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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 1  |  Page : 7-13

The impact of chronic periodontitis on serum tumor necrosis factor-α and HbA1c levels in type 2 diabetic patients


1 Periodontic Department, Khartoum Teaching Dental Hospital, Khartoum, Sudan
2 Department of Oral Rehabilitation, Faculty of Dentistry, University of Khartoum, Khartoum, Sudan

Date of Submission12-Oct-2020
Date of Decision11-Dec-2020
Date of Acceptance22-Dec-2020
Date of Web Publication26-Mar-2021

Correspondence Address:
Rehab Abdallah Abdalrahman
Khartoum Teaching Dental Hospital, Khartoum
Sudan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjhs.sjhs_224_20

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  Abstract 


Background: Diabetic patients are subject to chronic periodontitis which could adversely affect glycemic control. Aim: This study determined the impact of chronic periodontitis in patients with diabetes mellitus type 2 (DM 2). Materials and Methods: We compared the levels of serum tumor necrosis factor-alpha (TNF-α) and HbA1c% between DM 2 patients with chronic periodontitis (study group) and DM 2 patients without chronic periodontitis (control group). Results: Statistically significant differences in fasting blood glucose (FBS), HbA1c, and gingival index (GI) were observed between the study and control group. No differences were found in TNF-α between the patients of both the groups. However, higher levels of TNF-α and FBS were shown in diabetic patients with mild periodontitis group than in those with moderate or severe periodontitis. Conclusion: Chronic periodontitis could affect HbA1c levels in DM 2 patients. In addition, HbA1c was positively correlated with FBS and GI, while negatively correlated with TNF-α, which exhibited a higher level in mild periodontitis compared with severe and moderate periodontitis.

Keywords: Chronic periodontitis, diabetes mellitus type 2, gingival index, HbA1c, tumor necrosis factor-α


How to cite this article:
Abdalrahman RA, Gismalla BG. The impact of chronic periodontitis on serum tumor necrosis factor-α and HbA1c levels in type 2 diabetic patients. Saudi J Health Sci 2021;10:7-13

How to cite this URL:
Abdalrahman RA, Gismalla BG. The impact of chronic periodontitis on serum tumor necrosis factor-α and HbA1c levels in type 2 diabetic patients. Saudi J Health Sci [serial online] 2021 [cited 2021 Jul 23];10:7-13. Available from: https://www.saudijhealthsci.org/text.asp?2021/10/1/7/311956




  Introduction Top


Globally, the number of people with diabetes is increasing due to population growth, aging, urbanization, and the increasing prevalence of obesity and physical inactivity.[1] In Sudan, the actual prevalence of diabetes mellitus (DM) is unknown; however, it reaches 10.4% in Northern Sudan.[2] The classic major complications of diabetes are microangiopathy, nephropathy, neuropathy, retinopathy, macrovascular disease, delayed wound healing, and periodontitis. Bidirectional association between periodontitis and DM has been established; DM adversely affects periodontal conditions, while periodontitis adversely affects glycemic control, increasing the risk of complications in diabetic patients.[3] The effect of periodontal infections on DM is potentially explained by the resulting increase in levels of systemic pro-inflammatory mediators, which exacerbate insulin resistance.[4]

Hyperglycemia, the hallmark of DM, is associated with a range of acute and chronic complications and can eventually affect all organs in the body, including the gingival and periodontal tissues that surround and support the teeth. The link between DM and oral diseases has not been as widely discussed in the medical literature as the effects of DM on other systems.[4] However, numerous epidemiological studies hypothesized that DM increases the risk of developing chronic periodontitis.[5] The level of glycemic control is of key importance in determining increased risk. For example, in the US National Health and Nutrition Examination Survey III, adults with an HbA1c% level of >9% had a significantly higher prevalence of severe periodontitis than those without diabetes.[6] One study conducted in China in Chongqing city reported an association between oral hygiene practice and blood glucose level in individuals with diabetes, they found lower levels of blood glucose and HbA1c in individuals with better oral hygiene.[7] Long-term periodontal care provided in a clinical setting could lead to an improvement in long-term glycemic control among individuals with type 2 diabetes and periodontal disease.[8]

Although tumor necrosis factor-alpha (TNF-α) is one of the best-characterized inflammatory cytokines causing insulin resistance, several studies have reported that interleukin-6 also causes insulin resistance.[9] TNF-α is an adipocytokine involved in systemic inflammation and stimulates the acute phase reaction.[10] It is primarily secreted by macrophages and also by a broad variety of other cells including adipocytes.[11] Disturbance in the TNF-α metabolism may affect the onset of type 2 DM and the progression of the disease.[12],[13] The inflamed periodontium is highly vascular and may serve as an endocrine-like source for TNF-α and other inflammatory mediators.[14] Given the predominance of Gram-negative anaerobic bacteria in periodontal infection, the ulcerated pocket epithelium is thought to constitute a chronic source of systemic challenge from bacteria, bacterial products, and locally produced inflammatory mediators;[15] thus, it appears likely that periodontitis may influence circulating TNF-α levels and glycemic control.[16] Little is known, however, regarding the precise mechanism.[17] Long-term exposure of animals to TNF-α induces insulin resistance, whereas neutralization of TNF-α increases insulin sensitivity.[18] Many mechanisms may account for the metabolic effect of TNF-α, including the downregulation of genes related to normal insulin action and direct effects on insulin signaling, glucose transport, and pancreatic beta-cells.[19] Therefore, this mediator has detrimental effects on glucose metabolism.[17] TNF-α interferes with the insulin signaling pathway, particularly by inhibiting the tyrosine phosphorylation of the insulin receptor and insulin receptor substrate 1.[20] The lipolysis-stimulating effect of TNF-α leads to increased serum levels of free fatty acids, reducing insulin sensitivity, and TNF-α also has a direct inhibitory effect on insulin action in the liver.[21] These effects of TNF-α lead to reduced glucose uptake in muscle and to increased hepatic glucose production.[17] Obese mice with no functional genes for TNF-α or with mutant TNF-α receptors have been shown to remain insulin sensitive despite marked weight gain.[22] Thus, interfering with the TNF-α signaling pathway protects from obesity-induced insulin resistance.[17] The host response to Porphyromonas gingivalis infection in diabetic mice could be improved by TNF-α neutralization using an anti-TNF-α monoclonal antibody.[17] Anti-inflammatory pharmacological strategies that reduce the elevated levels of inflammatory mediators, such as TNF-α, may improve the host response to P. gingivalis infection and glycemic control.[17]

Periodontitis may initiate or propagate insulin resistance in a manner similar to that of obesity, by enhancing activation of the overall systemic immune response initiated by cytokines.[23],[24] Periodontitis may also contribute to the elevation of serum inflammatory mediators produced by monocytes. This may indicate an innate hyperresponsiveness of these monocytes to periodontal bacterial challenge.[16],[25] Periodontitis may also play a role through the translocation of Gram-negative species and their products from the periodontal biofilm into the circulation[14],[15] and through direct cytokinemia from the gingival crevicular fluid (i.e., translocation of cytokines from the periodontal space into the circulation).[16] Periodontal treatment that reduces periodontal inflammation may help to restore insulin sensitivity, thereby improving glycemic control.[26] Interventional studies showing a decrease in the level of systemic inflammatory markers and improved glycemic control following periodontal therapy would support such hypothesis. Studies of patients with both diabetes and periodontitis have shown that nonsurgical periodontal therapy with adjunctive local delivery of minocycline reduced circulating levels of TNF-α.[14],[27] In one of these studies, the reduction in serum levels of TNF-α was accompanied by, and strongly correlated with, a significant decrease in mean HbA1c values (from 8% to 7.1%).[27] Therefore, the purpose of this study was to investigate the effects of chronic periodontitis disease on the plasma levels of TNF-α and HbA1c % and metabolic control of diabetic type 2 Sudanese patients, in Khartoum State, Sudan.


  Materials and Methods Top


This is a cross-sectional case-control study, based on both clinical and laboratory investigations. It was approved by the Sudan Medical Specialization Board's Ethics Committee and Federal Ministry of Health Ethics Committee for Clinical Research. Forty diabetic type 2 male and female patients (DM 2) aged 30–70 years were recruited for this study. Data were collected over a period of 6 months from the outpatient clinics of three public diabetic centers in Khartoum State, Sudan (Jaber Aboalez Diabetic Centre [JADC], Diabetic and Endocrine Hospital [DEH], and Omdurman Military Hospital [OMH]). Patients were divided into two groups, DM 2 patients with chronic periodontitis (CP) as the study group (n = 23) and DM 2 patients without CP as a control group (n = 17). Before commencing the study, the research objectives were explained verbally to all participants, and thereafter, all of them were requested to sign an informed consent form for their participation in the clinical and laboratory investigations.

Inclusion criteria

Subjects who fulfilled the following inclusion criteria were invited to participate in the study including the willingness of the patient to participate in the study; diagnosed male and female patients with DM 2 at least 2 years earlier; all diabetic patients must be treated with oral antidiabetic agents. Patients with CP should have not received any periodontal therapy within the previous 3 months prior to the examination; had at least 12 teeth excluding third molars; a pocket depth (PD) of ≥4 mm in at least one region, and a clinical attachment loss (CAL) of ≥3 mm in at least one region at examination time. Data concerning the duration of DM and medications were retrieved from the medical records of the subjects at the beginning of the study.

Exclusion criteria

These included patients with cardiac problems, smokers, obesity, and acute infections. Patients who have hypertension, chronic microvascular and macrovascular complications, chronic obstructive pulmonary disease, renal or liver disease, malignity, a history of trauma up to 2 weeks earlier and the use of antibiotics in the previous 3 months, history of regular medication use (e.g., anti-inflammatories, steroids, immunosuppressant, antidepressant), HIV, pregnancy, and lactation.

Periodontal examinations

The probing depth (PPD) and CAL were assessed for all subjects using the same type of calibrated periodontal probe and mirror. Six sites were examined around each tooth (disto-buccal, buccal, mesio-buccal,-distolingual, lingual, and mesiolingual locations) by means of Michigan (O) William pattern probe for the whole mouth excluding third molars. Every patient was examined in the dental unit at hospital's dental clinic in JADC, OMH excluding one patient in DEH was examined in an ordinary chair. One examiner (the first author of the article) performed all clinical examinations. The diagnosis of gingivitis, mild, moderate, and sever periodontitis is made according to the criteria described by the American Academy of Periodontology.[28],[29]

Due to the site specificity and predilection of CP, the results were analyzed both by subjects and according to the specific site of the CP.[30] For example, the distobuccal site in every patient was dealt with as a separate parameter and the means of CAL distobuccal were calculated by the sum of CAL parameters at distobuccal sites in each patient divided by the number of remaining teeth; similarly, the other sites were calculated separately. The total-CAL means were calculated by the sum of the six parameters (distobuccal; buccal; mesiobuccal; distolingual; lingual, and mesiolingual) in each patient. This categorization was used because there is no consensus on a single accepted method to define CP in epidemiological studies.[5] Other justification for using this method was that the majority of subjects in the study group have localized CP. For this reason, loss of real measures could occur by the ordinary method.

Blood analysis

Glycated hemoglobin (HbA1c) and fasting blood glucose (FBS) levels were carried out for both the groups. Venous blood samples were collected in the morning before the periodontal examination from all participants after fasting overnight. 5 ml of blood were collected using sterile needles; 2.5 ml of blood were used for both HbA1c and FBS tests immediately in the Hospital laboratory. The other 2.5 ml of blood were collected in vacutainer plain collection tubes (KANG K JIAN, Sterile Vacuum Tube, China). The sample tubes were collected daily (in a specific container with tube carrier) and sent (with biohazard precautions) to the microbiology and immunology laboratory at the Institute of Endemic Diseases, Khartoum University, at which ELISA test for TNF-α was performed. Tubes were centrifuged according to the manufacturer's guidelines, then serum samples were collected from each tube separately, stored in cryovials tubes and labeled with patient's name and specific code number, and stored at −20°C till analyzed.

The HbA1c was estimated by (Labonno System, China), and FBS was determined using (Automatic Minbrai system, China). For TNF-α, the high-sensitivity sandwich enzyme-linked immunosorbent assay (ELISA) procedure was done according to the manufacturer's instructions (BD Biosciences, USA). 100 μl of capture antibody (antihuman TNF-α capture antibody) diluted in coating buffer (0.1 M carbonate/bicarbonate buffer 7.13 g NaHCO3 + 1.59 g Na2CO3 in 1 L/DW [pH 9.5]) was added to each well of the 96-well ELISA plates and incubated overnight at 4°C. After washing three times with a washing buffer (phosphate buffered saline with 0.05% Tween-20), 200 μl of assay diluent or blocking buffer (phosphate buffered saline with 10% fetal bovine serum [pH 7.0]) was added to each well and incubated for 1 h at room temperature. Following washing three times, 100 μl of standard and samples (which were prepared as recommended by the manufacture) were added into each well and incubated for 2 h at room temperature. After washing five times, 100 μl of working conjugate (detection antibody; biotinylated anti-human TNF-α detection antibody) plus enzyme reagent was added to each well and incubated for 1 h at room temperature. After seven washes, 100 μl of substrate solution tetramethylbenzidine and hydrogen peroxide (H2O2) was added to each well. The reaction mixture was then incubated for 30 min at room temperature in the dark. 50 μl of stop solution (2 N H2SO4) was then added to each well. Finally, the optical density was measured using microplate reader instrument (Thermo LabSystems, Finland) at 450 nm. The mean absorbance (O.D) for each set of duplicate standards, controls, and study was calculated. The cytokine concentration of the unknown was determined from the standard curve and then multiplied by the dilution factor.

Statistical analysis

Data collected from clinical and laboratory examinations were sorted in a data master sheet. The statistical software SPSS version 16.0 (SPSS Inc., Chicago, IL, USA) has been used for the analysis. Chi-square test and analysis of variance test were used in analysis and correlations, with the significance level set at P ≤ 0.05.


  Results Top


The demographic data of the forty patients who participated in the study were extracted from the patient's medical records of the three outpatient public diabetic centers in Khartoum state, Sudan. The patients were males and females in either group. There were 14 and 7 males and 9 and 10 females in the study group and the control group, respectively. The mean age was 53.7 ± 9.2 years for the study group patients and 49.5 ± 9.3 for the control group. For all patients, the mean number of years since diagnosis of diabetes was 5.9 ± 3.5 years. In all of the parameters, there were no differences between males and females. Therefore, males and females were grouped together in either group. The study group has been further subdivided into three subgroups according to the severity of the periodontitis: mild, moderate, and severe periodontitis.

[Table 1] shows no differences in the age, duration of DM, and number of missing teeth between study and control groups. Furthermore, no differences were observed between the control group and the groups of diabetic patients with mild, moderate, and severe chronic periodontitis in TNF-α and plaque index (PI). However, GI, HbA1c, and FBS show statistically significant differences (P ≤ 0.05) between the control group and the diabetic patients with mild and severe chronic periodontitis.
Table 1: Comparison between diabetes mellitus type 2 only patients (control group) with diabetes mellitus type 2 patients and mild, moderate, or severe chronic periodontitis

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A positive trend in the correlation between HbA1c and PI is shown in [Figure 1]. Similarly, positive correlation was observed between HbA1c and GI, T-PPD and T-CAL as shown in [Figure 2], [Figure 3], [Figure 4], respectively. We tested whether plasma TNF-α is associated with HbA1c and FBS where we found a trend for positive correlation with FBS (results not shown) and a negative correlation with HbA1c, as displayed in [Figure 5], while TNF-α was observed to have a trend for positive correlation with GI, as shown in [Figure 6]. In addition, it has been demonstrated that there were statistically significant differences in HbA1c % and FBS (mg/dl) between the study and control groups, as shown in [Figure 7] and [Figure 8], respectively.
Figure 1: A scatter plot of the study and control subjects shows a positive relation between HbA1c% and plaque index

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Figure 2: A scatter plot of the study and control subjects shows a positive relation between HbA1c% and gingival index

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Figure 3: A scatter plot of the study and control subjects shows a positive relation between HbA1c% and total periodontal pocket depth (mm)

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Figure 4: A scatter plot of the study and control subjects shows a positive relation between HbA1c % and clinical attachment loss (mm)

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Figure 5: A scatter plot of the study and control subjects shows a negative but no significant relation between HbA1c% and tumor necrosis factor-α (Pg/μl)

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Figure 6: A scatter plot of the study and control subjects shows a positive but no significant relation between tumor necrosis factor-a (Pg/μl) and gingival index

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Figure 7: Frequency distribution of the study and control group according to HbA1c %

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Figure 8: Frequency distribution of the study and control groups according to fasting blood sugar (mg/dl)

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  Discussion Top


Not like the majority of studies that correlate DM with chronic periodontitis, this study did not incorporate any kind of surgical or nonsurgical treatment interventions for subjects of the study. Still, we can compare our findings with their results, as they compare between DM 2 patients with chronic periodontitis and DM 2 patients after periodontal treatment, while in our study, we compare between DM 2 patients with chronic periodontitis and DM 2 patients without chronic periodontitis.

In this study, statistically significant differences were found between the study and control groups in HbA1c %. These results are in agreement with those from previous intervention studies that showed a decrease in HbA1c% in diabetic subjects following periodontal therapy.[31],[32],[33],[34] However, contradicting findings are reported.[21] They observed that the mean levels of HbA1c and FBS did not change for either group over time, whereas Joshipura et al. found no correlation between periodontitis and risk of diabetes.[35]

In addition, our observation of positive but no significant correlation between HbA1c and PI and the positive correlation between HbA1c and GI is in agreement with Kiran et al.,[32] who observed that the improvement in the HbA1c values was possibly due to the reduction in the GI and bleeding on probing value. Furthermore, this finding of positive correlation of HbA1c with T-PPD and T-CAL, in our study, is in agreement with those from previous studies in which periodontal therapy resulted in periodontal clinical benefits with a significant reduction in the glycemic control of diabetic subjects,[31],[32] while our results were in contrast with those from intervention studies,[36] in which no reduction was observed in metabolic control of diabetic subjects following periodontal therapy.

In this study, we found no statistically significant differences between the study and control groups in TNF-α, which is in accord with previous studies[37] where TNF-α levels were reported as not affected following periodontal treatment. While in the correlation of TNF-α with GI, there was a positive but no significant correlation. These findings are in agreement with a pervious study in which they stated that there is no direct relationship between TNF-α and the progress of both DM 2 and periodontitis.[38] In contrast, others have shown the association of TNF-α with more severe periodontitis in a large geriatric cohort,[39] which means periodontitis may influence circulating TNF-α levels. Other studies involving diabetic subjects have measured plasma TNF-α levels following treatment, suggesting that periodontal treatment may influence circulating TNF-α levels.[27] Another study reported a positive correlation between TNF-α and CAL, but no correlation between TNF-α and PPD, GI, or PI in DM2 patients with periodontitis.[16]

Our results of the negative correlation of plasma TNF-α with HbA1c were in contrast with a prior study, which found positive correlations between the two parameters.[30] However, the difference in FBS shown in this study between study and control groups supports the hypothesis that chronic periodontitis can affect glycemic control in DM2, which was in contrast with a prior study, which found that FBS did not change for either group over time.[30] Furthermore, the differences in HbA1c % and FBS between study and control groups support the hypothesis that chronic periodontitis can affect HbA1c level and thus has an impact on the metabolic control in type 2 DM patients. The outcomes of this study are in agreement with previous studies supporting an interaction between periodontal status and diabetic metabolic control.[40],[41] A different study in nondiabetic patients, comparing between patients with and others without chronic periodontitis, showed significantly higher serum levels of HbA1c in chronic periodontitis patients compared to periodontally healthy controls.[42]

In our study, we found that higher levels of TNF-α and FBS were shown in the mild periodontitis group than in moderate and severe groups. This finding was in contrast with a previous observation of subjects with mild disease, who had significantly lower TNF-α levels than those with moderate or severe periodontitis.[16] From these findings, we suggested that increased severity of chronic periodontitis in correlation with TNF-α is not necessarily by means of increased PPD or CAL in (mm) to confirm that chronic periodontitis affects plasma level of TNF-α. As there may be increased inflammatory response in mild cases of periodontitis, severe cases may show a low grade of inflammatory response as they could be in remission phase. Other assumption is that PD when increased in mm, this may form an isolated site for the periodontal pathogens to multiply without detectable stimulation of the immune system, while in the case of mild periodontitis, the initial phases of pocket formation can trigger the cell-mediated immune response that lead to release of pro-inflammatory cytokines such as TNF-α.

The limitations of our study were that, while the strict inclusion and exclusion criteria helped minimize confounding factors, it also limited the patient's sample to a relatively small size. CP is associated with increased TNF-α level, which can increase insulin resistance; some studies support and others contradict this hypothesis. These controversies need to be resolved in clinical trials. Especially, interventional studies are needed to determine the clinical significance of the relationship between periodontal inflammation and glycemic control.


  Conclusion Top


The results of the present study indicate that chronic periodontitis could affect HbA1c levels in type 2 DM patients. In addition, HbA1c was positively correlated with FBS and GI, while negatively correlated with TNF-α, which exhibited a higher level in mild periodontitis compared with severe and moderate periodontitis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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