Advances in Medical Sciences 59 (2014) 126–131
Contents lists available at ScienceDirect
Advances in Medical Sciences journal homepage: www.elsevier.com/locate/advms
Original Research Article
Association between type 1 diabetes and periodontal health Anna Popławska-Kita a,*, Katarzyna Siewko a, Piotr Szpak a, Beata Kro´l b, Beata Telejko a, Piotr Adrian Klimiuk c, Wanda Stokowska b, Maria Go´rska a, Małgorzata Szelachowska a a
Department of Endocrinology, Diabetology and Internal Diseases, Medical University of Bialystok, Bialystok, Poland Department of Restorative Dentistry, Medical University of Bialystok, Bialystok, Poland c Department of Rheumatology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 21 May 2013 Accepted 4 October 2013 Available online 15 March 2014
Purpose: We assessed periodontal status in patients with type 1 diabetes and healthy individuals in relation to their glycemic control, smoking and inflammatory biomarkers. Material/methods: Periodontal status was examined in 107 patients with diabetes and 40 controls, using Oral Hygiene Index (OHI), Community Periodontal Index (CPI) and tooth number. CPI values of 0–2 and 3–4 were classified as non-periodontitis and periodontitis, respectively. Blood samples were analyzed for glucose, HbA1c, CRP, fibrinogen, interleukin-1 and tumor necrosis factor-alpha (TNF-a). Results: Periodontitis was found in 15.0% of the controls and 57.9% of diabetic patients, including 40.0% of these with good metabolic control (GMC) and 59.5% of those with poor metabolic control (PMC). Severe periodontitis was more frequent in the PMC than in the GMC group and in the controls (26.0% vs. 20.0% vs. 5.0%). The PMC patients had lower number of sextants with CPI 0 and higher number of sextants with CPI 3 and CPI 4 as well as lower tooth number in comparison with the controls. The patients with periodontitis had higher TNF-a (p < 0.001) and OHI (p < 0.001) than the patients without periodontitis. The number of sextants with CPI 0 correlated negatively with fibrinogen and TNF-a levels, whereas the number of sextants with CPI 3 correlated positively with TNF-a and fasting glucose level. Conclusions: There is good evidence that type 1 diabetes increases the risk of periodontal disease. Our results suggest that poor metabolic control of diabetes together with smoking and inadequate oral hygiene increase the risk of severe periodontal destruction in patients with type 1 diabetes. ß 2014 Medical University of Bialystok. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
Keywords: Diabetes Hyperglycemia Periodontitis Cytokines
1. Introduction Type 1 diabetes is a systemic disease leading to abnormal fat, carbohydrate, and protein metabolism due to the absence of insulin. The main complications of diabetes affect organs and tissues rich in capillary vessels and these complications are secondary to the development of microangiopathy. Similar changes in small vessels can be found in the oral tissues [1]. Clinical studies suggest that diabetes is a risk factor for periodontal disease, pointing out that its prevalence, incidence and severity are higher in diabetic patients in comparison with healthy individuals [2–5]. Thus, many researchers consider periodontal disease as the sixth complication of diabetes [6–10]. So far most studies have focused on type 2 diabetes, probably because both diseases have historically tended to develop in patients in their 40s and 50s [10–
* Corresponding author at: Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, M. Sklodowskiej-Curie 24A, 15276 Bialystok, Poland. Tel.: +48 604 425 324; fax: +48 85 744 7611. E-mail address: [email protected] (A. Popławska-Kita).
12]. However, the evidence concerning an association between type 1 diabetes and periodontitis is controversial. Periodontal disease includes gingivitis (in which the inflammation is limited to the gingiva and is reversible with good oral hygiene) and periodontitis (in which the inflammation extends and results in tissue destruction and alveolar bone resorption). Periodontitis is one of the major chronic inflammatory diseases associated with increased production of numerous proinflammatory cytokines, which lead to the destruction of periodontal tissues and ultimately loss of teeth. Tissue destruction in periodontitis results in breakdown of the collagen fibers of the periodontal ligament, resulting in the formation of a periodontal pocket between the gingiva and the tooth [2,3]. There is emerging evidence of a two-way relationship between diabetes and periodontitis, with diabetes increasing the risk for periodontitis, and periodontal inflammation negatively affecting glycemic control and the progression of vascular complications [6,7,11–16]. The mechanisms by which diabetes may influence periodontal disease include vascular abnormalities, neutrophil dysfunction, abnormalities in collagen synthesis and genetic predisposition [17]. It has been shown that basement membrane
1896-1126/$ – see front matter ß 2014 Medical University of Bialystok. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved. http://dx.doi.org/10.1016/j.advms.2014.01.002
A. Popławska-Kita et al. / Advances in Medical Sciences 59 (2014) 126–131
proteins undergo non-enzymatic glycation when subjected to hyperglycemic condition [17]. Because of high vascularity of the inflamed periodontium, it may serve as a source of tumor necrosis factor-alpha (TNF-a) and other inflammatory mediators [18]. Therefore, it has been hypothesized that diabetes-induced exacerbation of immune response plays a crucial role in the pathogenesis if periodontal disease, as glucose-mediated advanced glycation end products can increase the production of proinflammatory cytokines and mediators, contributing to periodontal destruction [18]. The second hypothesis proposes that a fortuitous combination of genes (gene sets) could result in a host, who under the influence of a variety of environmental stressors could develop either periodontitis or diabetes, or both [19]. On the other hand prospective studies have proved that periodontal disease can increase the risk of the disturbances of glucose metabolism and the occurrence of diabetes, and that periodontopathies in patients with diabetes are associated with a worse metabolic control and higher risk of complications [20]. However, other studies do not confirm an apparent association between periodontitis and incident diabetes [21]. Furthermore, the effect of smoking on the periodontal tissues has been discussed for decades and it has been shown that smokers have more periodontal problems than non-smokers [22]. According to the World Health Organization tobacco smoking is a risk factor for the development of periodontal disease [23]. It was also reported that diabetic patients who smoke are 1.7 times more likely to develop periodontal disease than those who do not [23]. Since there is still some uncertainty concerning the role of hyperglycemia in the development of periodontal disease, in the present study we hypothesized that insufficient metabolic control not the presence of type 1 diabetes is the key factor leading to the development of periodonthopathy. To test this hypothesis, we assessed oral hygiene and periodontal status in healthy individuals and patients with type 1 diabetes in relation to (i) their glycemic control, (ii) smoking, and (iii) serum inflammatory biomarkers.
2. Material and methods The study group consisted of 107 patients with type 1 diabetes attending the outpatient diabetology clinic of the Medical University of Bialystok, and 40 healthy controls of a similar age and sex distribution, The exclusion criteria were as follows: the presence of systemic diseases other than type 1 diabetes that could influence the course of periodontal disease, intake of immunosuppressive drugs, steroids or non-steroidal anti-inflammatory drugs, pregnancy and fixed orthodontic appliances. All patients and controls gave their informed consent to participate in the study and the protocol was approved by the local ethics committee (Medical University of Bialystok). Complete clinical periodontal examinations included an assessment of Oral Hygiene Index (OHI) and Community Periodontal Index Treatment Needs (CPITN), as recommended by the World Health Organization. The mouth was divided into six sections, with index teeth 11, 16, 17, 26, 27, 31, 36, 37, 46 and 47, representing each section. The results of the examination of an index tooth represented periodontal health of each section. The highest community periodontal index (CPI) code was recorded in each segment (code 0: no signs of periodontal disease, code 1: gingival bleeding after gentle probing, code 2: supragingival or subgingival calculus, code 3: 4–5 mm deep pathologic pockets, code 4: 6 mm or deeper pathologic pockets). Periodontal status was divided into three categories according to the CPI code: 0–1, 2– 3 and 4. CPI values of 0–2 and 3–4 were classified as nonperiodontitis and periodontitis, respectively. All examinations were performed by an experienced dentist.
127
The oral hygiene condition was evaluated visually by examining all teeth present without using staining solution as: (1) good, plaque covering less than one-third of tooth surfaces; (2) fair, plaque covering more than one-third but less than two-thirds of tooth surfaces; and (3) poor, plaque covering more than two-thirds of tooth surfaces. The worst score was recorded as representative for the patient. Blood samples were collected from antecubital vein after an overnight fast, then clotted for 30 min and centrifuged for 10 min at 1000 g. Serum aliquots were frozen at 80 8C and stored until assayed. Plasma glucose concentration was measured using oxidase method (CORMAY, Poland). Glycated hemoglobin (HbA1c) was assayed by a high performance liquid chromatography technique (BIO-RAD Laboratories, Germany). Total cholesterol, HDL-cholesterol and triglyceride concentrations were measured by enzymatic methods (ANALCO-GBG, Poland). LDL-cholesterol concentrations were calculated using the Friedewald equation. Serum TNF-a level was measured by commercial ELISA (Bender MedSystems, Vienna, Austria). The sensitivity of the assay was 0.5 pg/ml. C-reactive protein (CRP) was measured by Sandwich Enzyme Immunoassay (DSL-10-42100 Active, DSL, Webster, TX, USA). Interleukin-1 (IL-1) levels were measured by a high sensitivity multiplex ELISA (R&D systems, Minneapolis, MN) in duplicate according to the manufacturer’s protocol in 2010. Study participants with type 1 diabetes were divided into two groups, according to their HbA1c value: good metabolic control group (GMC) with HbA1c 6.5% (22 patients, 14F/4M), and poor metabolic control group (PMC) with HbA1c >6.5% (85 patients; 35F/50M). 2.1. Statistical analysis The data were analyzed by the STATISTICA 10.0 for Windows Software (StatSoft Inc., Tulsa, USA). Before analysis, data were tested for normality of distribution using the Shapiro–Wilk test. Differences between the groups were compared by Student’s t-test or Mann–Whitney U test, as appropriate, and relationships between variables were tested by Spearman’s rank correlations. p value less than 0.05 was regarded as statistically significant. 3. Results In the present study, periodontitis was found in 15.0% of the controls and 57.9% of diabetic patients, including 40.0% of these with good metabolic control (HbA1c 6.5%) and 59.5% of those with poor metabolic control. The clinical and biochemical characteristics of the groups with good and poor metabolic control were shown in Table 1. The patients with good metabolic control had the lowest values of systolic and diastolic blood pressure, as well as the lowest concentration of triglycerides, CRP and TNF-a among all groups studied. In contrast, type 1 diabetes patients with poor metabolic control had significantly higher HbA1c and fasting glucose level (p < 0.01) (as expected), and higher CRP concentration than the values observed in the other groups (Table 1). The PMC group had also significantly lower number of teeth (p < 0.05), lower number of sextants with CPI 0 (p < 0.001), and significantly higher number of sextants with CPI 3 (p < 0.001) and CPI 4 (p < 0.01) in comparison with the controls, whereas in the GMC group the number of teeth and the number of sextants with each CPI code were comparable with the numbers noted in the healthy individuals (Table 1). The values of OHI were also higher in the PMC group as compared with the GMC group and the controls, but the differences were not significant (Table 1). As it was shown in Fig. 1, the majority of healthy controls had CPI code of 0 and 1. The patients with type 1 diabetes from GMC group had mostly CPI 1 and CPI 2 code, but the percentages of the subject with CPI code of
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A. Popławska-Kita et al. / Advances in Medical Sciences 59 (2014) 126–131
Table 1 The clinical and biochemical characteristics of the groups of type 1 diabetic patients with good and poor metabolic control and control subjects.
Age (years) Weight (kg) Systolic pressure (mmHg) Diastolic pressure (mmHg) HbA1c (%) Fasting glucose (mg/dl) Total cholesterol (mg/dl) HDL-cholesterol (mg/dl) LDL-cholesterol (mg/dl) Triglycerides (mg/dl) CRP (ng/ml) IL-1 (ng/ml) TNF-a (pg/ml) Teeth number OHI CPI 0 CPI 1 CPI 2 CPI 3 CPI 4
Type 1 diabetes Good metabolic control HbA1c 6.5% n = 22 (14F/4M)
Type 1 diabetes Poor metabolic control HbA1c >6.5% n = 85 (35F/50M)
Control group n = 40
34.8 10.9 70.2 14.0 117.5 8.6* 76.0 7.0a 6.0 0.6** 126.0 60.9* 159.9 29.2 56.6 9.6 91.6 24.7 59.3 18.3*b 4.8 1.2** 0.7 0.5 1.0 0.6b 26.1 5.4 1.1 0.5 1.5 2.1 2.1 1.5 1.5 1.4 0.6 0.9 0.3 0.6
37.9 3.7 70.8 12.6 126.3 12.8 80.75 8.9 9.8 2.4 172.83 72.4b 180.8 0.43 54.3 21.3 104.0 35.7 119.7 109.3 10.9 23.2 0.6 0.8 1.25 1.06a 21.8 9.1a 1.6 0.8 1.3 1.8 c 1.5 1.4 1.2 1.4 0.9 1.3c 0.5 1.2b
32.3 1.0 78.1 22.7 128.6 16.4 84.5 12.3 – 86.9 7.0 178.8 3.8 50.5 14.9 106.8 26.4 111.6 74.1 7.1 8.5 0.5 0.9 1.5 1.6 24.7 8.4 1.0 0.7 2.8 2.2 1.7 1.5 0.8 1.4 0.2 0.6 0.0 0.2
Data are shown as mean SD. OHI – oral hygiene index; CPI – community periodontal index. Differences between diabetic patients with control group at ap < 0.05, bp < 0.01, cp < 0.001. Differences between diabetic patients with GMC and PMC at *p < 0.05, **p < 0.01, ***p < 0.001.
2, 3 and 4 were much higher in this group than in the controls. As expected, the highest percentages of CPI 3 and CPI 4 codes were observed in the patients from PMC group. The clinical and biochemical characteristics of the type 1 diabetic patients and healthy controls with and without periodontitis were summarized in Table 2. The patients with type 1 diabetes with periodontitis were much older (p < 0.001), had higher body weight (p < 0.05), higher fibrinogen (p < 0.01) and TNF-a (p < 0.001) concentrations, as well as higher OHI (p < 0.001) and lower teeth number (p < 0.001) in comparison with the patients with type 1 diabetes without periodontitis. The subjects without diabetes but with periodontitis were older, had higher cholesterol and triglyceride concentrations and markedly higher OHI, as well as lower number of teeth than had the subject without periodontitis (Table 2).
Metabolic parameters and the results of periodontal examinations of the patients with diabetes depending on smoking status, are shown in Table 3. Current smokers had significantly higher HbA1c (p < 0.01), fasting glucose (p < 0.05), total and LDLcholesterol (p < 0.05 and p < 0.01, respectively), and triglyceride (p < 0.05) levels, as well as lower teeth number (p < 0.05) than had the non-smokers. Mean OHI value was also higher in the smokers than in the non-smokers, but the difference was not significant. In the patients with type 1 diabetes, OHI correlated positively with blood pressure and serum TNF-a level, and negatively with teeth number (Table 4). There was also a negative correlation between OHI and the number of sextants with CPI 1 code, and positive correlations between OHI and the number of sextants with CPI 2 and CPI 3 codes. The number of teeth correlated positively with the number of sextants with CPI 0 and CPI 1 codes, and negatively with the number of sextants with CPI 3 and CPI 4 codes. The number of sextants with CPI 0 correlated negatively with fibrinogen and TNF-a levels, whereas the number of sextants with CPI 3 correlated positively with TNF-a and fasting glucose level. There was also a positive correlation between the number of sextants with CPI 4 and systolic blood pressure (Table 4). 4. Discussion
Fig. 1. The percentage of Community Periodontal Index (CPI) 0, CPI 1, CPI 2, CPI 3 and CPI 4 in type 1 diabetic patients with good and poor metabolic control, and healthy controls.
In the present study periodontitis was observed in 57.9% of patients with type 1 diabetes and in 15.0% of the healthy controls. Our results are consistent with other studies showing that the prevalence and severity of periodontal diseases are higher in diabetic patients in comparison with healthy individuals [2– 5,24,25]. Mealey and Oates [14] concluded that the risk of periodontitis is increased by approximately threefold in diabetic as compared with non-diabetic patients. However, other authors reported no significant difference in the CPI index between diabetic and non-diabetic groups [26]. These conflicting results might be explained by the differences in the populations studied (i.e. various ethnicity, gender, and age) and the level of metabolic control. It is worth noting that periodontitis is one of the most frequent chronic inflammatory disease in the general population [2]. Awuti et al. [27] demonstrated that in non-diabetic individuals the prevalence
A. Popławska-Kita et al. / Advances in Medical Sciences 59 (2014) 126–131
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Table 2 The clinical and biochemical characteristics of patients with type 1 diabetes and healthy controls with and without periodontitis.
Age (years) Weight (kg) Systolic pressure (mmHg) Diastolic pressure (mmHg) HbA1c (%) Fasting glucose (mg/dl) Total cholesterol (mg/dl) HDL-cholesterol (mg/dl) LDL-cholesterol (mg/dl) Triglycerides (mg/dl) Fibrinogen (ng/dl) CRP (ng/ml) IL-1 (ng/ml) TNFa (pg/ml) Teeth number OHI
Type 1 diabetes No-periodontitis n = 45
Type 1 diabetes With periodontitis n = 62
Control group No-periodontitis n = 34
Control group With periodontitis n=6
30.7 11.1*** 68.1 11.7* 123.1 12.0 79.3 7.9 9.2 2.6 160.0 71.02 178.1 58.3 51.7 15.5 101.9 41.4 128.8 45.7 300.4 85.3** 5.3 1.8 0.6 0.9 0.8 0.5***1 27.4 4.1*** 1.0 0.9***
42.6 12.7a 72.7 13.2 127.2 13.1 81.0 9.5 9.4 2.6 172.0 69.1 178.9 41.3 56.5 23.2 103.2 29.8 101.5 59.3 371.3 114.7 13.3 27.3 02 02a 1.6 1.2 18.6 9.6 2.1 0.7
29.4 9.5 79.3 23.9 126.4 14.8 83.3 12.0 n/e 86.8 17.9 176.5 31.8 49.1 14.2 106.8 24.1 101.4 54.5 342.9 86.3 5.6 2.0 0.5 0.5 1.7 1.7 25.7 8.0 0.8 0.6
48.3 2.1 71.5 14.8 141.0 20.7 891.1 13.4 n/e 87.5 4.9 189.8 46.9 58.0 18.3 106.8 41.6 172.8 140.1 347.8 133.4 5.9 1.7 0.7 1.0 0.8 0.5 19.3 8.8 2.0 0.5
Data are shown as mean SD. OHI – oral hygiene index; CPI – community periodontal index; n/e – not examined. Differences between type 1 diabetics with periodontitis and control group with periodontitis at ap < 0.05. Differences between type 1 diabetics with periodontitis and non-periodontitis at *p < 0.05, **p < 0.01, ***p < 0.001. Differences between type 1 diabetics non-periodontitis and control group non-periodontitis at 1p < 0.05, 2p < 0.01.
of mild, moderate and severe periodontitis was 28.9%, 10.2% and 8.0%, respectively. However, the most important risk factor for severe periodontitis seems to be hyperglycemia. For example, in the US National Health and Nutrition Examination Survey (NHANES) III, adults with HbA1c >9% had significantly higher prevalence of severe periodontitis than those without diabetes, after controlling for age, ethnicity, education, sex and smoking [28]. Hodge et al. [29] also reported that the prevalence of severe periodontitis was higher in poorly controlled patients with type 1 diabetes (27.2%) than in the whole group of diabetic subjects (24.1%) and the healthy controls (20.5%). In our study the presence of periodontitis was confirmed in 59.5% of the diabetic patients with PMC and in 40.0% of these with good metabolic control (HbA1c 6.5%). The prevalence of severe periodontitis (CPI 4) was also higher in the diabetic group with poor metabolic control (26.0%) than in the GMC patients (20.0%), and much higher than in the controls (5.0%). Moreover, the Table 3 Clinical and biochemical characteristics and the results of periodontal examination in current smokers and non-smokers.
Weight (kg) Systolic pressure (mmHg) Diastolic pressure (mmHg) HbA1c (%) Fasting glucose (mg/dl) Total cholesterol (mg/dl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mg/dl) CRP (ng/ml) IL-1 (ng/ml) TNF-a (pg/ml) Teeth number OHI CPI 0 CPI 1 CPI 2 CPI 3 CPI 4
Type 1 diabetes Non-smokers n = 75
Type 1 diabetes Smokers n = 32
70.1 13.6 125.3 12.5 80.1 7.7 8.9 2.5b 156.5 68.4a 171.1 40.5a 56.6 21.6 95.8 29.3b 98.5 84.5a 12.1 5.7 0.5 0.4 1.1 0.7 25.5 6.2a 1.5 0.8 1.5 1.9 1.5 1.3 1.2 1.4 0.8 1.2 0.6 1.2
72.5 10.1 125.3 13.6 80.6 11.6 10.6 2.4 199.3 77.3 197.8 62.8 49.0 15.8 120.4 41.8 150.8 40.5 6.1 5.5 0.8 1.3 1.7 1.1 21.2 9.4 1.8 0.8 0.8 1.5 1.8 1.5 1.4 1.4 1.2 1.2 0.4 0.5
Data are shown as mean SD. OHI – oral hygiene index; CPI – community periodontal index; RP – blood pressure. Differences between smokers and non-smokers are significant at ap < 0.05, bp < 0.01.
number of sextants with CPI 3 correlated positively with fasting glucose level. However, no correlation between HbA1c and the results of periodontal examination was observed in the present study. This was in agreement with the results obtained by Alpagot et al. [30], who also found no association between HbA1c and clinical signs of periodontal disease. On the other hand, in the present study the results of periodontal examination of the patients with GMC were comparable with these of the healthy subjects, indicating that good metabolic control is a key factor protecting diabetic patients from the development of periodontal disease. Although the cross-sectional design of our study limits any speculations about a causal relationship between type 1 diabetes and periodontitis, the possibility of a two-way association between these two diseases, with diabetes increasing the risk of periodontal disease and periodontal disease worsening glycemic control, cannot be ruled of. This hypothesis is strongly supported by the observation of Grossi et al. [24], who reported that the treatment of periodontal disease in diabetic patients reduces glycated hemoglobin. It is also worth noting that in the present study patients with type 1 diabetes and periodontitis were much older and had higher body weight than the patients without periodontitis, however lipid levels did not differ significantly between these two Table 4 Spearman’s correlation coefficients of the results of periodontal examination and other variables studied in patients with type 1 diabetes. Variable OHI/systolic BP OHI/diastolic BP OHI/TNF-a OHI/teeth number CPI 0/fibrinogen CPI 0/TNF-a CPI 0/teeth number CPI 1/teeth number CPI 1/OHI CPI 2/OHI CPI 3/TNF-a CPI 3/fasting/glucose CPI 3/teeth number CPI 3/OHI CPI 4/systolic BP CPI 4/teeth number CPI 4/OHI
R
p 0.256 0.222 0.252 0.392 0.272 0.233 0.378 0.408 0.451 0.336 0.348 0.217 0.282 0.518 0.219 0.456 0.498
Contents lists available at ScienceDirect
Advances in Medical Sciences journal homepage: www.elsevier.com/locate/advms
Original Research Article
Association between type 1 diabetes and periodontal health Anna Popławska-Kita a,*, Katarzyna Siewko a, Piotr Szpak a, Beata Kro´l b, Beata Telejko a, Piotr Adrian Klimiuk c, Wanda Stokowska b, Maria Go´rska a, Małgorzata Szelachowska a a
Department of Endocrinology, Diabetology and Internal Diseases, Medical University of Bialystok, Bialystok, Poland Department of Restorative Dentistry, Medical University of Bialystok, Bialystok, Poland c Department of Rheumatology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 21 May 2013 Accepted 4 October 2013 Available online 15 March 2014
Purpose: We assessed periodontal status in patients with type 1 diabetes and healthy individuals in relation to their glycemic control, smoking and inflammatory biomarkers. Material/methods: Periodontal status was examined in 107 patients with diabetes and 40 controls, using Oral Hygiene Index (OHI), Community Periodontal Index (CPI) and tooth number. CPI values of 0–2 and 3–4 were classified as non-periodontitis and periodontitis, respectively. Blood samples were analyzed for glucose, HbA1c, CRP, fibrinogen, interleukin-1 and tumor necrosis factor-alpha (TNF-a). Results: Periodontitis was found in 15.0% of the controls and 57.9% of diabetic patients, including 40.0% of these with good metabolic control (GMC) and 59.5% of those with poor metabolic control (PMC). Severe periodontitis was more frequent in the PMC than in the GMC group and in the controls (26.0% vs. 20.0% vs. 5.0%). The PMC patients had lower number of sextants with CPI 0 and higher number of sextants with CPI 3 and CPI 4 as well as lower tooth number in comparison with the controls. The patients with periodontitis had higher TNF-a (p < 0.001) and OHI (p < 0.001) than the patients without periodontitis. The number of sextants with CPI 0 correlated negatively with fibrinogen and TNF-a levels, whereas the number of sextants with CPI 3 correlated positively with TNF-a and fasting glucose level. Conclusions: There is good evidence that type 1 diabetes increases the risk of periodontal disease. Our results suggest that poor metabolic control of diabetes together with smoking and inadequate oral hygiene increase the risk of severe periodontal destruction in patients with type 1 diabetes. ß 2014 Medical University of Bialystok. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
Keywords: Diabetes Hyperglycemia Periodontitis Cytokines
1. Introduction Type 1 diabetes is a systemic disease leading to abnormal fat, carbohydrate, and protein metabolism due to the absence of insulin. The main complications of diabetes affect organs and tissues rich in capillary vessels and these complications are secondary to the development of microangiopathy. Similar changes in small vessels can be found in the oral tissues [1]. Clinical studies suggest that diabetes is a risk factor for periodontal disease, pointing out that its prevalence, incidence and severity are higher in diabetic patients in comparison with healthy individuals [2–5]. Thus, many researchers consider periodontal disease as the sixth complication of diabetes [6–10]. So far most studies have focused on type 2 diabetes, probably because both diseases have historically tended to develop in patients in their 40s and 50s [10–
* Corresponding author at: Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, M. Sklodowskiej-Curie 24A, 15276 Bialystok, Poland. Tel.: +48 604 425 324; fax: +48 85 744 7611. E-mail address: [email protected] (A. Popławska-Kita).
12]. However, the evidence concerning an association between type 1 diabetes and periodontitis is controversial. Periodontal disease includes gingivitis (in which the inflammation is limited to the gingiva and is reversible with good oral hygiene) and periodontitis (in which the inflammation extends and results in tissue destruction and alveolar bone resorption). Periodontitis is one of the major chronic inflammatory diseases associated with increased production of numerous proinflammatory cytokines, which lead to the destruction of periodontal tissues and ultimately loss of teeth. Tissue destruction in periodontitis results in breakdown of the collagen fibers of the periodontal ligament, resulting in the formation of a periodontal pocket between the gingiva and the tooth [2,3]. There is emerging evidence of a two-way relationship between diabetes and periodontitis, with diabetes increasing the risk for periodontitis, and periodontal inflammation negatively affecting glycemic control and the progression of vascular complications [6,7,11–16]. The mechanisms by which diabetes may influence periodontal disease include vascular abnormalities, neutrophil dysfunction, abnormalities in collagen synthesis and genetic predisposition [17]. It has been shown that basement membrane
1896-1126/$ – see front matter ß 2014 Medical University of Bialystok. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved. http://dx.doi.org/10.1016/j.advms.2014.01.002
A. Popławska-Kita et al. / Advances in Medical Sciences 59 (2014) 126–131
proteins undergo non-enzymatic glycation when subjected to hyperglycemic condition [17]. Because of high vascularity of the inflamed periodontium, it may serve as a source of tumor necrosis factor-alpha (TNF-a) and other inflammatory mediators [18]. Therefore, it has been hypothesized that diabetes-induced exacerbation of immune response plays a crucial role in the pathogenesis if periodontal disease, as glucose-mediated advanced glycation end products can increase the production of proinflammatory cytokines and mediators, contributing to periodontal destruction [18]. The second hypothesis proposes that a fortuitous combination of genes (gene sets) could result in a host, who under the influence of a variety of environmental stressors could develop either periodontitis or diabetes, or both [19]. On the other hand prospective studies have proved that periodontal disease can increase the risk of the disturbances of glucose metabolism and the occurrence of diabetes, and that periodontopathies in patients with diabetes are associated with a worse metabolic control and higher risk of complications [20]. However, other studies do not confirm an apparent association between periodontitis and incident diabetes [21]. Furthermore, the effect of smoking on the periodontal tissues has been discussed for decades and it has been shown that smokers have more periodontal problems than non-smokers [22]. According to the World Health Organization tobacco smoking is a risk factor for the development of periodontal disease [23]. It was also reported that diabetic patients who smoke are 1.7 times more likely to develop periodontal disease than those who do not [23]. Since there is still some uncertainty concerning the role of hyperglycemia in the development of periodontal disease, in the present study we hypothesized that insufficient metabolic control not the presence of type 1 diabetes is the key factor leading to the development of periodonthopathy. To test this hypothesis, we assessed oral hygiene and periodontal status in healthy individuals and patients with type 1 diabetes in relation to (i) their glycemic control, (ii) smoking, and (iii) serum inflammatory biomarkers.
2. Material and methods The study group consisted of 107 patients with type 1 diabetes attending the outpatient diabetology clinic of the Medical University of Bialystok, and 40 healthy controls of a similar age and sex distribution, The exclusion criteria were as follows: the presence of systemic diseases other than type 1 diabetes that could influence the course of periodontal disease, intake of immunosuppressive drugs, steroids or non-steroidal anti-inflammatory drugs, pregnancy and fixed orthodontic appliances. All patients and controls gave their informed consent to participate in the study and the protocol was approved by the local ethics committee (Medical University of Bialystok). Complete clinical periodontal examinations included an assessment of Oral Hygiene Index (OHI) and Community Periodontal Index Treatment Needs (CPITN), as recommended by the World Health Organization. The mouth was divided into six sections, with index teeth 11, 16, 17, 26, 27, 31, 36, 37, 46 and 47, representing each section. The results of the examination of an index tooth represented periodontal health of each section. The highest community periodontal index (CPI) code was recorded in each segment (code 0: no signs of periodontal disease, code 1: gingival bleeding after gentle probing, code 2: supragingival or subgingival calculus, code 3: 4–5 mm deep pathologic pockets, code 4: 6 mm or deeper pathologic pockets). Periodontal status was divided into three categories according to the CPI code: 0–1, 2– 3 and 4. CPI values of 0–2 and 3–4 were classified as nonperiodontitis and periodontitis, respectively. All examinations were performed by an experienced dentist.
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The oral hygiene condition was evaluated visually by examining all teeth present without using staining solution as: (1) good, plaque covering less than one-third of tooth surfaces; (2) fair, plaque covering more than one-third but less than two-thirds of tooth surfaces; and (3) poor, plaque covering more than two-thirds of tooth surfaces. The worst score was recorded as representative for the patient. Blood samples were collected from antecubital vein after an overnight fast, then clotted for 30 min and centrifuged for 10 min at 1000 g. Serum aliquots were frozen at 80 8C and stored until assayed. Plasma glucose concentration was measured using oxidase method (CORMAY, Poland). Glycated hemoglobin (HbA1c) was assayed by a high performance liquid chromatography technique (BIO-RAD Laboratories, Germany). Total cholesterol, HDL-cholesterol and triglyceride concentrations were measured by enzymatic methods (ANALCO-GBG, Poland). LDL-cholesterol concentrations were calculated using the Friedewald equation. Serum TNF-a level was measured by commercial ELISA (Bender MedSystems, Vienna, Austria). The sensitivity of the assay was 0.5 pg/ml. C-reactive protein (CRP) was measured by Sandwich Enzyme Immunoassay (DSL-10-42100 Active, DSL, Webster, TX, USA). Interleukin-1 (IL-1) levels were measured by a high sensitivity multiplex ELISA (R&D systems, Minneapolis, MN) in duplicate according to the manufacturer’s protocol in 2010. Study participants with type 1 diabetes were divided into two groups, according to their HbA1c value: good metabolic control group (GMC) with HbA1c 6.5% (22 patients, 14F/4M), and poor metabolic control group (PMC) with HbA1c >6.5% (85 patients; 35F/50M). 2.1. Statistical analysis The data were analyzed by the STATISTICA 10.0 for Windows Software (StatSoft Inc., Tulsa, USA). Before analysis, data were tested for normality of distribution using the Shapiro–Wilk test. Differences between the groups were compared by Student’s t-test or Mann–Whitney U test, as appropriate, and relationships between variables were tested by Spearman’s rank correlations. p value less than 0.05 was regarded as statistically significant. 3. Results In the present study, periodontitis was found in 15.0% of the controls and 57.9% of diabetic patients, including 40.0% of these with good metabolic control (HbA1c 6.5%) and 59.5% of those with poor metabolic control. The clinical and biochemical characteristics of the groups with good and poor metabolic control were shown in Table 1. The patients with good metabolic control had the lowest values of systolic and diastolic blood pressure, as well as the lowest concentration of triglycerides, CRP and TNF-a among all groups studied. In contrast, type 1 diabetes patients with poor metabolic control had significantly higher HbA1c and fasting glucose level (p < 0.01) (as expected), and higher CRP concentration than the values observed in the other groups (Table 1). The PMC group had also significantly lower number of teeth (p < 0.05), lower number of sextants with CPI 0 (p < 0.001), and significantly higher number of sextants with CPI 3 (p < 0.001) and CPI 4 (p < 0.01) in comparison with the controls, whereas in the GMC group the number of teeth and the number of sextants with each CPI code were comparable with the numbers noted in the healthy individuals (Table 1). The values of OHI were also higher in the PMC group as compared with the GMC group and the controls, but the differences were not significant (Table 1). As it was shown in Fig. 1, the majority of healthy controls had CPI code of 0 and 1. The patients with type 1 diabetes from GMC group had mostly CPI 1 and CPI 2 code, but the percentages of the subject with CPI code of
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Table 1 The clinical and biochemical characteristics of the groups of type 1 diabetic patients with good and poor metabolic control and control subjects.
Age (years) Weight (kg) Systolic pressure (mmHg) Diastolic pressure (mmHg) HbA1c (%) Fasting glucose (mg/dl) Total cholesterol (mg/dl) HDL-cholesterol (mg/dl) LDL-cholesterol (mg/dl) Triglycerides (mg/dl) CRP (ng/ml) IL-1 (ng/ml) TNF-a (pg/ml) Teeth number OHI CPI 0 CPI 1 CPI 2 CPI 3 CPI 4
Type 1 diabetes Good metabolic control HbA1c 6.5% n = 22 (14F/4M)
Type 1 diabetes Poor metabolic control HbA1c >6.5% n = 85 (35F/50M)
Control group n = 40
34.8 10.9 70.2 14.0 117.5 8.6* 76.0 7.0a 6.0 0.6** 126.0 60.9* 159.9 29.2 56.6 9.6 91.6 24.7 59.3 18.3*b 4.8 1.2** 0.7 0.5 1.0 0.6b 26.1 5.4 1.1 0.5 1.5 2.1 2.1 1.5 1.5 1.4 0.6 0.9 0.3 0.6
37.9 3.7 70.8 12.6 126.3 12.8 80.75 8.9 9.8 2.4 172.83 72.4b 180.8 0.43 54.3 21.3 104.0 35.7 119.7 109.3 10.9 23.2 0.6 0.8 1.25 1.06a 21.8 9.1a 1.6 0.8 1.3 1.8 c 1.5 1.4 1.2 1.4 0.9 1.3c 0.5 1.2b
32.3 1.0 78.1 22.7 128.6 16.4 84.5 12.3 – 86.9 7.0 178.8 3.8 50.5 14.9 106.8 26.4 111.6 74.1 7.1 8.5 0.5 0.9 1.5 1.6 24.7 8.4 1.0 0.7 2.8 2.2 1.7 1.5 0.8 1.4 0.2 0.6 0.0 0.2
Data are shown as mean SD. OHI – oral hygiene index; CPI – community periodontal index. Differences between diabetic patients with control group at ap < 0.05, bp < 0.01, cp < 0.001. Differences between diabetic patients with GMC and PMC at *p < 0.05, **p < 0.01, ***p < 0.001.
2, 3 and 4 were much higher in this group than in the controls. As expected, the highest percentages of CPI 3 and CPI 4 codes were observed in the patients from PMC group. The clinical and biochemical characteristics of the type 1 diabetic patients and healthy controls with and without periodontitis were summarized in Table 2. The patients with type 1 diabetes with periodontitis were much older (p < 0.001), had higher body weight (p < 0.05), higher fibrinogen (p < 0.01) and TNF-a (p < 0.001) concentrations, as well as higher OHI (p < 0.001) and lower teeth number (p < 0.001) in comparison with the patients with type 1 diabetes without periodontitis. The subjects without diabetes but with periodontitis were older, had higher cholesterol and triglyceride concentrations and markedly higher OHI, as well as lower number of teeth than had the subject without periodontitis (Table 2).
Metabolic parameters and the results of periodontal examinations of the patients with diabetes depending on smoking status, are shown in Table 3. Current smokers had significantly higher HbA1c (p < 0.01), fasting glucose (p < 0.05), total and LDLcholesterol (p < 0.05 and p < 0.01, respectively), and triglyceride (p < 0.05) levels, as well as lower teeth number (p < 0.05) than had the non-smokers. Mean OHI value was also higher in the smokers than in the non-smokers, but the difference was not significant. In the patients with type 1 diabetes, OHI correlated positively with blood pressure and serum TNF-a level, and negatively with teeth number (Table 4). There was also a negative correlation between OHI and the number of sextants with CPI 1 code, and positive correlations between OHI and the number of sextants with CPI 2 and CPI 3 codes. The number of teeth correlated positively with the number of sextants with CPI 0 and CPI 1 codes, and negatively with the number of sextants with CPI 3 and CPI 4 codes. The number of sextants with CPI 0 correlated negatively with fibrinogen and TNF-a levels, whereas the number of sextants with CPI 3 correlated positively with TNF-a and fasting glucose level. There was also a positive correlation between the number of sextants with CPI 4 and systolic blood pressure (Table 4). 4. Discussion
Fig. 1. The percentage of Community Periodontal Index (CPI) 0, CPI 1, CPI 2, CPI 3 and CPI 4 in type 1 diabetic patients with good and poor metabolic control, and healthy controls.
In the present study periodontitis was observed in 57.9% of patients with type 1 diabetes and in 15.0% of the healthy controls. Our results are consistent with other studies showing that the prevalence and severity of periodontal diseases are higher in diabetic patients in comparison with healthy individuals [2– 5,24,25]. Mealey and Oates [14] concluded that the risk of periodontitis is increased by approximately threefold in diabetic as compared with non-diabetic patients. However, other authors reported no significant difference in the CPI index between diabetic and non-diabetic groups [26]. These conflicting results might be explained by the differences in the populations studied (i.e. various ethnicity, gender, and age) and the level of metabolic control. It is worth noting that periodontitis is one of the most frequent chronic inflammatory disease in the general population [2]. Awuti et al. [27] demonstrated that in non-diabetic individuals the prevalence
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Table 2 The clinical and biochemical characteristics of patients with type 1 diabetes and healthy controls with and without periodontitis.
Age (years) Weight (kg) Systolic pressure (mmHg) Diastolic pressure (mmHg) HbA1c (%) Fasting glucose (mg/dl) Total cholesterol (mg/dl) HDL-cholesterol (mg/dl) LDL-cholesterol (mg/dl) Triglycerides (mg/dl) Fibrinogen (ng/dl) CRP (ng/ml) IL-1 (ng/ml) TNFa (pg/ml) Teeth number OHI
Type 1 diabetes No-periodontitis n = 45
Type 1 diabetes With periodontitis n = 62
Control group No-periodontitis n = 34
Control group With periodontitis n=6
30.7 11.1*** 68.1 11.7* 123.1 12.0 79.3 7.9 9.2 2.6 160.0 71.02 178.1 58.3 51.7 15.5 101.9 41.4 128.8 45.7 300.4 85.3** 5.3 1.8 0.6 0.9 0.8 0.5***1 27.4 4.1*** 1.0 0.9***
42.6 12.7a 72.7 13.2 127.2 13.1 81.0 9.5 9.4 2.6 172.0 69.1 178.9 41.3 56.5 23.2 103.2 29.8 101.5 59.3 371.3 114.7 13.3 27.3 02 02a 1.6 1.2 18.6 9.6 2.1 0.7
29.4 9.5 79.3 23.9 126.4 14.8 83.3 12.0 n/e 86.8 17.9 176.5 31.8 49.1 14.2 106.8 24.1 101.4 54.5 342.9 86.3 5.6 2.0 0.5 0.5 1.7 1.7 25.7 8.0 0.8 0.6
48.3 2.1 71.5 14.8 141.0 20.7 891.1 13.4 n/e 87.5 4.9 189.8 46.9 58.0 18.3 106.8 41.6 172.8 140.1 347.8 133.4 5.9 1.7 0.7 1.0 0.8 0.5 19.3 8.8 2.0 0.5
Data are shown as mean SD. OHI – oral hygiene index; CPI – community periodontal index; n/e – not examined. Differences between type 1 diabetics with periodontitis and control group with periodontitis at ap < 0.05. Differences between type 1 diabetics with periodontitis and non-periodontitis at *p < 0.05, **p < 0.01, ***p < 0.001. Differences between type 1 diabetics non-periodontitis and control group non-periodontitis at 1p < 0.05, 2p < 0.01.
of mild, moderate and severe periodontitis was 28.9%, 10.2% and 8.0%, respectively. However, the most important risk factor for severe periodontitis seems to be hyperglycemia. For example, in the US National Health and Nutrition Examination Survey (NHANES) III, adults with HbA1c >9% had significantly higher prevalence of severe periodontitis than those without diabetes, after controlling for age, ethnicity, education, sex and smoking [28]. Hodge et al. [29] also reported that the prevalence of severe periodontitis was higher in poorly controlled patients with type 1 diabetes (27.2%) than in the whole group of diabetic subjects (24.1%) and the healthy controls (20.5%). In our study the presence of periodontitis was confirmed in 59.5% of the diabetic patients with PMC and in 40.0% of these with good metabolic control (HbA1c 6.5%). The prevalence of severe periodontitis (CPI 4) was also higher in the diabetic group with poor metabolic control (26.0%) than in the GMC patients (20.0%), and much higher than in the controls (5.0%). Moreover, the Table 3 Clinical and biochemical characteristics and the results of periodontal examination in current smokers and non-smokers.
Weight (kg) Systolic pressure (mmHg) Diastolic pressure (mmHg) HbA1c (%) Fasting glucose (mg/dl) Total cholesterol (mg/dl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mg/dl) CRP (ng/ml) IL-1 (ng/ml) TNF-a (pg/ml) Teeth number OHI CPI 0 CPI 1 CPI 2 CPI 3 CPI 4
Type 1 diabetes Non-smokers n = 75
Type 1 diabetes Smokers n = 32
70.1 13.6 125.3 12.5 80.1 7.7 8.9 2.5b 156.5 68.4a 171.1 40.5a 56.6 21.6 95.8 29.3b 98.5 84.5a 12.1 5.7 0.5 0.4 1.1 0.7 25.5 6.2a 1.5 0.8 1.5 1.9 1.5 1.3 1.2 1.4 0.8 1.2 0.6 1.2
72.5 10.1 125.3 13.6 80.6 11.6 10.6 2.4 199.3 77.3 197.8 62.8 49.0 15.8 120.4 41.8 150.8 40.5 6.1 5.5 0.8 1.3 1.7 1.1 21.2 9.4 1.8 0.8 0.8 1.5 1.8 1.5 1.4 1.4 1.2 1.2 0.4 0.5
Data are shown as mean SD. OHI – oral hygiene index; CPI – community periodontal index; RP – blood pressure. Differences between smokers and non-smokers are significant at ap < 0.05, bp < 0.01.
number of sextants with CPI 3 correlated positively with fasting glucose level. However, no correlation between HbA1c and the results of periodontal examination was observed in the present study. This was in agreement with the results obtained by Alpagot et al. [30], who also found no association between HbA1c and clinical signs of periodontal disease. On the other hand, in the present study the results of periodontal examination of the patients with GMC were comparable with these of the healthy subjects, indicating that good metabolic control is a key factor protecting diabetic patients from the development of periodontal disease. Although the cross-sectional design of our study limits any speculations about a causal relationship between type 1 diabetes and periodontitis, the possibility of a two-way association between these two diseases, with diabetes increasing the risk of periodontal disease and periodontal disease worsening glycemic control, cannot be ruled of. This hypothesis is strongly supported by the observation of Grossi et al. [24], who reported that the treatment of periodontal disease in diabetic patients reduces glycated hemoglobin. It is also worth noting that in the present study patients with type 1 diabetes and periodontitis were much older and had higher body weight than the patients without periodontitis, however lipid levels did not differ significantly between these two Table 4 Spearman’s correlation coefficients of the results of periodontal examination and other variables studied in patients with type 1 diabetes. Variable OHI/systolic BP OHI/diastolic BP OHI/TNF-a OHI/teeth number CPI 0/fibrinogen CPI 0/TNF-a CPI 0/teeth number CPI 1/teeth number CPI 1/OHI CPI 2/OHI CPI 3/TNF-a CPI 3/fasting/glucose CPI 3/teeth number CPI 3/OHI CPI 4/systolic BP CPI 4/teeth number CPI 4/OHI
R
p 0.256 0.222 0.252 0.392 0.272 0.233 0.378 0.408 0.451 0.336 0.348 0.217 0.282 0.518 0.219 0.456 0.498
