Abstract
Periodontal disease often develops in patients with diabetes, and further exacerbated with diabetic complications. It would be clinically important to clarify the relationship between diabetic microvascular diseases and periodontal disease. This study aimed to evaluate the association between periodontal disease and diabetic complications in patients with type 2 diabetes with poor glycemic control. A total of 447 patients with type 2 diabetes hospitalized at Rakuwakai Otowa Hospital, Japan, were initially recruited in this study. After excluding 134 patients who lacked clinical data or were edentulous, 312 were included in our study. The severity of periodontal disease was evaluated based on the average bone resorption rate. Patients with diabetic nephropathy developed severe periodontal disease (multivariate-adjusted odds ratio, 3.00 [95% CI 1.41–5.19]). Diabetic neuropathy was positively associated with the severity of periodontal disease; the multivariate-adjusted odds ratio (95% CI) was 1.62 (0.87‒2.99) for moderate and 4.26 (2.21‒8.20) for severe periodontal disease. In contrast, diabetic retinopathy was linked with moderate periodontal disease (multivariate-adjusted odds ratio 2.23 [95% CI 1.10–4.10]), but not with severe conditions (multivariate-adjusted odds ratio 0.92 [95% CI 0.67–3.07]). In conclusion, periodontal disease, evaluated by average bone resorption rate, was associated with diabetic nephropathy and neuropathy.
Supplementary Information
The online version contains supplementary material available at 10.1007/s13340-022-00591-0.
Keywords: Bone resorption rate, Diabetic complications, Diabetic neuropathy, Diabetic nephropathy, Diabetic retinopathy, Periodontal disease
Introduction
Patients with diabetes often suffer from periodontal diseases [1–3]. Nelson et al. showed that the prevalence of periodontal disease was 2.6 times higher in patients with type 2 diabetes than in those without diabetes [4]. A population-based study, after controlling for age, education, smoking status, and tartar, also documented individuals with poorly controlled diabetes were more likely to have severe periodontal diseases than those without diabetes [5], suggesting that hyperglycemia would be a key factor to accelerate these periodontal disorders. Therefore, it has been proposed that periodontal diseases could be a major complication of diabetes, similar to nephropathy, neuropathy, retinopathy, micro- and macrovascular disorders [6].
A potential mechanism by which diabetes causes periodontal diseases is pathological inflammatory reactions in response to hyperglycemia as it is known to disturb several immune responses due to neutrophil chemotaxis, adhesion, and phagocytosis activation [7, 8]. Excessive glucose can also react with several proteins to form advanced glycation products, which then interact with collagen I and laminin to form pathological matrix in periodontal tissues [9]. Inflammatory cytokines released from periodontal disease also contribute to the reduction of insulin sensitivity and impair blood glucose control [9, 10]. While periodontal inflammation is often caused by bacterial infection, a study showed that blocking periodontal inflammation using antibiotics was capable of ameliorating glycemic control in Japanese patients with type 2 diabetes [11, 12]. Likewise, a Chinese study also demonstrated that a therapeutic intervention against periodontal disease could improve glycemic control, insulin resistance, and lipid profile along with a reduction in serum inflammatory cytokines and an increase in serum adiponectin levels in them [13]. These data suggest that interventions targeting periodontal disease might be a therapeutic option to improve diabetes although this issue remains controversial [14, 15].
In terms of evaluating periodontal diseases, the depth of periodontal pocket is often used as a marker, but the usefulness is still unclear [16, 17]. This is because periodontal pocket is not always associated with periodontal disease and is also deepened by gingivitis. The Japanese Society of Periodontology now recommends the use of bone resorption as a marker of periodontal disease [16], considering that alveolar bone destruction is specific to pathological changes [17]. Alveolar bone destruction can be objectively evaluated by examining bone resorption using radiography.
Diabetic complications are caused by several pathological processes, including vascular injury and inflammation, which are also risk factors for periodontal disease. Hence, we assume that diabetic complications are associated with periodontal disease in diabetic patients. Therefore, this study aimed to address this issue and examined the association of diabetic complications with periodontal disease, evaluated by bone resorption rate, in patients with type 2 diabetes.
Materials and methods
Patients
A total of 447 patients with diabetes who were hospitalized for diabetes education between April 2010 and March 2017 at Rakuwakai Otowa Hospital, Japan, were admitted to the study. The initial evaluation excluded 30 patients for refusing dental checkup, 30 for neither undergoing radiography nor measurement of periodontal pockets, 41 with type 1 diabetes, and 34 with edentulous jaw. Finally, 312 patients with type 2 diabetes were included in this study (Fig. 1).
Fig. 1.
Flow chart for study population
Classification of periodontal disease
The average bone resorption rate was used to evaluate periodontal disease. The bone resorption rate was measured at the mesial and distal sides of each tooth according to the method described by Schei et al. [18]. A rate of < 25% was considered mild, 25‒35% was moderate, and > 35% was severe periodontal disease, according to typical domestic epidemiological research [17, 19, 20]. The average bone resorption rate was measured by a periodontal specialist of the Japanese Society of Periodontology and calculated using the following formula: Average bone resorption rate (%) = length to the average bone top ÷ length from the cement-enamel junction to the apex × 100. A periodontal pocket was defined as a distance of ≥ 4 mm, from the gingival margin to the base, and determined by examining six sites per tooth (mesiobuccal, mid-buccal, distobuccal, mesiolingual/palatal, mid-lingual/palatal, and distolingual/palatal). Bleeding on probing (BOP) was bleeding induced by gentle manipulation of the tissue at the depth of the gingival sulcus, or the interface between the gingiva and the tooth.
Background and diabetic factors
Age, sex, body mass index (BMI), duration of diabetes, presence or absence of insulin treatment, diastolic and systolic blood pressure, presence or absence of antihypertensive agents, smoking, and presence of customary drinking were regarded as background factors. Glycated hemoglobin (HbA1c) (%), low-density lipoprotein (LDL) (mg/dL), high-density lipoprotein (HDL) (mg/dL), triglyceride (TG) (mg/dL), uric acid (UA) (mg/dL), fasting blood glucose levels (mg/dL), and creatinine (Cr) (mg/dL) were measured as diabetic factors. Intima Media Thickness (IMT) ≥ 1.1 mm, heart-ankle Pulse Wave Velocity (PWV) ≥ 1400 cm/s, and Ankle Pressure Index (API) < 0.9 were utilized as markers of vascular injuries. The conditions for collecting blood samples were used as the baseline at admission to diabetes education. A hexokinase-UV method for measurement serum glucose concentration, a HPLC method for HbA1c, a direct method for LDL-C and HDL-C, an enzyme colorimetric method for TG, a uricase-peroxidase method for UA, and an enzyme method for Cr were used. For the inter-assay, two different controls (normal and abnormal ranges) in pool serum were measured 10 times, respectively. In terms of the intra-assay, two concentrations (normal and abnormal ranges) were measured while the daily difference reproducibility for 20 days was investigated without calibration. The coefficient of variations for each assay measuring blood markers are all < 5% (Supplementary Table 1). Diabetic nephropathy is defined as an estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 mm2 with either urine protein/creatinine > 0.5 g/gCr, or urine albumin (U-ALB) > 30 mg/day according to diagnostic criteria of the Japan Society of Nephrology [21]. Diabetic retinopathy was examined by ophthalmologists in our hospital and classified into four stages by the Davis classification: (1) No diabetic retinopathy (NDR); (2) Simple diabetic retinopathy (SDR); (3) Pre-proliferative diabetic retinopathy (PPDR); and (4) Proliferative diabetic retinopathy (PDR). Diabetic retinopathy was defined by the presence of either SDR, PPDR, or PDR. The diagnosis of diabetic neuropathy was made based on two or more of the following three criteria according to the Diabetic Neuropathy Study Group in Japan: (i) subjective neuropathic sensory symptoms in the bilateral lower limbs or feet, (ii) loss of or decreased ankle jerk reflex, or (iii) decreased vibration perception, assessed using a C128 tuning fork and bilaterally measured at the medial malleoli. Neuropathic sensory signs or symptoms were defined as bilateral spontaneous pain, hypoesthesia, including decreased perception to pinprick and temperature (cold tuning fork), or paresthesia of the legs. This retrospective study determined the presence of coronary and cerebrovascular disease and obtained a history of angina pectoris, myocardial infarction, cerebral thrombus, cerebral embolism, cerebral hemorrhage, and subarachnoid hemorrhage.
Statistical analysis
Age- and sex-adjusted mean values and proportions of the degree of bone resorption were calculated. To investigate the relationship between periodontal disease severity and diabetes-related disease, multivariate-adjusted odds ratios, confidential interval and P value were calculated using logistic regression analysis. Continuous variable of P value were calculated using ANOVA, and category variable of P value were calculated using chi (2)-square test. For multivariate adjustment, Model 2 was adjusted for sex, age, body mass index, smoking habits, and drinking habits, Model 3 was adjusted for HbA1c, and Model 4 was adjusted for duration of diabetes in addition. We used Pearson's correlation coefficient for evaluating multicollinearity among independent variables. All statistical analyses were performed using STATA 14 in 2019 (STATA Corp., College Station, TX, USA). Statistical significance was set at two-tailed P < 0.05.
Results
The number of patients with either mild, moderate, or severe periodontal disease were 111, 112, and 89, respectively and average ages were 58.9, 66.0, 66.2 years, respectively (Table 1). The severity of periodontal disease was positively associated with age (P < 0.001). The proportion of men in each group was 48% in mild, 44% in moderate, and 29% in severe periodontal disease and the severity of periodontal disease was positively associated with sex (P = 0.003) (Table 1). The severity of periodontal disease was also negatively correlated with the current number of teeth (P < 0.001) but was positively associated with the proportion of periodontal pockets (P < 0.001) and BOP (P = 0.02) (Table 1). Thus, three parameters (the current number of teeth, the proportion of periodontal pockets, and BOP) related to periodontal disease were then associated with disease severity. The proportion of diabetic nephropathy, retinopathy and neuropathy in each group was 34%, 22% and 14% in mild; 49%, 35% and 26% in moderate; and 54%, 27% and 27% in severe periodontal disease, respectively. The severity of periodontal disease was positively associated with diabetic nephropathy (P = 0.001), diabetic retinopathy (P = 0.001), and diabetic neuropathy (P = 0.021). There were no differences in other clinical parameters.
Table 1.
Characteristics of the study sample used for multivariate analysis
| Examined factors | Average bone resorption rate | P value | ||
|---|---|---|---|---|
| Mild (< 25%) n = 111 |
Moderate (25–35%) n = 112 |
Severe (≥ 35%) n = 89 |
||
| Age; years old (SD) | 58.9 (1.3) | 66.0 (1.3) | 66.2 (1.5) | < 0.001 |
| Male; n (%) | 48 (43.2) | 44 (39.4) | 29 (32.1) | 0.003 |
| BMI; kg/m2 (SD) | 26.1 (0.5) | 24.9 (0.5) | 25. 2 (0.5) | 0.23 |
| HbA1c; % (SD) | 10.1 (0.21) | 10.3 (0.2) | 10.4 (0.2) | 0.34 |
| Currently smoking; n (%) | 16 (14.1) | 17 (14.9) | 26 (29.1) | 0.73 |
| Drunk habit; n (%) | 34 (30.6) | 26 (23.6) | 27 (30.9) | 0.97 |
| Insulin treatment; n (%) | 55 (50.3) | 60 (53.5) | 55 (61.5) | 0.16 |
| Duration of Diabetes; years (SD) | 9.5 (1.1) | 12.5 (1.3) | 11.4 (1.4) | 0.25 |
| LDL; mg/dL (SD) | 110.9 (3.6) | 112.1 (3.7) | 111.5 (4.1) | 0.89 |
| HDL; mg/dL (SD) | 49.1 (1.4) | 48.2 (1.4) | 46.8 (1.6) | 0.29 |
| TG; mg/dL (SD) | 150.8 (14.8) | 175.3 (14.9) | 195.9 (16.7) | 0.05 |
| UA; mg/dL (SD) | 5.1 (0.16) | 5.1 (0.2) | 5.3 (0.2) | 0.36 |
| Glucose; mg/dL (SD) | 223.2 (9.5) | 193.5 (9.6) | 209.5 (10.7) | 0.29 |
| Cr; mg/dL (SD) | 0.8 (0.1) | 0.8 (0.1) | 0.9 (0.1) | 0.06 |
| eGFR; mL/min (SD) | 78.7 (3.3) | 79.9 (3.4) | 74.2 (3.8) | 0.40 |
| Thickened IMT (%) | 33.5 | 33.4 | 31.8 | 0.81 |
| Increased PWV (%) | 76.9 | 70.8 | 80.3 | 0.66 |
| Decreased API (%) | 89.8 | 89.0 | 87.1 | 0.59 |
| Diastolic BP; mmHg (SD) | 130.6 (1.9) | 135.3 (1.9) | 132.4 (2.1) | 0.48 |
| Systolic BP; mmHg (SD) | 75.4 (1.2) | 77.0 (1.2) | 77.9 (1.3) | 0.17 |
| Hypertension (%) | 56.0 | 62.5 | 60.2 | 0.55 |
| Current number of teeth (SD) | 20.9 (0.8) | 20.7 (0.8) | 14.2 (0.9) | < 0.001 |
| Periodontal pocket ≥ 4 mm; % (SD) | 31.6 (3.1) | 37.6 (3.1) | 60.4 (3.5) | < 0.001 |
| Bleeding on Probing; % (SD) | 48.2 (3.3) | 51.3 (3.3) | 60.3 (3.7) | 0.02 |
| Diabetic nephropathy; n (%) | 34 (30.6) | 49 (43.8) | 54 (60.7) | 0.001 |
| Diabetic retinopathy; n (%) | 22 (19.8) | 35 (31.3) | 27 (30.3) | 0.001 |
| Diabetic neuropathy; n (%) | 14 (12.6) | 26 (23.2) | 27 (30.3) | 0.021 |
| Cardiovascular disease; n (%) | 27 (24.3) | 35 (31.3) | 23 (25.8) | 0.41 |
| Cerebral vascular disease; n (%) | 7 (6.3) | 6 (5.4) | 7 (7.9) | 0.60 |
Thickened IMT; IMT ≥ 1.1 mm
Increased PWV; PWV ≥ 1,400 cm/s
Decreased API; API < 0.9
Hypertension; Systolic BP (mmHg) ≥ 140 higher and/or Diastolic BP ≥ 90 higher and/or antihypertensive drug taking
The relationship between the severity of periodontal disease (evaluated by the degree of bone resorption) and diabetic microvascular complications is shown in Table 2. Diabetic nephropathy was associated with severe periodontal disease (Model 1; age- and sex-adjusted odds ratio 3.19 [95% CI 1.46–4.91]) but not with moderate periodontal disease (Model 1; age- and sex-adjusted odds ratio 1.29 [95% CI 0.82–2.57]). When adjusted for age, sex, BMI, smoking habit, drinking habits, HbA1c and the duration of diabetes (Model 2, 3 and 4), diabetic nephropathy was associated with severe periodontal disease compared to mild periodontal disease, but not with moderate periodontal disease. Diabetic neuropathy was also positively associated with the severity of periodontal disease; the age- and sex-adjusted odds ratio (95% CI) was 2.69 (1.33‒6.02). Similarly, in multivariate-adjusted regression analysis, diabetic neuropathy was likely associated with severe periodontal disease compared to mild periodontal disease. Diabetic retinopathy occurred more frequently with moderate periodontal disease (Model 1; age- and sex-adjusted odds ratio 2.14 [95% CI 1.07–4.11]) but not with severe periodontal disease (Model 1; age- and sex-adjusted odds ratio 1.01 [95% CI 0.69–3.06]). Similarly, in Model 2 and 3, diabetic retinopathy was likely associated with moderate periodontal disease, but without severe periodontal disease. However, in Model 4, diabetic retinopathy was not associated with periodontal disease. The relationship between the severity of periodontal disease and diabetic macrovascular complications is shown in Table 3. Neither cardiovascular nor cerebrovascular diseases were associated with periodontal disease. The relationship between the severity of periodontal disease and surrogate markers for diabetic microvascular complications is shown in Table 4. Similarly, IMT, PWV, and API were not associated with periodontal disease, with or without adjustments (Supplementary Table 2).
Table 2.
Relationship between periodontal disease severity and microvascular complications
| Severity of periodontal diseases Number |
Average bone resorption rate | ||
|---|---|---|---|
| Mild (< 25%) n = 111 |
Moderate (25–35%) n = 112 |
Severe (≥ 35%) n = 89 |
|
| Nephropathy | |||
| Model 1 | 1.00 |
1.29 (0.82–2.57) 0.19 |
3.19 (1.46–4.91) 0.001 |
| Model 2 | 1.00 |
0.79 (0.69–2.34) 0.43 |
3.04 (1.43–5.25) 0.002 |
| Model 3 | 1.00 |
0.76 (0.68–2.32) 0.45 |
3.00 (1.41–5.19) 0.003 |
| Model 4 | 1.00 |
1.82 (0.80–2.32) 0.16 |
2.59 4.15–6.13) 0.03 |
| Retinopathy | |||
| Model 1 | 1.00 |
2.14 (1.07–4.11) 0.03 |
1.01 (0.69–3.06) 0.31 |
| Model 2 | 1.00 |
2.24 (1.10–4.40) 0.03 |
0.92 (0.67–3.07) 0.36 |
| Model 3 | 1.00 |
2.23 (1.10–4.40) 0.03 |
0.92 (0.67–3.07) 0.36 |
| Model 4 | 1.00 |
1.47 (0.62–3.46) 0.38 |
1.36 (0.54–3.42) 0.50 |
| Neuropathy | |||
| Model 1 | 1.00 |
1.61 (0.88–3.88) 0.11 |
2.69 (1.33–6.02) 0.01 |
| Model 2 | 1.00 |
1.34 (0.78–3.62) 0.18 |
2.64 (1.32–6.45) 0.008 |
| Model 3 | 1.00 |
1.62 (0.87–2.99) 0.17 |
4.26 (2.21–8.20) 0.01 |
| Model 4 | 1.00 |
2.21 (0.80–6.15) 0.13 |
3.41 (1.18–9.88) 0.02 |
Model 1; Adjusted by age, sex
Model 2; Adjusted by age, sex, Body Mass Index, currently smoking, drunk habit
Model 3; Adjusted by age, sex, Body Mass Index, currently smoking, drunk habit, HbA1c
Model 4; Adjusted by age, sex, Body Mass Index, currently smoking, drunk habit, HbA1c, duration of diabetes
Odds ratio, 95% confidence interval, and P value were shown
Table 3.
Relationship between periodontal disease severity and macrovascular complications
| Severity of periodontal diseases Number |
Average bone resorption rate | ||
|---|---|---|---|
| Mild (< 25%) n = 111 |
Moderate (25–35%) n = 112 |
Severe (≥ 35%) n = 89 |
|
| Cardiovascular disease | |||
| Model 1 | 1.00 |
1.04 (0.55–1.96) 0.90 |
0.69 (0.34–1.37) 0.29 |
| Model 2 | 1.00 |
0.91 (0.47–1.74) 0.76 |
0.70 (0.35–1.42) 0.33 |
| Model 3 | 1.00 |
0.76 (0.48–1.75) 0.783 |
1.00 (0.35–1.44) 0.343 |
| Model 4 | 1.00 |
1.60 (0.67–3.79) 0.29 |
0.82 (0.30–2.23) 0.70 |
| Cerebral vascular disease | |||
| Model 1 | 1.00 |
0.65 (0.21–2.05) 0.46 |
1.05 (0.35–3.09) 0.94 |
| Model 2 | 1.00 |
0.73 (0.21–2.50) 0.62 |
0.95 (0.28–3.17) 0.93 |
| Model 3 | 1.00 |
0.91 (0.22–2.67) 0.67 |
0.71 (0.29–3.44) 0.99 |
| Model 4 | 1.00 |
0.48 (0.08–3.05) 0.44 |
0.95 (0.18–4.92) 0.95 |
Model 1; Adjusted by age, sex
Model 2; Adjusted by age, sex, Body Mass Index, currently smoking, drunk habit
Model 3; Adjusted by age, sex, Body Mass Index, currently smoking, drunk habit, HbA1c
Model 4; Adjusted by age, sex, Body Mass Index, currently smoking, drunk habit, HbA1c, duration of diabetes
Odds ratio, 95% confidence interval, and P value were shown
Table 4.
Relationship between periodontal disease severity and surrogate markers for macrovascular complications
| Severity of periodontal diseases Number |
Average bone resorption rate | ||
|---|---|---|---|
| Mild (< 25%) n = 111 |
Moderate (25–35%) n = 112 |
Severe (≥ 35%) n = 89 |
|
| IMT | |||
| Model 1 | 1.00 |
0.99 (0.52–1.89) 0.98 |
0.93 (0.47–1.85) 0.84 |
| Model 2 | 1.00 |
0.94 (0.49–1.82) 0.86 |
0.88 (0.44–1.78) 0.73 |
| Model 3 | 1.00 |
0.95 (0.49–1.84) 0.88 |
0.89 (0.44–1.79) 0.74 |
| Model 4 | 1.00 |
1.59 (0.67–3.78) 0.30 |
1.09 (0.43–2.75) 0.86 |
| PWV | |||
| Model 1 | 1.00 |
0.61 (0.25–1.45) 0.26 |
1.89 (0.48–4.83) 0.48 |
| Model 2 | 1.00 |
0.61 (0.21–2.50) 0.62 |
1.52 (0.28–3.17) 0.93 |
| Model 3 | 1.00 |
0.91 (0.22–2.67) 0.67 |
0.71 (0.29–3.44) 0.99 |
| Model 4 | 1.00 |
0.84 (0.24–2.89) 0.78 |
2.00 (0.38–10.64) 0.42 |
| API | |||
| Model 1 | 1.00 |
0.43 (0.10–1.91) 0.27 |
0.33 (0.06–1.82) 0.20 |
| Model 2 | 1.00 |
0.36 (0.79–1.66) 0.19 |
0.29 (0.05–1.66) 0.16 |
| Model 3 | 1.00 |
0.28 (0.59–1.38) 0.12 |
0.22 (0.04–1.38) 0.11 |
| Model 4 | 1.00 |
0.37 (0.58–2.37) 0.30 |
0.55 (0.24–1.34) 0.12 |
Model 1; Adjusted by age, sex
Model 2; Adjusted by age, sex, Body Mass Index, currently smoking, drunk habit
Model 3; Adjusted by age, sex, Body Mass Index, currently smoking, drunk habit, HbA1c
Model 4; Adjusted by age, sex, Body Mass Index, currently smoking, drunk habit, HbA1c, duration of diabetes
Odds ratio, 95% confidence interval, and P value were shown
There was no multicollinearity among the independent variables included in the model (Supplementary Table 3).
Discussion
In this study, we performed a cross-sectional study in a single facility and evaluated the relationship between diabetic complications and periodontal disease using bone resorption. In these Japanese patients with type 2 diabetes, alveolar bone resorption was associated with major diabetic microvascular complications, including diabetic nephropathy and neuropathy. The severity of nephropathy and neuropathy positively correlated with the severity of periodontal disease. Diabetic retinopathy occurred more frequently with moderate periodontal disease but not with severe conditions. Similarly, in multivariate-adjusted regression analysis, diabetic retinopathy was likely associated with mild periodontal disease but without severe conditions. Compared to the patients with mild periodontal diseases, those with moderate or severe periodontal disease were associated with neuropathy and nephropathy, independently of HbA1c. Perhaps, in the moderate or severe periodontal disease, microvascular injury or inflammation, rather than high glucose, might contribute to the activity of periodontal disease. In terms of macrovascular disorders, we did not find any association with diabetic periodontal disease. These findings were also confirmed by the surrogate markers for macrovascular diseases, including IMT, PWV and API. While alveolar bone resorption might be a better marker for periodontal disease, there are other methods to evaluate periodontal conditions. For example, the Community Periodontal Index of Treatment Needs (CPITN) is often used in epidemiological studies as it correlates with periodontal disease severity based on gingival BOP, tartar depositions, and periodontal pockets [22]. Nitta et al. used the Community Periodontal Index (CPI), which is also another tool to easily evaluate periodontal disease, to examine periodontal disease in Japanese patients with diabetes with microvascular complications [23]. In their study, the severity of periodontal disease was positively correlated with the number of microvascular complications, including retinopathy, nephropathy, and neuropathy [23].
In this study, we found the association between periodontal disease and diabetic nephropathy. A potential mechanism would be that inflammation in periodontal tissues produces several cytokines, acting on mesangial cells to stimulate collagen production, and causing renal fibrosis in the kidney [24, 25]. Alternatively, lipopolysaccharide (LPS) could be released from Porphyromonas gingivalis and bind to type II toll-like receptors in glomerular endothelial cells [26].
In terms of diabetic retinopathy, several studies showed the different results. Alvarenga MOP, et al. [27] performed systematic review and found that five observational studies showed a significant relationship between the prevalence of diabetic retinopathy and periodontal disease. A different point of their study from ours is that three markers, including periodontal pockets, BOP, and CAL were used to make a diagnosis with periodontal diseases. Wu et al. [28] also found that periodontal disease was associated with diabetic retinopathy and nephropathy in type 2 diabetic patients. The different results from our study may be accounted for by blood glucose level and BMI. Relative obesity with poor controlled diabetes may mask the effect of the inflammation of periodontal disease compared to non-obese with well controlled glucose. There are several limitations to this study. First, this was a cross-sectional study, and therefore we could not verify a causal relationship. Second, we enrolled patients with diabetes who were hospitalized for education because of their poor glycemic control. Third, we did not discuss the association between periodontal disease and neuropathy because there are no studies regarding this issue to be of reference. Finally, this was a retrospective study in nature and the number of patients who had asymptomatic myocardial ischemia or stroke was small; thus, we decided not to include them in this study.
In conclusion, periodontal disease, evaluated by average bone resorption rate, is associated with diabetic nephropathy and neuropathy. The association of retinopathy with the periodontal disease remains elusive, and future studies are warranted.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We would like to thank Editage (http://www.editage.com) for English language editing.
Declarations
Conflict of interest
All authors declare no conflict interest associated with this manuscript.
Human rights statement and informed consent
This study was conducted with the Ethics Review Committee of Rakuwakai Otowa Hospital (The approval number 17-014), which was approved on Apr. 27. 2017, and the Ethics Committee of Okayama University (The approval number 1706-041), which was approved on June.16, 2017. Written informed consent was waived due to its retrospective nature. An opt-out procedure was conducted to allow patients to withdraw from the study by informing them of the study protocol on the hospital homepage website, as advised by the committee.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Taylor GW, Burt BA, Becker MP, Genco RJ, Shlossman M, Knowler WC, et al. Severe periodontitis and risk for poor glycemic control in patients with non-insulin-dependent diabetes mellitus. J Periodontol. 1996;67:1085–1093. doi: 10.1902/jop.1996.67.10s.1085. [DOI] [PubMed] [Google Scholar]
- 2.Demmer RT, Jacobs DR, Jr, Desvarieux M. Periodontal disease and incident type 2 diabetes: results from the First National Health and Nutrition Examination Survey and its epidemiologic follow-up study. Diabetes Care. 2008;31:1373–1379. doi: 10.2337/dc08-0026. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Costa FO, Miranda Cota LO, Pereira Lages EJ, Soares Dutra Oliveira AM, Dutra Oliveira PA, Cyrino RM, et al. Progression of periodontitis and tooth loss associated with glycemic control in individuals undergoing periodontal maintenance therapy: a 5-year follow-up study. J Periodontol. 2013;84:595–605. doi: 10.1902/jop.2012.120255. [DOI] [PubMed] [Google Scholar]
- 4.Nelson RG, Shlossman M, Budding LM, Pettitt DJ, Saad MF, Genco RJ, et al. Periodontal disease and NIDDM in Pima Indians. Diabetes Care. 1990;13:836–840. doi: 10.2337/diacare.13.8.836. [DOI] [PubMed] [Google Scholar]
- 5.Tsai C, Hayes C, Taylor GW. Glycemic control of type 2 diabetes and severe periodontal disease in the US adult population. Community Dent Oral Epidemiol. 2002;30:182–192. doi: 10.1034/j.1600-0528.2002.300304.x. [DOI] [PubMed] [Google Scholar]
- 6.Löe H. Periodontal disease. The sixth complication of diabetes mellitus. Diabetes Care. 1993;16(329):34. doi: 10.2337/diacare.16.1.329. [DOI] [PubMed] [Google Scholar]
- 7.Koh GC, Peacock SJ, van der Poll T, Wiersinga WJ. The impact of diabetes on the pathogenesis of sepsis. Eur J Clin Microbiol Infect Dis. 2012;31:379–388. doi: 10.1007/s10096-011-1337-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Jafar N, Edriss H, Nugent K. The effect of short-term hyperglycemia on the innate immune system. Am J Med Sci. 2016;351:201–211. doi: 10.1016/j.amjms.2015.11.011. [DOI] [PubMed] [Google Scholar]
- 9.Lalla E, Papapanou PN. Diabetes mellitus and periodontitis: a tale of two common interrelated diseases. Nat Rev Endocrinol. 2011;7:738–748. doi: 10.1038/nrendo.2011.106. [DOI] [PubMed] [Google Scholar]
- 10.Demmer RT, Squillaro A, Papapanou PN, Rosenbaum M, Friedewald WT, Jacobs DR, Jr, et al. Periodontal infection, systemic inflammation, and insulin resistance: results from the continuous National Health and Nutrition Examination Survey (NHANES) 1999–2004. Diabetes Care. 2012;35:2235–2242. doi: 10.2337/dc12-0072. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Katagiri S, Nitta H, Nagasawa T, Izumi Y, Kanazawa M, Matsuo A, et al. Effect of glycemic control on periodontitis in type 2 diabetic patients with periodontal disease. J Diabetes Investig. 2013;4:320–325. doi: 10.1111/jdi.12026. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Munenaga Y, Hiroshima Study Group. Yamashina T, Tanaka J, Nishimura F. Improvement of glycated hemoglobin in Japanese subjects with type 2 diabetes by resolution of periodontal inflammation using adjunct topical antibiotics: results from the Hiroshima Study. Diabetes Res Clin Pract. 2013;100:53–60. doi: 10.1016/j.diabres.2013.01.028. [DOI] [PubMed] [Google Scholar]
- 13.Sun WL, Chen LL, Zhang SZ, Wu YM, Ren YZ, Qin GM. Inflammatory cytokines, adiponectin, insulin resistance and metabolic control after periodontal intervention in patients with type 2 diabetes and chronic periodontitis. Intern Med. 2011;50:1569–1574. doi: 10.2169/internalmedicine.50.5166. [DOI] [PubMed] [Google Scholar]
- 14.Engebretson SP, Hyman LG, Michalowicz BS, Schoenfeld ER, Gelato MC, Hou W, et al. The effect of nonsurgical periodontal therapy on hemoglobin A1c levels in persons with type 2 diabetes and chronic periodontitis: a randomized clinical trial. JAMA. 2013;310:2523–2532. doi: 10.1001/jama.2013.282431. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Chen L, Luo G, Xuan D, Wei B, Liu F, Li J, et al. Effects of non-surgical periodontal treatment on clinical response, serum inflammatory parameters, and metabolic control in patients with type 2 diabetes: a randomized study. J Periodontol. 2012;83:435–443. doi: 10.1902/jop.2011.110327. [DOI] [PubMed] [Google Scholar]
- 16.Nishimura F, Yamazaki K, Nomura Y, Minabe M, Miyata T, Morita M. Report from periodontal medicine committee (in Japanese) J Jpn Assoc Periodontol. 2011;53:197–200. doi: 10.2329/perio.53.197. [DOI] [Google Scholar]
- 17.Friedewald VE, Kornman KS, Beck JD, Genco R, Goldfine A, Libby P, et al. The American Journal of Cardiology and Journal of Periodontology Editors’ Consensus: periodontitis and atherosclerotic cardiovascular disease. Am J Cardiol. 2009;104:59–68. doi: 10.1016/j.amjcard.2009.05.002. [DOI] [PubMed] [Google Scholar]
- 18.Schei O, Waerhaug J, Lovdal A, Arno A. Alveolar bone loss as related to oral hygiene and age. J Periodontol. 1959;30:7–16. doi: 10.1902/jop.1959.30.1.7. [DOI] [Google Scholar]
- 19.Nakarai H, Yamashita A, Takagi M, Adachi M, Sugiyama M, Noda H, et al. Periodontal disease and hypertriglyceridemia in Japanese subjects: potential association with enhanced lipolysis. Metabolism. 2011;60:823–829. doi: 10.1016/j.metabol.2010.07.034. [DOI] [PubMed] [Google Scholar]
- 20.Nakajima T, Honda T, Domon H, Okui T, Kajita K, Ito H, et al. Periodontitis-associated up-regulation of systemic inflammatory mediator level may increase the risk of coronary heart disease. J Periodontal Res. 2010;45:116–122. doi: 10.1111/j.1600-0765.2009.01209.x. [DOI] [PubMed] [Google Scholar]
- 21.Haneda M, Utsunomiya K, Koya D, Babazono T, Moriya T, Makino H, et al. Classification of diabetic Nephropathy 2014. Nihon Jinzo Gakkai Shi. 2014;56:547–552. [PubMed] [Google Scholar]
- 22.Sadzeviciene R, Paipaliene P, Zekonis G, Zilinskas J. The influence of microvascular complications caused by diabetes mellitus on the inflammatory pathology of periodontal tissues. Stomatologija. 2005;7:121–124. [PubMed] [Google Scholar]
- 23.Nitta H, Katagiri S, Nagasawa T, Izumi Y, Ishikawa I, Izumiyama H, et al. The number of microvascular complications is associated with an increased risk for severity of periodontitis in type 2 diabetes patients: results of a multicenter hospital-based cross-sectional study. J Diabetes Investig. 2017;8:677–686. doi: 10.1111/jdi.12633. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Honda T, Domon H, Okui T, Kajita K, Amanuma R, Yamazaki K. Balance of inflammatory response in stable gingivitis and progressive periodontitis lesions. Clin Exp Immunol. 2006;144:35–40. doi: 10.1111/j.1365-2249.2006.03028.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Eitner F, Westerhuis R, Burg M, Weinhold B, Gröne HJ, Ostendorf T, et al. Role of interleukin-6 in mediating mesangial cell proliferation and matrix production in vivo. Kidney Int. 1997;51:69–78. doi: 10.1038/ki.1997.9. [DOI] [PubMed] [Google Scholar]
- 26.Sawa Y, Takata S, Hatakeyama Y, Ishikawa H, Tsuruga E. Expression of toll-like receptor 2 in glomerular endothelial cells and promotion of diabetic nephropathy by Porphyromonas gingivalis lipopolysaccharide. PLoS One. 2014;9:e97165. doi: 10.1371/journal.pone.0097165. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Alvarenga MOP, Miranda GHN, Ferreira RO, Saito MT, Fagundes NCF, Maia LC, et al. Association between diabetic retinopathy and periodontitis—a systematic review. Front Public Health. 2020;8:550614. doi: 10.3389/fpubh.2020.550614. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Wu HQ, Wei X, Yao JY, Qi JY, Xie HM, Sang AM, et al. Association between retinopathy, nephropathy, and periodontitis in type 2 diabetic patients: a meta-analysis. Int J Ophthalmol. 2021;14:141–147. doi: 10.18240/ijo.2021.01.20. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.