms of pathogenesis that are related to immune-inflammatory responses at local and systemic levels. Controlling blood sugar is also effective in reducing gingival and apical inflammation [31]. Furthermore, it has been recognized that salivary IL-6 levels could be considered to be a marker of systemic disease as a predictive indicator of DM [32].
The results of the present study showed that, there was a significant association between endodontic treatment and decrease in CRP、IL-6、TNF-α levels in the DM groups. These results were in agreement with previous observation which showed down-regulated serum inflammatory factors in DM subjects after periodontal and periapical treatments [33]. There are metabolic and immune pathways that having evolved to illuminate the etiology and pathogenesis of insulin resistance due to dental inflammation [34]. It is now apparent that inflammatory responses can activate intracellular signaling pathway and inhibit insulin signaling. As a result of it, we could assume that the local inflammatory mediators reduce insulin sensitivity and thus increase glucose intolerance. It has been demonstrated that key mediators such as IL-6 and TNF-α, produced by periapical inflammation, impede insulin receptor signaling in skeletal muscle and liver [35]. These cytokines promoting serine phosphorylation to mediate heterologous inhibition of IRS-1 signaling, which, in turn, counter-regulates the insulin response [36].
In accordance, recent molecular evidence, which related to periapical lesions and immunoinflammatory response, offers new therapeutic guidance for endodontic treatment in DM subjects. As a consequence, elimination of microorganisms may be of systemic importance in T2DM maintenance [37]. This trial showed relevant facts that the need for insulin decreased markedly during the following 2-weeks and 3-month when the fasting glycemic was controlled within the regular regimen. We can implies that agents with an affinity to insulin receptors must be partly removed after local inflammation treatment. However, we find an increase in fasting glucose levels at 6-month follow-up, it is reasonable to assume that the increase was also resulted from some other factors such as obesity. In our trial, the limitation that we did not allocate according to weight should be considered. Taking the difficulty of glucose control into consideration, because DM is a multifactorial disease, the present results are encouraging for poorly controlled T2DM subjects with AP.
HbA1c is an early glycation product in response to haemoglobin interactions with sugars in erythrocytes. The binding of glucose to hemoglobin is highly stable, therefore hemoglobin remains glycated for the life span of the erythrocyte [38]. The HbA1c test provides an estimate of the average glucose level over the 30 to 90 days preceding the test [39]. Therefore, the short-term fluctuations may not be accounted by this test. It is often used to monitor long-term blood glucose control in diabetic patients and to determine treatment plans. The recent studies in DM patients also revealed a decrease in HbA1c after a periodontal treatment [40]. However, in contrast to the findings of Cintra et al. [41], they demonstrated that the increase of HbA1c is regardless of the presence of AP and/or periodontal disease. As in our study, no statistically insignificant obtained between the groups in short-term is somewhat due to the reason that periapical healing is sometimes slow and final results may not be possible to assess in a short time.
A strength of this trial is that subjects received standardized RCT and were followed up over a period of 6 months. The availability of repeated clinical and laboratory assessment over a long follow-up period made it possible to detect the changes in the treatment outcome. However, there are some limitations to the present trial that need to be addressed. The study design did not included a group without RCT due to ethical consideration. Therefore, we selected systemic healthy subjects as a group to control the confounders of systemic disease. Further limitation includes its sample size, which limited the precision of finding some significant differences that we hypothesized to be detected prior to our trial. Larger studies are required to confirm our finding and determine whether endodontic therapy confers a significant benefit on T2DM patients.
Author contribution statement
Shengming Wang: conceived and designed the experiments, analyzed and interpreted the data and wrote the paper.
Xiaoqing Wang, Feng Bai, Xinlian Shi and Tingting Zhou: performed the experiments, analyzed and interpreted the data.
Fangfang Li: analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data and wrote the paper.
Funding statement
Fangfang Li was supported by Jiangsu Commission of Health [Identifier code:JSYGY-2-2021-PJ133].
Data availability statement
Data associated with this study has been deposited at https://www.editorialmanager.com/dib/default1.aspx (accession number: lff32)
Declaration of interest’s statement
The authors declare no competing interests.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data associated with this study has been deposited at https://www.editorialmanager.com/dib/default1.aspx (accession number: lff32)
