1. Background
Diabetes is a common metabolic disorder worldwide. Diabetes is one the major causes of death due to micro and macro-vascular complications (1, 2).
Various oral soft tissue presentations are associated with hyperglycemia. These complications include periodontitis and gingivitis, salivary gland dysfunction leading to low salivary flow rate and changes in salivary components, and disorders of taste. In addition, other oral problems consist of fungal and bacterial infections, geographic tongue, benign migratory glossitis, stomatitis, fissured tongue, lichen planus, lichenoid reaction, traumatic ulcer, and angular chelitis (3-7).
In addition, high frequency of delayed mucosal wound healing, dental carries, and tooth loss has been reported in patients with diabetes compared to healthy individuals (8). The chance of initiation and progression of oral mucosal lesions were found to be high in diabetic patients compared to non-diabetic controls (9). Periodontal disorders have been known as the 6th complication of diabetes mellitus (10). Retinopathy and nephropathy are known micro-vascular complications of diabetes. Although relationships between oral mucosal lesions and diabetic retinopathy and nephropathy has not been fully explored. In one study, among normal weight subjects with type 2 diabetes, IgG titers for Porphyromonas gingivalis, an oral pathogen, were correlated with the urinary albumin excretion rate (11). The level of IL-6 in the vitreous fluid had positive correlation with the severity of periodontal disease in diabetic persons (12). Due to the lack of data in this field in our region, this study was set to assess the relationship between oral soft tissue presentations and nephropathy and retinopathy in type 2 diabetic subjects in the Yazd province with high prevalence of diabetes. Lotfi et al. in 2014, reported that 16.3% of people in the Yazd province (a city in the middle of Iran) suffered from known diabetes (13).
2. Methods
The study was an analytical cross-sectional, which was done in a diabetes research center during 2014 - 2016 in Yazd. Census sampling method was done. The inclusion criteria were type 2 diabetes mellitus (T2DM) on oral anti hyperglycemic agents or insulin therapy, patients older than 30 years, and at least 2 years known diabetes. If there were glomerular filtration rate (GFR) less than 60, oro-pharyngeal cancer, pregnancy, lactation, type one diabetes, or newly diagnosed diabetes (< 2 years) were excluded from the study. The subjects’ demographic data and the data recorded in their files, consisting of age, gender, educational level, medications used, smoking or use of any other habit-forming drugs, use of toothbrushes, dental floss, and mouth rinses were recorded. All the subjects underwent history taking and thorough oro-dontal examination procedures. Oral examination was performed by an oral medicine specialist who had already been trained for the purpose of this study after evaluation of their files. The oral examinations were carried out under natural light by retracting the lips and cheeks in all the oral cavity areas. Oral lesions were diagnosed based on clinical views and biopsies were taken by the oral medicine specialist in suspected cases. In relation to the periodontal status, the definition presented in Carranza’s clinical periodontology textbook (14) was used. The pathologic findings of the oral cavity soft tissues in the subjects consisted of candidiasis lesions, including different forms of oral candidiasis and related lesions, i.e. denture stomatitis, angular cheilitis, median rhomboid glossitis, and complete atrophy of lingual papilla. Non-candida lesions consisted of periodontitis, gingivitis, xerostomia, geographic tongue, lichen planus, gingival hyperplasia, delay oral wound healing, fissured tongue, and burning mouth sensation.
Fasting blood sugar (FBS), HbA1c, and micro-albuminuria were checked in diabetes research center laboratory. Diabetic nephropathy defined to increase the excretion rate of urinary albumin above 30 mg/g creatinine (15), according to the last laboratory findings at least three months ago.
Evaluation of diabetic retinopathy was performed by an expert ophthalmologist (retinal specialist) during 6 months and available in the patient’s medical file. The retinopathy grading was categorized as no retinopathy, mild none proliferative diabetic retinopathy (NPDR), moderate NPDR, severe NPDR, and proliferative diabetic retinopathy (PDR). In our study, subjects were divided into two groups based up retinopathy examination, no retinopathy and the other group had a variable degree of retinopathy (mild, moderate, severe, and PDR). Finally frequency of soft tissue oral lesions in individuals with and without retinopathy and nephropathy were compared.
2.1. Research Ethics
This research was presented to the Ethics Committee of Shahid Sadoughi University of Medical Sciences and accepted by the Internal Medicine Department. The Ethics Committee approved the study with the number IR.SSU.REC.MEDICINE.REC.17/1/221184. The patients learned about the aim and study protocol, and written consent before the study was filled.
2.2. Statistical Analyses
The sample size was calculated based on the comparison of two proportions considering α: 0.05, β: 20%, and 10% differences. SPSS version 20.0 for Windows computer software package (SPSS Inc., Chicago, IL, USA) was applied. Studied population description was done by frequency (%), and mean (standard deviation). The normality of data were analyzed, Chi-square test (χ2) and Fisher’s exact test were done for analytic analysis. Binary logistic regression was done and odds ratios (ORs) were used to evaluate the risk factors associated with oral lesions in studied patients.
Statistical significance less than 0.05 were accepted.
3. Results
During the study period, 1509 diabetic patients were examined, totally, 274 patients (48% male) fulfilled the inclusion criteria without exclusion. Most of the patients (70.8%) suffer from at least one of the diabetic microvascular complications (retinopathy, nephropathy or both) and 80 diabetic patients (29.2%) had no microvascular complications. Descriptive characteristics of patients were shown in Table 1.
Table 1.Descriptive Characteristics of Studied Patients
| Variables | Micro-Vascular Complications | P Value | |
|---|---|---|---|
| Yes | No | ||
| Age, y (mean ± SD) | 59.47 ± 9.5 | 54.75 ± 11.11 | 0.001 |
| Gender, male (%) | 87 (52.7) | 45 (35) | 0.063 |
| Smoker (%) | 13 (7.9) | 8 (7.1) | 0.889 |
| Duration of diabetes (mean ± SD) | 10.48 ± 5.41 | 6.30 ± 5.12 | 0.001 |
| FBS, mg/dL (mean ± SD) | 154.57 ± 45.43 | 146.67 ± 41.63 | 0.158 |
| HbA1c% (mean ± SD) | 8.01 ± 1.33 | 7.56 ± 1.28 | 0.071 |
Tables 2 and 3 show the oral lesion frequency among patients with and without microvascular complications and oral lesions are more prevalent in patients with retinopathy (P = 0.047) and nephropathy (P = 0.049).
Table 2.Oral Lesion Frequency Comparison in Patients with and Without Retinopathy
| Oral Lesions | Retinopathy | P Value | |
|---|---|---|---|
| Yes (N = 130)a | No (N = 143)a | ||
| Candidiasis | 29 (22.3) | 38 (26.6) | 0.402 |
| Gingivitis | 19 (14.7) | 12 (8.55) | 0.049 |
| Xerostomia | 39 (30) | 42 (29.4) | 0.500 |
| Geographic tongue | 22 (16.9) | 16 (11.2) | 0.065 |
| Gingival hyperplasia | 6 (4.6) | 4 (2.8) | 0.317 |
| Fissured tongue | 12 (9.2) | 6 (4.2) | 0.047 |
| Burning mouth sensation | 12 (9.2) | 9 (6.3) | 0.247 |
| Lichen planus | 5 (3.8) | 7 (4.9) | 0.397 |
| Periodontitis | 50 (38.5) | 63 (44.1) | 0.303 |
| Delayed wound healing | 14 (10.8) | 11 (7.7) | 0.435 |
| Presence of at least one of the oral lesions | 120 (91.2) | 69 (48.2) | 0.047 |
aValues are expressed as No. (%).
Table 3.Oral Lesion Frequency Comparison in Patients with and Without Nephropathy
| Oral Lesions | Nephropathy | P Value | |
|---|---|---|---|
| Yes (N = 118)a | No (N = 156)a | ||
| Candidiasis | 31 (26.5) | 36 (23.1) | 0.424 |
| Gingivitis | 11 (9.5) | 20 (12.9) | 0.51 |
| Xerostomia | 27 (23.1) | 54 (34.6) | 0.053 |
| Geographic tongue | 18 (15.4) | 20 (12.8) | 0.332 |
| Gingival hyperplasia | 5 (4.3) | 5 (3.2) | 0.439 |
| Fissured tongue | 8 (6.8) | 10 (6.4) | 0.047 |
| Burning mouth sensation | 7 (6) | 14 (9) | 0.248 |
| Lichen planus | 2 (1.7) | 4 (2.6) | 0. 31 |
| Periodontitis | 46 (39.3) | 67 (42.9) | 0.67 |
| Delayed wound healing | 16 (13.7) | 9 (5.8) | 0.039 |
| Presence of at least one of the oral lesions | 105 (88.9) | 85 (54.2) | 0.049 |
aValues are expressed as No. (%).
The binary logistic regressions showed that age, duration of diabetes, and HbA1c were not statistically associated with oral lesion frequency in type 2 diabetic patients (Table 4).
Table 4.The Binary Logistic Regression Odds Ratios (and 95% CIs) for Risk Factors Associated with Oral Lesion in Type 2 Diabetes
| Factors | Odds Ratio (95% CI) | P Value |
|---|---|---|
| Age, y | 0.975 (0.706 - 1.19) | 0.302 |
| Duration of diabetes, y | 1.053 (0.484 - 1.76) | 0.298 |
| HbA1c% | 1.404 (0.982 - 1.47) | 0.145 |
4. Discussion
Periodontal problems have been known as the sixth complication after microvascular and cardiovascular complications of diabetes mellitus (10). Probable mechanisms of periodontal disease maybe differences in the subgingival microflora (16), dysfunction of immune cells, high level of tumor necrosis factor-α (17), advanced glycation end products (18), and increase in messenger RNA for RAGEs (receptors for AGEs) in the periodontal organs of type 2 diabetics compared to healthy subjects (19). This study was designed to compare the frequency of oral soft tissue lesions between diabetics with microvascular involvement (retinopathy and nephropathy) and without involvement.
In this article, base line characteristics of subjects with and without micro-vascular complications such as age and duration of diabetes differ. Due to the fact that micro-vascular complications happen with advancing and prolongation of disease, age and duration of diabetes of individuals with micro-vascular complications is higher than the other group. Smoking is associated with periodontal disease (20, 21) and may confound the results, however, smoking in subjects with and without micro-vascular complications did not differ.
Gingivitis and fissured tongues were more prevalent in retinopathic persons compared to other groups. Frequency of other soft tissue lesions was not different with respect to retinopathy.
Song et al. showed that diabetic retinopathy had positive correlation with periodontitis in normal weight diabetic Korean adults (22). Other oral lesions were not evaluated in this study. In addition, sample size was greater than our study. Another study revealed positive correlation between the level of IL-6 in the vitreous fluid and severity of periodontal disease in diabetes (12). In the mentioned studies, both gingivitis and periodontitis categorized as periodontitis but these lesions categorized separately in our research. Gingivitis is mild degree of periodontitis that is statistically significant differences between retinopathy and other group in our study. In addition, retinopathy was significantly higher among diabetics with oral diseases in Bajaj et al. study (23). Association between median rhomboid glossitis (a form of candidiasis) and retinopathy was seen in Guggenheimer et al. study (7). This association was not seen in our study, although median rhomboid glossitis categorized as a sub-group of candidiasis in our article.
Fissured tongue in diabetic persons was higher than healthy non diabetic subjects (24), however, correlation of this lesion with retinopathy was not assessed in the mentioned article. In our study, fissured tongue was more prevalent in retinopathic persons than other groups. Future studies maybe helpful in this regard.
In addition, we compared the frequency of the presence of at least one of the oral lesions in retinopathy and normal group. Results showed a statistically significant difference between two groups. Due to the fact that some baseline characteristics of two groups differs, it may be possible that confounding factors such as age, duration of T2DM, and HbA1c affect these results. Therefore, the regression model was used. This test showed that the change in age, duration of diabetes, and HbA1c do not influence the oral lesion frequency in type 2 diabetic patients.
Fissured tongue and delayed wound healing were more prevalent in nephropathic persons compared to other groups. Frequency of other soft tissue lesions was not differing with respect to nephropathy. Association between median rhomboid glossitis (a form of candidiasis) and neohropathy was seen in the study of Guggenheimer et al. (7).
One longitudinal study of diabetes and complications showed that periodontitis predicts development of overt nephropathy in type 2 diabetic subjects (25).
In one study, IgG titers for Porphyromonas gingivalis, were positive correlations with the urinary albumin excretion ratio among non-obese subjects with type 2 diabetes (11).
Naruishi et al. showed higher rate of periodontal problems in patients with diabetic nephropathy and negative correlation between glomerular filtration rate and the number of missing teeth in Japanese adults (26). Missing teeth were not evaluated in our study. In addition, we exclude subjects with glomerular filtration rate (GFR) less than 60 in the study; therefore, it is not possible to assess this variable. In the study of Bajaj, association was not seen between nephropathy and oral presentations of diabetes (23).
Although fissured tongue was higher in diabetic persons compared to healthy non-diabetic subjects (24), correlation of this lesion with nephropathy was not assessed in the mentioned article. In our study, fissured tongue was more prevalent in subjects with nephropathy than other groups. Future studies may be helpful in this regard.
Vesterinen et al. evaluated oral presentation of individuals with diabetic nephropathy and other cause of nephropathy in persons with chronic kidney disease (CKD). Results showed increased dental caries in subjects with diabetic nephropathy than other cause of nephropathy. In addition, lower stimulated salivary flow rate in diabetic patients than other CKD individuals was seen. Periodontal health of two groups did not differ (27).
Etiology of delayed oral wound healing in diabetes include decreased vascularization, low blood flow, dysfunction of innate immunity, decreased production of growth factor, and emotional stress (28).
Delay mucosal wound healing has been reported in patients with diabetes (8). No article was found in the high rate of delayed oral wound healing in the diabetic nephropathy persons. Although, it is possible that with the duration of diabetes and initiation of micro-vascular complications, other unusual presentation happens.
Finally, we compare frequency of presence of at least one of the oral lesions in nephropathy and normal groups. Results showed statistically significant difference between two groups. Due to some baseline differences of two groups, the regression model was used. This test showed that the change in age, duration of diabetes, and HbA1c do not influence on the oral lesion frequency in type 2 diabetic patients.
This article had some limitations such as study design (cross-sectional), therefore, it is not possible to determine a causality relationship. In addition, with regard to high prevalence of diabetes and two years sampling period in this study, the limited sample size remain as a major limitation of this study. Future studies with large sample size may be necessary. It is noticeable that for evaluation causality of diabetes microvascular complication on oral lesions, some studies with large sample size and prospective design are needed. Finally, we did not assess other comorbidities such as hypertension and obesity, which may be as the confounders.
4.1. Conclusion
High frequency of oral presentations in subjects with micro-vascular complications compared to other groups were found. Closer cooperation between oral medicine specialist and endocrinologist is required and effective in managing diabetic patients. Knowledge of oral problems among people with diabetes, especially with micro-vascular complications, is necessary to improve the oral health of diabetic patients.
